Abstract Novel compounds and more efficient treatment options are urgently needed for the treatment of cystic echinococcosis (CE), which is caused by Echinococcus granulosus. The decoction of Sophora moorcroftiana (Fabaceae) has been used to treat parasitosis for years in traditional Tibetan medicine. The aim of this study was to screen insecticidal water-soluble alkaloids from S. moorcroftiana seeds and evaluate the therapeutic effects against CE and the immune response induced by the alkaloidal fraction. Low polarity compounds (E2-a) were isolated from water-soluble alkaloid (E2) and matrine and sophocarpine were identified as major components. The E2-a fraction was more effective against protoscoleces than other constituents from S. moorcroftiana. After 20 weeks of secondary infection with protoscoleces, mice were orally treated with E2-a (100 mg/kg/day) for 6 weeks to evaluate therapeutic and immunoregulatory activities. Compared with the untreated group, E2-a treatment induced a significant reduction in cyst weight (mean 2.93 g) (p < 0.05) and an impaired ultrastructural modification of the cyst. Interestingly, the application of E2-a resulted in a significant increased frequency of CD3+CD4+ T-cell subsets and decreased frequency of CD3+PD-1+ T-cell subsets, compared with protoscolece-infected mice without treatment. The E2-a fraction of S. moorcroftiana can inhibit the cyst development of CE and boost the specific immune response by reducing the expression of PD-1 and accelerate the cytokine secretion of antigen-specific T-cells. All data suggest the E2-a fraction from S. moorcroftiana seeds may be used as a new potential therapeutic option against E. granulosus infection.
Zuotai is composed mainly of β-HgS, while cinnabar mainly contains α-HgS. Both forms of HgS are used in traditional medicines and their safety is of concern. This study aimed to compare the hepatotoxicity potential of Zuotai and α-HgS with mercury chloride (HgCl2) and methylmercury (MeHg) in mice. Mice were orally administrated with Zuotai (30 mg/kg), α-HgS (HgS, 30 mg/kg), HgCl2 (33.6 mg/kg), or CH3HgCl (3.1 mg/kg) for 7 days, and liver injury and gene expressions related to toxicity, inflammation and Nrf2 were examined. Animal body weights were decreased by HgCl2 and to a less extent by MeHg. HgCl2 and MeHg produced spotted hepatocyte swelling and inflammation, while such lesions are mild in Zuotai and HgS-treated mice. Liver Hg contents reached 45-70 ng/mg in HgCl2 and MeHg groups; but only 1-2 ng/mg in Zuotai and HgS groups. HgCl2 and MeHg increased the expression of liver injury biomarker genes metallothionein-1 (MT-1) and heme oxygenase-1 (HO-1); the inflammation biomarkers early growth response gene (Egr1), glutathione S-transferase (Gst-mu), chemokine (mKC) and microphage inflammatory protein (MIP-2), while these changes were insignificant in Zuotai and HgS groups. However, all mercury compounds were able to increase the Nrf2 pathway genesNAD(P)H: quinone oxidoreductase 1 (Nqo1) and Glutamate-cysteine ligase, catalytic subunit (Gclc). In conclusion, the Tibetan medicine Zuotai and HgS are less hepatotoxic than HgCl2 and MeHg, and differ from HgCl2 and MeHg in hepatic Hg accumulation and toxicological responses.
UNLABELLED: Zuotai is composed mainly of β-HgS, while cinnabar mainly contains α-HgS. Both forms of HgS are used in traditional medicines and their safety is of concern. This study aimed to compare the hepatotoxicity potential of Zuotai and α-HgS with mercury chloride (HgCl2) and methylmercury (MeHg) in mice. Mice were orally administrated with Zuotai (30 mg/kg), α-HgS (HgS, 30 mg/kg), HgCl2 (33.6 mg/kg), or CH3HgCl (3.1 mg/kg) for 7 days, and liver injury and gene expressions related to toxicity, inflammation and Nrf2 were examined. Animal body weights were decreased by HgCl2 and to a less extent by MeHg. HgCl2 and MeHg produced spotted hepatocyte swelling and inflammation, while such lesions are mild in Zuotai and HgS-treated mice. Liver Hg contents reached 45-70 ng/mg in HgCl2 and MeHg groups; but only 1-2 ng/mg in Zuotai and HgS groups. HgCl2 and MeHg increased the expression of liver injury biomarker genes metallothionein-1 (MT-1) and heme oxygenase-1 (HO-1); the inflammation biomarkers early growth response gene (Egr1), glutathione S-transferase (Gst-mu), chemokine (mKC) and microphage inflammatory protein (MIP-2), while these changes were insignificant in Zuotai and HgS groups. However, all mercury compounds were able to increase the Nrf2 pathway genes NAD(P)H: quinone oxidoreductase 1 (Nqo1) and Glutamate-cysteine ligase, catalytic subunit (Gclc). In conclusion, the Tibetan medicine Zuotai and HgS are less hepatotoxic than HgCl2 and MeHg, and differ from HgCl2 and MeHg in hepatic Hg accumulation and toxicological responses.
