Obvious Hepatotoxicity Research Articles

Renal-clearable luminescent gold nanoparticles incorporating active and bio-orthogonal tumor-targeting for drug delivery and controlled release

The use of ultrasmall gold nanoparticles (AuNPs) as drug delivery systems (DDSs) represents certain challenges, including limited targeting efficiency, uncontrolled drug release, and off-target drug toxicity. Herein, we synthesize a series of second near-infrared (NIR-II) region emitting AuNPs by incorporating both c(RGDfC) peptide and cucurbit[7]uril (CB[7]) for active and bio-orthogonal tumor-targeting, respectively. The CB[7]/c(RGDfC)-AuNPs exhibited rapid tumor accumulation and prolonged retention, which were utilized as nanocarriers to load oxaliplatin (OX) to afford OX@CB[7]/c(RGDfC)-AuNPs for targeted drug delivery and tumor chemotherapy. The mice treated with OX@CB[7]/c(RGDfC)-AuNPs achieved superior therapeutic outcomes compared to three times the dose of OX treatment (H-OX group). Meanwhile, the AuNPs showed excellent biosafety as opposed to obvious hepatotoxicity and severe hepatorenal toxicity observed in the mice treated with low dose of OX and H-OX, respectively. This renal-clearable DDS holds promise for precise drug delivery and controlled release, offering new perspectives and methods for clinical cancer treatment.

Integration of Multi-Omics, Histological, and Biochemical Analysis Reveals the Toxic Responses of Nile Tilapia Liver to Chronic Microcystin-LR Exposure.

Microcystin-LR (MC-LR) is a cyanobacterial metabolite produced during cyanobacterial blooms and is toxic to aquatic animals, and the liver is the main targeted organ of MC-LR. To comprehensively understand the toxicity mechanism of chronic exposure to environmental levels of MC-LR on the liver of fish, juvenile Nile tilapia were exposed to 0 μg/L (control), 1 μg/L (M1), 3 μg/L (M3), 10 μg/L (M10), and 30 μg/L (M30) MC-LR for 60 days. Then, the liver hepatotoxicity induced by MC-LR exposure was systematically evaluated via histological and biochemical determinations, and the underlying mechanisms were explored through combining analysis of biochemical parameters, multi-omics (transcriptome and metabolome), and gene expression. The results exhibited that chronic MC-LR exposure caused slight liver minor structural damage and lipid accumulation in the M10 group, while resulting in serious histological damage and lipid accumulation in the M30 group, indicating obvious hepatotoxicity, which was confirmed by increased toxicity indexes (i.e., AST, ALT, and AKP). Transcriptomic and metabolomic analysis revealed that chronic MC-LR exposure induced extensive changes in gene expression and metabolites in six typical pathways, including oxidative stress, apoptosis, autophagy, amino acid metabolism, primary bile acid biosynthesis, and lipid metabolism. Taken together, chronic MC-LR exposure induced oxidative stress, apoptosis, and autophagy, inhibited primary bile acid biosynthesis, and caused fatty deposition in the liver of Nile tilapia.

CHIR-98014, a GSK 3β Inhibitor, Protects Against Triptolide/Lipopolysaccharide-Induced Hepatotoxicity by Mitochondria-Dependent Apoptosis Inhibition.

Triptolide (TP) is a remarkable anti-inflammatory and immunosuppressive component separated from Tripterygium wilfordii Hook. F. However, its hepatotoxicity limits its application in the clinical. Our group has proposed a new perspective on TP-induced hepatotoxicity, in which TP enhances liver hypersensitivity upon lipopolysaccharide (LPS) stimulation. Because the cause of the disease is unknown, there is currently no uniform treatment available. In this study, we attempted to determine whether the GSK-3β-JNK pathway affects liver damage and its regulatory mechanism in response to TP/LPS costimulation. In addition, we investigated the effect of CsA or the GSK 3β inhibitor CHIR-98014 on TP/LPS-induced hepatotoxicity. The results showed that the TP/LPS cotreatment mice exhibited obvious hepatotoxicity, as indicated by a remarkable increase in the serum ALT and AST levels, glycogen depletion, GSK 3β-JNK upregulation, and increased apoptosis. Instead of the specific knockdown of JNK1, the specific knockdown of JNK2 had a protective effect. Additionally, 40 mg/kg of CsA and 30 mg/kg of CHIR-98014 might provide protection. In summary, CHIR-98014 could protect against TP/LPS- or TP/TNF-α-induced activation of the GSK 3β-JNK pathway and mitochondria-dependent apoptosis, improving the indirect hepatotoxicity induced by TP.