Background. The circadian clock is involved in drug metabolism, efficacy and toxicity. Drugs could in turn affect the biological clock as a mechanism of their actions. Zuotai is an essential component of many popular Tibetan medicines for sedation, tranquil and "detoxification," and is mainly composed of metacinnabar (β-HgS). The pharmacological and/or toxicological basis of its action is unknown. This study aimed to examine the effect of Zuotai on biological clock gene expression in the liver of mice. Materials and methods. Mice were orally given Zuotai (10 mg/kg, 1.5-fold of clinical dose) daily for 7 days, and livers were collected every 4 h during the 24 h period. Total RNA was extracted and subjected to real-time RT-PCR analysis of circadian clock gene expression. Results. Zuotai decreased the oscillation amplitude of the clock core gene Clock, neuronal PAS domain protein 2 (Npas2), Brain and muscle Arnt-like protein-1 (Bmal1) at 10:00. For the clock feedback negative control genes, Zuotai had no effect on the oscillation of the clock gene Cryptochrome (Cry1) and Period genes (Per1-3). For the clock-driven target genes, Zuotai increased the oscillation amplitude of the PAR-bZip family member D-box-binding protein (Dbp), decreased nuclear factor interleukin 3 (Nfil3) at 10:00, but had no effect on thyrotroph embryonic factor (Tef); Zuotai increased the expression of nuclear receptor Rev-Erbα (Nr1d1) at 18:00, but had little influence on the nuclear receptor Rev-Erbβ (Nr1d2) and RORα. Conclusion. The Tibetan medicine Zuotai could influence the expression of clock genes, which could contribute to pharmacological and/or toxicological effects of Zuotai.
Background. The circadian clock is involved in drug metabolism, efficacy and toxicity. Drugs could in turn affect the biological clock as a mechanism of their actions. Zuotai is an essential component of many popular Tibetan medicines for sedation, tranquil and "detoxification," and is mainly composed of metacinnabar (β-HgS). The pharmacological and/or toxicological basis of its action is unknown. This study aimed to examine the effect of Zuotai on biological clock gene expression in the liver of mice. Materials and methods. Mice were orally given Zuotai (10 mg/kg, 1.5-fold of clinical dose) daily for 7 days, and livers were collected every 4 h during the 24 h period. Total RNA was extracted and subjected to real-time RT-PCR analysis of circadian clock gene expression. Results. Zuotai decreased the oscillation amplitude of the clock core gene Clock, neuronal PAS domain protein 2 (Npas2), Brain and muscle Arnt-like protein-1 (Bmal1) at 10:00. For the clock feedback negative control genes, Zuotai had no effect on the oscillation of the clock gene Cryptochrome (Cry1) and Period genes (Per1-3). For the clock-driven target genes, Zuotai increased the oscillation amplitude of the PAR-bZip family member D-box-binding protein (Dbp), decreased nuclear factor interleukin 3 (Nfil3) at 10:00, but had no effect on thyrotroph embryonic factor (Tef); Zuotai increased the expression of nuclear receptor Rev-Erbα (Nr1d1) at 18:00, but had little influence on the nuclear receptor Rev-Erbβ (Nr1d2) and RORα. Conclusion. The Tibetan medicine Zuotai could influence the expression of clock genes, which could contribute to pharmacological and/or toxicological effects of Zuotai.
ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum tanguticum has been widely used as a remedy for infectious diseases in traditional Tibetan medicine in China. The total alkaloids of Aconitum tanguticum (TAA) are the main active components of Aconitum tanguticum and have been demonstrated to be effective in suppressing inflammation. Our aim was to investigate the protective effects of TAA on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in rats.MATERIALS AND METHODS: TAA was extracted in 95% ethanol and purified in chloroform. After vacuum drying, the TAA powder was dissolved in dimethyl sulfoxide. Adult male Sprague-Dawley rats were randomly divided into six groups. Rats were given dexamethasone (DXM, 4 mg/kg) or TAA (60 mg/kg, 30 mg/kg) before LPS injection. The PaO2and PaO2/FiO2 values, lung wet/dry (W/D) weight ratio and histological changes in lung tissue were measured. The cell counts, protein concentration, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in bronchoalveolar lavage fluid (BALF), and myeloperoxidase (MPO) activity in lung tissue were determined at 6, 12 or 24 h after LPS treatment. In addition, the NF-κ B activation in lung tissue was analyzed by western blot.
RESULTS: In ALI rats, TAA significantly reduced the lung W/D ratio and increased the value of PaO2 or PaO2/FiO2 at 6, 12 or 24 h after LPS challenge. TAA also reduced the total protein concentration and the number of total cells, neutrophils or lymphocytes in BALF. In addition, TAA decreased MPO activity in the lung and attenuated histological changes in the lung. Furthermore, TAA inhibited the concentration of TNF-α, IL-6 and IL-1β in BALF at 6, 12 or 24 h after LPS treatment. Further study demonstrated that TAA significantly inhibited NF-κ B activation in lung tissue.
CONCLUSIONS: The current study proved that TAA exhibited a potent protective effect on LPS-induced ALI in rats through its anti-inflammatory activity.
Traditional Chinese medicine is important for discovery of drug precursors. However, information about trace chemical composition of them is very limited due to the lack of appropriate enrichment and chromatographic purification methods In our work, A. kansuensis was taken as an example, a novel two-dimensional reversed-phase/hydrophilic interaction liquid chromatography coupled with UniElut C18AEX solid-phase extraction re-enrichment method based on anti-inflammatory bioactivity-guided assay was developed for gathering and purifying trace β-carboline alkaloids with high purity from the ethyl acetate extract of A. kansuensis. Extraction with ethyl acetate as the first enrichment method, then, a UniElut C18AEX column was employed to re-enrich trace fraction which was hardly detected by diode array detector during high performance liquid chromatography analysis, eighteen grams of UniElut C18AEX was used as sorbent material to pack a 60mL pipette tip for the extraction of β-carboline alkaloids from 100mL of ethyl acetate sample. The whole extraction process was finished in 10min, and the volume of eluent used was only 120mL. The enriching fraction (100mg) was used for the following two-dimensional purification. First-dimensional preparation was carried on a RP-Megress-C18 prep column, and four anti-inflammatory fractions were obtained from the 100mg re-enriching sample with a recovery of 66.9%. A HILIC-XAmide prep column was selected for the second dimensional preparation. Finally, two pair of analogue β-carboline alkaloids and one other β-carboline alkaloid were purified from A. kansuensis. The purity of the isolated compounds was ≫>98%, which indicated that the method was efficient to re-enrich and manufacture single trace β-carboline alkaloids with high purity from A. kansuensis. Additionally, this method showed great potential to serve as a good example for the purification and enrichment of analogue structure anti-inflammation carboline alkaloids from other plant materials.
• TCM therapies showed potential positive effect for alleviating fatigue symptoms. • Whether TCM could improve the QOL of patients is still inconclusive. • We could not draw a firm conclusion about the safety of TCM on CFS.<br>Background: There is no curative treatment for chronic fatigue syndrome (CFS). Traditional Chinese medicine (TCM) is widely used in the treatment of CFS in China.<br>Objective: To evaluate the effectiveness and safety of TCM for CFS.<br>Methods: The protocol of this review is registered at PROSPERO. We searched six main databases for randomized clinical trials (RCTs) on TCM for CFS from their inception to September 2013. The Cochrane risk of bias tool was used to assess the methodological quality. We used RevMan 5.1 to synthesize the results.<br>Results: 23 RCTs involving 1776 participants were identified. The risk of bias of the included studies was high. The types of TCM interventions varied, including Chinese herbal medicine, acupuncture, qigong, moxibustion, and acupoint application. The results of meta-analyses and several individual studies showed that TCM alone or in combination with other interventions significantly alleviated fatigue symptoms as measured by Chalder's fatigue scale, fatigue severity scale, fatigue assessment instrument by Joseph E. Schwartz, Bell's fatigue scale, and guiding principle of clinical research on new drugs of TCM for fatigue symptom. There was no enough evidence that TCM could improve the quality of life for CFS patients. The included studies did not report serious adverse events.<br>Conclusions: TCM appears to be effective to alleviate the fatigue symptom for people with CFS. However, due to the high risk of bias of the included studies, larger, well-designed studies are needed to confirm the potential benefit in the future.