Method Validation and Monitoring of N-nitrosodimethylamine in Metformin Hydrochloride Products in China by GC-MS/MS

Background: N-nitrosodimethylamine (NDMA) are a sort of genotoxic impurities (GTIs) having strong carcinogenic effects and obvious hepatotoxicity. To monitor the NDMA content of metformin hydrochloride sustained-release tablets and enteric capsules in China from 2018 to 2022, a GC-MS/MS method was established and validated. Materials and Methods: The chromatographic column was Agilent VF-WAXms capillary column (30 m×0.25 mm, 0.25 μm). The GC-MS/MS method was equipped with multiple reaction monitoring (MRM) modes. To assess the quantity of NDMA, the molecular ion at mass-tocharge (m/z) of 74-44 was monitored under the 6 V collision energy, and to assess the quality of NDMA monitoring, the molecular ions at m/z 74-42 were determined. A total of 143 batches of metformin hydrochloride-finished products from 35 enterprises were determined by this method Results: The linear range of the method was 0.25 ~ 50.00 ng/mL, r = 0.9998, S/N > 10, and the limit of detection and quantitation were 0.06 ng/mL and 0.21 ng/mL, respectively. The average recovery was 98.62%, and the RSD was 4.31%. All batches of enteric capsules met the requirements; 38.21% of the 123 batches sustained-release tablets still exceeded the acceptable daily intake. Conclusion: The presented method is sensitive, accurate, precise, and available for both enteric capsules and sustained-release tablets of metformin hydrochloride, which can provide a reference for their quality control. The over-limit phenomenon of NDMA in metformin hydrochloride products poses new challenges and requirements for both the State Drug Administration and enterprises.

Hepatic function and structure in feral pigeons (Columba livia domestica) exposed to zinc oxide nanoparticles

BackgroundBroad applications of nanoparticles have invoked the concerns about their impacts on living organisms. This study aimed to evaluate the possible changes that could take place in the liver of feral pigeons (Columba livia domestica) after oral ingestion of zinc oxide nanoparticles (nano-ZnO).MethodsPigeons were acclimatized to the laboratory conditions with a photoperiod of 12:12 h at 20 ± 2 ˚C for 14 days and maintained on seed mixture and clean tap water ad libitum. The birds were randomly assigned to five groups of 10, including one control group and four experimental groups orally receiving 0, 30, 50, and 75 mg/kg b.w. of nano-ZnO through oral gavage for 7 and 14 consecutive days.ResultsThe oxidative stress (OS) biomarkers, namely lipid peroxidation content and catalase activity in the liver samples, and the level of hepatic necrosis markers (ALT, AST, and ALP) in the blood sera were increased in a concentration-dependent manner. Meanwhile, the total antioxidant capacity of liver samples measured by FRAP test was reduced. Histopathological changes revealed inflammatory cell infiltration, swelling area, vacuolization, and expansion of interstitial spaces in liver samples exposed to 75 mg/kg nano-ZnO.ConclusionsNano-ZnO induced obvious hepatotoxicity in the liver of pigeons, where the OS pathway may be the potential mechanism underlying this toxicity.

Toxicologic, transcriptomic, and metabolomic insights into the effect of a mixture of 26 veterinary antimicrobials on rat liver

To evaluate the maximum possible hazard of veterinary antimicrobial mixtures at doses accessible to humans, Sprague-Dawley male rats were orally dosed with a mixture of 26 commonly used veterinary antimicrobials for 90 consecutive days. The daily dosage of each component was 100 times (G1), 10 times (G2) and, 1 time (G3) of acceptable daily intake (ADI) in China. Hematology analysis and biochemical analysis found significant changes of several parameters, suggesting liver damage. Histopathological examination further indicated that mixtures of veterinary drugs at three levels caused obvious hepatotoxicity, and the severity of damage increased with dosage. LC-MS-based metabolomics analysis was carried out to detect metabolite changes in liver tissue. In G1, G2, and G3, 208, 165, and 195 differential accumulated metabolites (DAMs) compared with the Ctrl group were filtered, respectively. Similarly, RNA-seq helped us to filter a total of 183, 118, and 38 differentially expressed genes (DEGs) in G1, G2, and G3 compared with the Ctrl group, respectively. By integrating with the transcriptomic and metabolomic data, we revealed that mineral absorption, ascorbate and aldarate metabolism may be the major pathways affected by the veterinary antimicrobial mixtures in our study. This study provided useful data for the risk assessment of multiple chemicals.

Preparation and Evaluation of an Enrofloxacin Self-Micro Emulsion for Veterinary Use

We prepared an enrofloxacin self-micro emulsion and optimized the oil, emulsifier and co-emulsifiers using a pseudoternary phase diagram. The ratio of the oil phase to the emulsifier was used as the influencing factor, and the light transmittance was used as the evaluation index. The formulation was optimized using a star design-effect surface method. We examined the preparation versus enrofloxacin solution as the control group at the recommended clinical dosage of enrofloxacin for 7 days in healthy broiler chickens. The optimal formulation was composed of 2.5% enrofloxacin, oil phase 22% isopropyl myristate and 8% benzyl alcohol with the emulsifiers (i.e., 39% EL-40 and 13% Tween-80) and 17.5% 1,2-propanediol as co-emulsifier. The average particle size was 72 nm and emulsification time was 23 sec. The size and distribution of the microemulsion were uniform, and the cumulative dissolution at 30 min was >80%. The mental states, food and water intake of the chickens in the test group were normal as with the blood biochemical indices. Histopathological examination showed no obvious hepatotoxicity. Slight damage to the lung and intestinal mucosa was observed, but the degree of injury was similar to that of the enrofloxacin control solution. The self-micro emulsifying preparation of enrofloxacin possessed the advantages of simple preparation, good appearance, high emulsifying efficiency and good safety; therefore, it has a good application value in a veterinary clinic.

Integrating systematic pharmacology-based strategy and experimental validation to explore mechanism of Tripterygium glycoside on cholangiocyte-related liver injury

ObjectiveTripterygium glycoside (TG) is widely used in clinical practice for its multiple bioactivities including anti-inflammatory and immunosuppressive effects. However, emerging studies have frequently reported TG-induced adverse reactions to multiple organs, especially liver. Here, this study aimed to investigate the mechanism of liver damage induced by TG and explore representative components to reflect TG hepatotoxicity. MethodsNetwork pharmacology was used to determine the potential targets of bile duct injury caused by TG. Next, the hepatotoxic effects of TG, triptolide (TP) and celastrol (CEL) were investigated and compared in vivo and in vitro. Liver function was determined by measuring serum transaminase and histopathology staining. The cell proliferation and apoptosis were determined by cell viability assay, scratch assay and flow cytometry. The expression of gene of interest was determined by qPCR and Western blot. ResultsBased on the network pharmacological analysis of 12 bioactive ingredients found in TG, a total of 35 targets and 15 pathways related to bile duct injury were obtained. Both TG and TP resulted in cholangiocyte damage and liver injury, as illustrated by increased levels of serum transaminase and oxidative stress, stimulated portal edema and lymphocytic infiltration and decreased expression of cholangiocyte marker, cytoskeletal 19. In addition, TG and TP inhibited cell proliferation and migration, arrested cell cycle and promoted Caspase-dependent apoptosis of cholangiocytes via suppressing the phosphorylation of extracellular regulated protein kinases 1/2 (ERK1/2) and protein kinase B (AKT). While, CEL at equivalent dosage had no obvious hepatotoxicity. ConclusionWe revealed that TG-stimulated liver injury was specifically characterized by cholangiocyte damage and TP might be the decisive ingredient to reflect TG hepatotoxicity. Our results not only provide novel insights into the mechanism underlying the hepatotoxicity effects of TG but also offer reference for clinical rational use of TG.

Discovery of novel tacrine derivatives as potent antiproliferative agents with CDKs inhibitory property