India and China face the same challenge of having too few trained psychiatric personnel to manage effectively the substantial burden of mental illness within their population. At the same time, both countries have many practitioners of traditional, complementary, and alternative medicine who are a potential resource for delivery of mental health care. In our paper, part of The Lancet and Lancet Psychiatry's Series about the China-India Mental Health Alliance, we describe and compare types of traditional, complementary, and alternative medicine in India and China. Further, we provide a systematic overview of evidence assessing the effectiveness of these alternative approaches for mental illness and discuss challenges in research. We suggest how practitioners of traditional, complementary, and alternative medicine and mental health professionals might forge collaborative relationships to provide more accessible, affordable, and acceptable mental health care in India and China. A substantial proportion of individuals with mental illness use traditional, complementary, and alternative medicine, either exclusively or with biomedicine, for reasons ranging from faith and cultural congruence to accessibility, cost, and belief that these approaches are safe. Systematic reviews of the effectiveness of traditional, complementary, and alternative medicine find several approaches to be promising for treatment of mental illness, but most clinical trials included in these systematic reviews have methodological limitations. Contemporary methods to establish efficacy and safety-typically through randomised controlled trials-need to be complemented by other means. The community of practice built on collaborative relationships between practitioners of traditional, complementary, and alternative medicine and providers of mental health care holds promise in bridging the treatment gap in mental health care in India and China.
Around 70-80% of drugs used in traditional Tibetan medicine (TTM) come from Qinghai Tibet Plateau, the majority of which are plants. The biological and medicinal culture diversity on Qinghai Tibet Plateau are amazing and constitute a less tapped resource for innovative drug research and development. Meanwhile, the problem of the exhausting Tibetan medicine resources is worrying. Here, the latest awareness, as well as the gaps of the traditional Tibetan medicinal plant issues in drug development and clinical usage of TTM compounds, was systematically reviewed and highlighted. The TTM resource studies should be enhanced within the context of deeper and more extensive investigations of molecular biology and genomics of TTM plants, phytometabolites and metabolomics and ethnopharmacology-based bioactivity, thus enabling the sustainable conservation and exploitation of Tibetan medicinal resource.
Around 70-80% of drugs used in traditional Tibetan medicine (TTM) come from Qinghai Tibet Plateau, the majority of which are plants. The biological and medicinal culture diversity on Qinghai Tibet Plateau are amazing and constitute a less tapped resource for innovative drug research and development. Meanwhile, the problem of the exhausting Tibetan medicine resources is worrying. Here, the latest awareness, as well as the gaps of the traditional Tibetan medicinal plant issues in drug development and clinical usage of TTM compounds, was systematically reviewed and highlighted. The TTM resource studies should be enhanced within the context of deeper and more extensive investigations of molecular biology and genomics of TTM plants, phytometabolites and metabolomics and ethnopharmacology-based bioactivity, thus enabling the sustainable conservation and exploitation of Tibetan medicinal resource.
Around 70–80% of drugs used in traditional Tibetan medicine (TTM) come from Qinghai Tibet Plateau, the majority of which are plants. The biological and medicinal culture diversity on Qinghai Tibet Plateau are amazing and constitute a less tapped resource for innovative drug research and development. Meanwhile, the problem of the exhausting Tibetan medicine resources is worrying. Here, the latest awareness, as well as the gaps of the traditional Tibetan medicinal plant issues in drug development and clinical usage of TTM compounds, was systematically reviewed and highlighted. The TTM resource studies should be enhanced within the context of deeper and more extensive investigations of molecular biology and genomics of TTM plants, phytometabolites and metabolomics and ethnopharmacology-based bioactivity, thus enabling the sustainable conservation and exploitation of Tibetan medicinal resource.