Tacrine was the first approved drug by the FDA for the treatment of Alzheimer’s disease (AD) but was withdrawn from the market due to its dose-dependent hepatotoxicity. Herein, we describe our efforts toward the discovery of a novel series of tacrine derivatives for cancer therapeutics. Intensive structural modifications of tacrine led to the identification of N-(4-{9-[(3S)-3-aminopyrrolidin-1-yl]-5,6,7,8-tetrahydroacridin-2-yl}pyridin-2-yl)cyclopropanecarboxamide hydrochloride ((S)-45, ZLWT-37) as a potent antiproliferative agent (GI50 = 0.029 μM for HCT116). In addition, ZLWT-37 exhibited lower inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) compared to tacrine. The in vitro studies demonstrated that ZLWT-37 could significantly induce apoptosis and arrest the cell cycle in the G2/M phase in HCT116 cells. The in vivo studies revealed that compound ZLWT-37 showed excellent antitumor efficacy in HCT116 xenograft tumor model and favorable pharmacokinetics profiles (F% = 28.70%) as well as low toxicity in the acute toxicity test with a median lethal dose (LD50) of 380.3 mg/kg. Encouragingly, ZLWT-37 had no obvious hepatotoxicity, nephrotoxicity, and hematologic toxicity. Kinase assay suggested that ZLWT-37 possessed potent cyclin-dependent kinase 9 (CDK9) inhibitory activity (IC50 = 0.002 μM) and good selectivity over CDK2 (IC50 = 0.054 μM). Collectively, these findings indicate that compound ZLWT-37 is a promising anti-cancer agent that deserves further preclinical evaluation.

Development of naringenin-O-alkylamine derivatives as multifunctional agents for the treatment of Alzheimer’s disease

In this study, a series of naringenin-O-alkylamine derivatives were designed and obtained by introducing an alkylamine fragment into the naringenin skeleton. The in vitro biological activity results revealed that compounds 5f and 7k showed good antioxidant activity with ORAC values of 2.3eq and 1.2eq, respectively. Compounds 5f and 7k were reversible and excellent huAChE inhibitors with IC50 values of 0.91 μM and 0.57 μM, respectively. Moreover, compounds 5f and 7k could inhibit self-induced Aβ 1–42 aggregation with 62.1% and 43.8% inhibition rate, respectively, and significantly inhibited huAChE-Aβ 1–40 aggregation with 51.7% and 43.4% inhibition rate, respectively. In addition, compounds 5f and 7k were selective metal chelators and remarkably inhibited Cu2+-induced Aβ 1–42 aggregation with 73.5% and 68.7% inhibition rates, respectively. Furthermore, compounds 5f and 7k could cross the blood-brain barrier in vitro and displayed good neuroprotective effects and anti-inflammatory properties. Further investigation showed that compound 5f did not show obvious hepatotoxicity and displayed a good hepatoprotective effect by its antioxidant activity. The in vivo study displayed that compound 5f significantly improved scopolamine-induced mice memory impairment. Therefore, compound 5f was a potential multifunctional candidate for the treatment of AD.

Dimeric Tacrine(10)-hupyridone as a Multitarget-Directed Ligand To Treat Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder with multiple pathological features. Therefore, a multitarget-directed ligands (MTDLs) strategy has been developed to treat AD. We have previously designed and synthesized dimeric tacrine(10)-hupyridone (A10E), a novel tacrine derivative with acetylcholinesterase (AChE) inhibition and brain-derived neurotrophic factor (BDNF) activation activity, by linking tacrine and a fragment of huperzine A. However, it was largely unknown whether A10E could act on other AD targets and produce cognitive-enhancing ability in AD animal models. In this study, A10E could prevent cognitive impairments in APP/PS1 transgenic mice and β-amyloid (Aβ) oligomers-treated mice, with higher potency than tacrine and huperzine A. Moreover, A10E could effectively inhibit Aβ production and deposition, alleviate neuroinflammation, enhance BDNF expression, and elevate cholinergic neurotransmission in vivo. At nanomolar concentrations, A10E could inhibit Aβ oligomers-induced neurotoxicity via the activation of tyrosine kinase receptor B (TrkB)/Akt pathway in SH-SY5Y cells. Furthermore, Aβ oligomerization and fibrillization could be directly disrupted by A10E. Importantly, A10E at high concentrations did not produce obvious hepatotoxicity. Our results indicated that A10E could produce anti-AD neuroprotective effects via the inhibition of Aβ aggregation, the activation of the BDNF/TrkB pathway, the alleviation of neuroinflammation, and the decrease of AChE activity. As MTDLs could produce additional benefits, such as overcoming the deficits of drug combination and enhancing the compliance of AD patients, our results also suggested that A10E might be developed as a promising MTDL lead for the treatment of AD.

Exosome-based biomimetic nanoparticles targeted to inflamed joints for enhanced treatment of rheumatoid arthritis

BackgroundGlucocorticoids (GCs) show powerful treatment effect on rheumatoid arthritis (RA). However, the clinical application is limited by their nonspecific distribution after systemic administration, serious adverse reactions during long-term administration. To achieve better treatment, reduce side effect, we here established a biomimetic exosome (Exo) encapsulating dexamethasone sodium phosphate (Dex) nanoparticle (Exo/Dex), whose surface was modified with folic acid (FA)-polyethylene glycol (PEG)-cholesterol (Chol) compound to attain FPC-Exo/Dex active targeting drug delivery system.ResultsThe size of FPC-Exo/Dex was 128.43 ± 16.27 nm, with a polydispersity index (PDI) of 0.36 ± 0.05, and the Zeta potential was − 22.73 ± 0.91 mV. The encapsulation efficiency (EE) of the preparation was 10.26 ± 0.73%, with drug loading efficiency (DLE) of 18.81 ± 2.05%. In vitro study showed this system displayed enhanced endocytosis and excellent anti-inflammation effect against RAW264.7 cells by suppressing pro-inflammatory cytokines and increasing anti-inflammatory cytokine. Further biodistribution study showed the fluorescence intensity of FPC-Exo/Dex was stronger than other Dex formulations in joints, suggesting its enhanced accumulation to inflammation sites. In vivo biodistribution experiment displayed FPC-Exo/Dex could preserve the bone and cartilage of CIA mice better and significantly reduce inflamed joints. Next in vivo safety evaluation demonstrated this biomimetic drug delivery system had no obvious hepatotoxicity and exhibited desirable biocompatibility.ConclusionThe present study provides a promising strategy for using exosome as nanocarrier to enhance the therapeutic effect of GCs against RA.

Chrysophanol: a review of its pharmacology, toxicity and pharmacokinetics.

Chrysophanol is a natural anthraquinone, also known as chrysophanic acid and 1,8-dihydroxy-3-methyl-anthraquinone. It has been widely used in the food and pharmaceutical fields. This review is intended to provide a comprehensive overview of the pharmacology, toxicity and pharmacokinetic researches of chrysophanol. Information on chrysophanol was collected from the Internet database PubMed, Elsevier, ResearchGate, Web of Science, Wiley Online Library and Europe PM using a combination of keywords including 'pharmacology', 'toxicology' and 'pharmacokinetics'. The literature we collected included from January 2010 to June 2019. Chrysophanol has a wide spectrum of pharmacological effects, including anticancer, antioxidation, neuroprotection, antibacterial and antiviral, and regulating blood lipids. However, chrysophanol has obvious hepatotoxicity and nephrotoxicity, and pharmacokinetics indicate that the use of chrysophanol in combination with other drugs can reduce toxicity and enhance efficacy. Chrysophanol can be used in many diseases. Future research directions include how the concentration of chrysophanol affects pharmacological effects and toxicity; the mechanism of synergy between chrysophanol and other drugs.

A new perspective of triptolide-associated hepatotoxicity: Liver hypersensitivity upon LPS stimulation

ObjectiveThis study was designed to investigate whether the mice treated with triptolide (TP) could disrupt the liver immune homeostasis, resulting in the inability of the liver to eliminate the harmful response induced by lipopolysaccharide (LPS). In addition, we explored whether apoptosis and necroptosis played a critical role in the progression of the hepatotoxicity induced by TP-LPS co-treatment. MethodsFemale C57BL/6 mice were continuously administrated with two different doses of TP (250 μg/kg and 500 μg/kg) intragastrically for 7 days. Subsequently, a single dose of LPS (0.1 mg/kg) was injected intraperitoneally to testify whether the liver possesses the normal immune function to detoxicate the exogenous pathogen’s stimulation. To prove the involvement of apoptosis and necroptosis in the liver damage induced by TP-LPS co-treatment, apoptosis inhibitor Z-VAD-FMK (FMK) and necroptosis inhibitor necrostatin (Nec-1) were applied before the stimulation of LPS to diminish the apoptosis and necroptosis respectively. ResultsTP or LPS alone did not induce significant liver damage. However, compared with TP or LPS treated mice, TP-LPS co-treatment mice showed obvious hepatotoxicity with a remarkable elevation of serum ALT and AST accompanied by abnormal bile acid metabolism, a depletion of liver glycogen storage, aberrant glucose metabolism, an up-regulation of inflammatory cell infiltration, and an increase of apoptosis and necroptosis. Intraperitoneal injection of FMK or Nec-1 could counteract the toxic reactions induced by TP-LPS co-treatment. ConclusionTP could disrupt the immune response, resulting in hypersensitivity of the liver upon LPS stimulation, ultimately leading to abnormal liver function and cell death. Additionally, apoptosis and necroptosis played a vital role in the development of liver damage induced by TP-LPS co-treatment.