Highly elevated concentrations of total mercury (THg) and methylmercury (MeHg) were found in the municipal sewage in Tibet. Material flow analysis supports the hypothesis that these elevated concentrations are related to regular ingestion of Hg-containing Traditional Tibetan Medicine (TTM). In Tibet in 2015, a total of 3600 kg of THg was released from human body into the terrestrial environment as a result of TTM ingestion, amounting to 45% of the total THg release into the terrestrial environment in Tibet, hence substantially enhancing the environmental Hg burden. Regular ingestion of TTM leads to chronic exposure of Tibetans to inorganic Hg (IHg) and MeHg, which is 34 to 3000-fold and 0-12-fold higher than from any other known dietary sources, respectively. Application of a human physiology model demonstrated that ingestion of TTM can induce high blood IHg and MeHg levels in the human body. Moreover, 180 days would be required for the MeHg to be cleared out of the human body and return to the initial concentration i.e. prior to the ingestion of 1 TTM pill. Our analysis suggests that high Hg level contained in TTM could be harmful to human health and elevate the environmental Hg burden in Tibet.
Highly elevated concentrations of total mercury (THg) and methylmercury (MeHg) were found in the municipal sewage in Tibet. Material flow analysis supports the hypothesis that these elevated concentrations are related to regular ingestion of Hg-containing Traditional Tibetan Medicine (TTM). In Tibet in 2015, a total of 3600 kg of THg was released from human body into the terrestrial environment as a result of TTM ingestion, amounting to 45% of the total THg release into the terrestrial environment in Tibet, hence substantially enhancing the environmental Hg burden. Regular ingestion of TTM leads to chronic exposure of Tibetans to inorganic Hg (IHg) and MeHg, which is 34 to 3000-fold and 0-12-fold higher than from any other known dietary sources, respectively. Application of a human physiology model demonstrated that ingestion of TTM can induce high blood IHg and MeHg levels in the human body. Moreover, 180 days would be required for the MeHg to be cleared out of the human body and return to the initial concentration i.e. prior to the ingestion of 1 TTM pill. Our analysis suggests that high Hg level contained in TTM could be harmful to human health and elevate the environmental Hg burden in Tibet.
Traditional Tibetan medicine is important for discovery of drug precursors. However, information about the chemical composition of traditional Tibetan medicine is very limited due to the lack of appropriate chromatographic purification methods. In the present work, A. kansuensis was taken as an example and a novel two-dimensional reversed-phase/hydrophilic interaction liquid chromatography(HILIC) method based on on-line HPLC-DPPH bioactivity-guided assay was developed for the purification of analogue antioxidant compounds with high purity from the extract of A. kansuensis. Based on the separation results of many different chromatographic stationary phases, the first-dimensional (1D) preparation was carried on a RP-C18HCE prep column, and 2 antioxidant fractions were obtained from the 800mg crude sample with a recovery of 56.7%. A HILIC-XAmide prep column was selected for the second-dimensional (2D) preparation. Finally, a novel antioxidant β-carboline Alkaloids (Glusodichotomine AK) and 4 known compounds (Tricin, Homoeriodictyol, Luteolin, Glucodichotomine B) were purified from A. kansuensis. The purity of the compounds isolated from the crude extract was >98%, which indicated that the method built in this work was efficient to manufacture single analogue antioxidant compounds of high purity from the extract of A. kansuensis. Additionally, this method showed great potential in the preparation of analogue structure antioxidant compounds and can serve as a good example for the purification of analogue structure antioxidant carboline alkaloids and flavonoids from other plant materials.
From the whole plant of <i>Morina nepalensis</i> var. <i>alba</i> Hand.-Mazz., two new acylated flavonoid glycosides (<b>1</b> and <b>2</b>), together with four known flavonoid glycosides (<b>3-6</b>), were isolated. Their structures were determined to be quercetin 3-<i>O</i>-[2″′-<i>O</i>-(<i>E</i>)-caffeoyl]-α-L-arabinopyranosyl-(1→6)-β-D-galactopyranoside (monepalin A, <b>1</b>), quercetin 3-<i>O</i>-[2″′-<i>O</i>-(<i>E</i>)-caffeoyl]-α-L-arabinopyranosyl-(1→6)-β-D-glucopyranoside (monepalin B, <b>2</b>), quercetin 3-<i>O</i>-α-L-arabinopyranosyl-(1→6)-β-D-galactopyranoside (rumarin, <b>3</b>), quercetin 3-<i>O</i>-β-D-galactopyranoside (<b>4</b>), quercetin 3-<i>O</i>-β-D-glucopyranoside (<b>5</b>) and apigenin 4<sup>′</sup>-<i>O</i>-β-D-glucopyranoside (<b>6</b>). Their structures were determined on the basis of chemical and spectroscopic evidence. Complete assignments of the ¹H and <sup>13</sup>C NMR spectra of all compounds were achieved from the 2D NMR spectra, including H-H COSY, HMQC, HMBC and 2D HMQC-TOCSY spectra. Copyright © 2002 John Wiley & Sons, Ltd.