Metabolism and Bioactivation of Corynoline With Characterization of the Glutathione/Cysteine Conjugate and Evaluation of Its Hepatotoxicity in Mice.

Corynoline (CRL), an isoquinoline alkaloid, is the major constituent derived from Corydalis bungeana Herba, which is a well-known Chinese herbal medicine widely used in many prescriptions. The purpose of this study was to comprehensively investigate the metabolism and bioactivation of CRL, and identify the CYP450 isoforms involved in reactive ortho-benzoquinone metabolites formation and evaluate its hepatotoxicity in mice. Here, high resolution and triple quadrupole mass spectrometry were used for studying the metabolism of CRL. Three metabolites (M1–M3) and four glutathione conjugates (M4–M7) of CRL ortho-benzoquinone reactive metabolite were found in vitro using rat and human liver microsomes supplemented with NADPH and glutathione. Four cysteine conjugates (M8–M11) were trapped in mice besides M1–M7. Using human recombinant CYP450 enzymes and chemical inhibitor method, we found that CYP3A4, CYP2C19, CYP2C9, and CYP2D6 were mainly involved in the bioactivation of CRL. Furthermore, CRL had no obvious hepatotoxicity and did not induce acute liver injuries in the experimental dosage (125–500 mg/kg) used in this study. However, phenomena of abnormal behaviors and low body temperature appeared in mice after drug administration, and three of them were dead. Tissue distribution study of CRL in mice showed that the main target organ of CRL was liver, then kidney, heart, and brain. CRL could traverse the blood–brain barrier, and have relative high concentration in brain. So, we surmise that toxicity effect of CRL on other organs may have occurred, and more attention should be paid on the traditional Chinese medicine contained CRL in clinic.

Triptolide impairs thioredoxin system by suppressing Notch1-mediated PTEN/Akt/Txnip signaling in hepatocytes

Triptolide (TP) is the main ingredient of Chinese herb Tripterygium wilfordii Hook f. (TWHF). Despite of its multifunction in pharmaceutics, accumulating evidences showed that TP caused obvious hepatotoxicity in clinic. The current study investigated the role of Notch1 signaling in TP-induced hepatotoxicity. Our data indicated that TP inhibited the protein expression of Notch1 and its active form Notch intracellular domain (NICD) leading to increased PTEN (phosphatase and tensin homolog deleted on chromosome ten) expression. Moreover, PTEN triggered Txnip (thioredoxin-interacting protein) activation by inhibiting Akt phosphorylation, which resulted in reduction of Trx (thioredoxin). In conclusion, TP caused liver injury through initiating oxidative stress in hepatocyte. This study indicated the potency of Notch1 to protect against TP-induced hepatotoxicity.

In vitro study of the cytotoxic effects of microcystin-LR, cylindrospermopsin and their mixture in the neuronal SH-SY5Y cell line

Hepatic macrophages are central players in the pathogenesis of some liver diseases, but few studies have examined the effect of triptolide (TP) on these cells. In this study, we investigated the possible role of hepatic macrophage recruitment and activation in triptolide-induced hepatotoxicity based on a non-hepatotoxic dose of lipopolysaccharides (LPS). The results showed that continuous administration of TP for two weeks and a single challenge of low-dose lipopolysaccharides increased the number of hepatic macrophages but inhibited their phagocytic function. TP induced the liver to recruit monocyte-derived macrophages (MoMFs) in response to a single challenge of low-dose LPS, resulting in acute inflammation and increased sensitivity to the endotoxin. Concurrent administration of TP with LPS resulted in obvious hepatotoxicity, but a single dose of LPS did not induce hepatotoxicity. These results indicate that TP could change the number and function of hepatic macrophages to reduce the ability of the liver to clear mild endotoxins, thus increasing blood endotoxin levels and increasing the sensitivity of the liver to low-dose LPS. By investigating the critical function of hepatic macrophages in TP-induced hepatotoxicity, this study elucidated the mechanism underlying TP-induced hepatotoxicity.

An Efficient Bivalent Cyclic RGD-PIK3CB siRNA Conjugate for Specific Targeted Therapy against Glioblastoma In Vitro and In Vivo

The PI3K-AKT-mTOR-signaling pathway is frequently activated in glioblastoma (GBM). Inhibition of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB)/p110β (a PI3K catalytic isoform) by RNAi substantially suppresses GBM growth with less toxicity to normal astrocytes. However, insufficient and non-specific small interfering RNA (siRNA) delivery may limit the efficacy of RNAi-based therapies against GBM. Here we prepared a novel methoxy-modified PIK3CB siRNA molecule (siPIK3CB) that was covalently conjugated to a [cyclo(Arg-Gly-Asp-D-Phe-Lys)-Ahx]2-Glu-PEG-MAL (biRGD) peptide, which selectively binds to integrin αvβ3 receptors. The αvβ3-positive U87MG cell line was selected as a representative for GBM. An orthotopic GBM xenograft model based on luciferase-expressing U87MG was established and validated in vivo to investigate bio-distribution and anti-tumor efficacy of biRGD-siPIK3CB. In vitro, biRGD-siPIK3CB specifically entered and silenced PIK3CB expression in GBM cells in an αvβ3 receptor-dependent manner, thus inhibiting cell cycle progression and migration and enhancing apoptosis. In vivo, intravenously injected biRGD-siPIK3CB substantially slowed GBM growth and prolonged survival by reducing tumor viability with silencing PIK3CB expression. Furthermore, biRGD-siPIK3CB led to mild tubulointerstitial injury in the treatment of GBM without obvious hepatotoxicity, whereas co-infusion of Gelofusine obviously alleviated this injury without compromising anti-tumor efficacy. These findings revealed a great translational potential of biRGD-siPIK3CB conjugate as a novel molecule for GBM therapy.

Possible role of hepatic macrophage recruitment and activation in triptolide-induced hepatotoxicity

Hepatic macrophages are central players in the pathogenesis of some liver diseases, but few studies have examined the effect of triptolide (TP) on these cells. In this study, we investigated the possible role of hepatic macrophage recruitment and activation in triptolide-induced hepatotoxicity based on a non-hepatotoxic dose of lipopolysaccharides (LPS). The results showed that continuous administration of TP for two weeks and a single challenge of low-dose lipopolysaccharides increased the number of hepatic macrophages but inhibited their phagocytic function. TP induced the liver to recruit monocyte-derived macrophages (MoMFs) in response to a single challenge of low-dose LPS, resulting in acute inflammation and increased sensitivity to the endotoxin. Concurrent administration of TP with LPS resulted in obvious hepatotoxicity, but a single dose of LPS did not induce hepatotoxicity. These results indicate that TP could change the number and function of hepatic macrophages to reduce the ability of the liver to clear mild endotoxins, thus increasing blood endotoxin levels and increasing the sensitivity of the liver to low-dose LPS. By investigating the critical function of hepatic macrophages in TP-induced hepatotoxicity, this study elucidated the mechanism underlying TP-induced hepatotoxicity.

Chronic hepatotoxicity evaluation of Chinese medicinal herb Zishen Yutai pill prepared from Polygoni Multiflori Radix preparata in dogs

To study the chronic hepatotoxicity of Chinese medicine Zishen Yutai pill (ZYP) prepared from Polygonum multiflorum with the recommended dosage in normal Beagle dogs. Low, middle and high doses of ZYP (1.5, 3.0, 6.0 g·kg⁻¹; i.e. 3×, 6× and 12× equivalent doses) were given orally to dogs for 39 consecutive weeks. At the same time, the same volume of deionized water was used as the solvent control group, one time a day. The general condition of the animals was observed every day during the period of administration, and the blood was collected before and 13, 26, 39, 43 weeks after administration to detect the biomarkers related to the hepatotoxicity of the dog serum. 2/7, 3/7 and 2/7 animals were dissected after 13, 39, and 43 weeks of administration to observe the pathological changes of the animal organs, weigh the mass of main organs and conduct pathological examination of the liver. As compared to the solvent control group, 11 liver hepatotoxicity traditional biomarkers such as ALT, AST were found no ZYP-related changes at month 3, 6, 9 of the administration and month 1 in recovery period; There was no significant difference in liver viscera index and liver pathology. Therefore, no obvious hepatotoxicity was shown by ZYP administered up to 6.0 g·kg⁻¹ for 9 months in normal dogs at doses of 1.5, 3.0, and 6.0 g·kg⁻¹.