<br>Display Omitted<br>• Two new stilbenoid derivatives were isolated from <b>Sphaerophysa salsula</b>. • One compound were isolated for the first time from this species. • Eight known compounds were isolated from the plant. • These compounds enriched the structural types of natural products from <b>Sphaerophysa salsula</b>.<br>Two new compounds, gnetuhainins Fa (<b>1</b>) and cassigarols Ea (<b>2</b>), were isolated from the whole herb of <b>Sphaerophysa salsula</b> along with eight known compounds (<b>3</b>-<b>10</b>). The compounds (<b>4</b>) were isolated for the first time from this species. Their structures were elucidated by ESI-MS, UV, IR, 1D NMR and 2D NMR data.
Nitrogen (N) status has a great impact on methane (CH4) consumption by soils. Modeling studies predicting soil CH4 consumption assume a linear relationship between CH4 uptake and N addition rate. Here, we present evidence that a nonlinear relationship may better characterize changes in soil CH4 uptake with increasing N additions. By conducting a field experiment with eight N-input levels in a Tibetan alpine steppe, we observed a unimodal relationship; CH4 uptake increased at low to medium N levels but declined at high N levels. Environmental and microbial properties jointly determined this response pattern. The generality of the unimodal trend was further validated by two independent analyses: (i) we examined soil CH4 uptake across at least five N-input levels in upland ecosystems across China. A unimodal CH4 uptake-N addition rate relationship was observed in 3 out of 4 cases; and (ii) we performed a meta-analysis to explore the N-induced changes in soil CH4 uptake with increasing N additions across global upland ecosystems. Results showed that the changes in CH4 uptake exhibited a quadratic correlation with N addition rate. Overall, we suggest that the unimodal relationship should be considered in biogeochemistry models for accurately predicting soil CH4 consumption under global N enrichment.
Zuotais regarded as the king of Tibetan medicine. However, the major starting material ofZuotais mercury, which is one very toxic heavy metal. This has aroused serious doubts on the biosafety ofZuotacontaining drugs. In this study, we quantified the Hg contents in fourZuotasamples, monitored the release of Hg in simulated gastric/intestinal juice and evaluated their cytotoxicity to Caco-2 cells. Our results showed that the Hg contents inZuotasamples were in the range of 566–676 mg/g. Fortunately, the release of Hg fromZuotasamples was very low in simulated gastric juice, and much lower in simulated intestinal juice. Direct contact ofZuotawith Caco-2 cells led to dose-dependent cytotoxicity, including activity loss and membrane leakage. The toxicity was closely related to apoptosis, because the caspase 3/7 levels of Caco-2 cells increased after the exposure toZuota. Interestingly,Zuotasamples inhibited the oxidative stress at low concentrations, but the toxicity could be relived by antioxidants. The possible toxicity should be attributed to the cellular uptake ofZuotaparticulates. Beyond the cytotoxicity, significant differences amongZuotasamples from different institutions were observed, suggesting that the preparation process ofZuotahad meaningful influence of its biosafety. The implications to the safety and clinical applications ofZuotaare discussed. [ABSTRACT FROM AUTHOR]
Zuota is regarded as the king of Tibetan medicine. However, the major starting material of Zuota is mercury, which is one very toxic heavy metal. This has aroused serious doubts on the biosafety of Zuota containing drugs. In this study, we quantified the Hg contents in four Zuota samples, monitored the release of Hg in simulated gastric/intestinal juice and evaluated their cytotoxicity to Caco-2 cells. Our results showed that the Hg contents in Zuota samples were in the range of 566-676 mg/g. Fortunately, the release of Hg from Zuota samples was very low in simulated gastric juice, and much lower in simulated intestinal juice. Direct contact of Zuota with Caco-2 cells led to dose-dependent cytotoxicity, including activity loss and membrane leakage. The toxicity was closely related to apoptosis, because the caspase 3/7 levels of Caco-2 cells increased after the exposure to Zuota. Interestingly, Zuota samples inhibited the oxidative stress at low concentrations, but the toxicity could be relived by antioxidants. The possible toxicity should be attributed to the cellular uptake of Zuota particulates. Beyond the cytotoxicity, significant differences among Zuota samples from different institutions were observed, suggesting that the preparation process of Zuota had meaningful influence of its biosafety. The implications to the safety and clinical applications of Zuota are discussed.
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