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(searched for: doi:10.1016/j.jep.2017.08.037)
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Xue Tian, Xiaoying Lin, Jiating Zhao, Liwei Cui, Yuxi Gao, Yong-Liang Yu, Bai Li, Yu-Feng Li
Published: 1 January 2023
Journal: Toxicology
Taoguang Huo, Weiwei Zhang, Jing Yang, Jian Li, Yuwei Zhang, Haoqi Guo, Xinyu Wu, Aihong Li, Cong Feng, Hong Jiang
Published: 1 January 2023
Toxicology Letters, Volume 372, pp 1-13; https://doi.org/10.1016/j.toxlet.2022.10.002

Huifang Guan, Yan Xu, Chunyu Ma, Dexi Zhao
Evidence-Based Complementary and Alternative Medicine, Volume 2022, pp 1-15; https://doi.org/10.1155/2022/6369150

Abstract:
Ethnopharmacological Relevance. Mineral medicines are widely used traditional Chinese medicines with curative effects. These medicines are used for many refractory diseases. Aim of the Review. In this review, cinnabar (HgS) and realgar (AsS) serve as examples of mineral medicines, and their pharmacology, therapeutic toxicity, use in traditional medicine mixtures, and research perspectives are discussed. Materials and Methods. A search was performed for the literature on cinnabar and realgar in PubMed, the Chinese Pharmacopeia, Google, and other sources. The search included studies using single herbs, traditional formulations, or novel dosage forms. Results. Cinnabar and cinnabar formulas exhibit good efficacy for sedation, sleep improvement, anxiety alleviation, and brain protection. However, previous studies on neurotransmitters have reached different conclusions, and detailed pharmacological mechanisms are lacking. Realgar and its formulas exert promising antitumor activity through regulation of cell cycle arrest, intrinsic and extrinsic apoptosis, induction of differentiation, autophagy, metabolic reprogramming, matrix metalloproteinase-9 (MMP-9) signaling, and reactive oxygen species (ROS) generation. In addition, realgar can be used to treat a variety of refractory diseases by regulating immunity and exerting antibacterial, antiviral, and other effects. However, the existing pharmacological research on the use of realgar for epidemic prevention is insufficient, and animal experiments and research at the cellular level are lacking. Inappropriate applications of cinnabar and realgar can cause toxicity, including neurotoxicity, liver toxicity, kidney toxicity, and genotoxicity. The toxicological mechanism is complex, and molecular-level research is limited. For clinical applications, theory and clinical experience must be combined to guide scientific and rational drug use and to achieve reduced toxicity and increased efficacy through the use of modern preparation methods or combined drugs. Notably, when cinnabar and realgar are used to treat targeted diseases, these agents have a bidirectional effect of treatment and toxicity on the central nervous system in pathological and normal states. The pharmacological and toxicological mechanisms need to be elucidated in greater detail in the future. Overall, systematic research is needed to provide a basis for better promotion of the rational use of cinnabar and realgar in the clinic. Conclusion. Mineral medicines are multicomponent, multiactivity, and multitargeted substances. The pharmacology and mechanisms of the toxicity and action of realgar and cinnabar are extremely complex. A number of Chinese medicinal preparations of realgar and cinnabar have demonstrated unique efficacy in the treatment of refractory diseases.
Zonghong Li, Ruiming Zhang, Xuewei Yin, Nana Li, Siyuan Cui, Teng Wang, Xing Tan, Mingyue Shen, Yun Guo, Jinxin Wang, et al.
Published: 12 September 2022
Journal: Aging
Aging, Volume 14, pp 7109-7125; https://doi.org/10.18632/aging.204281

Yajun Qiao, Cen Li, Ming Zhang, Xingfang Zhang, Lixin Wei, Keshen Cao, Xiaoyuan Zhang, ,
Published: 2 September 2022
Frontiers in Pharmacology, Volume 13; https://doi.org/10.3389/fphar.2022.971243

Abstract:
Depression is a common mood disorder that has exhibited an increased incidence rate worldwide, but the overall clinical efficacy of antidepressants remains unsatisfactory. In traditional Ayurveda and Tibetan medicines, β-HgS-containing medicines have been used to treat neurological diseases for thousands of years, and our previous study found that β-HgS ameliorated depression-like behaviors in chronic restraint stress (CRS)-treated or chronic unpredictable mild stress (CUMS)-treated mice. Hence, present study investigated the effects of β-HgS combined with the clinical first-line antidepressants, imipramine (IMI) and sertraline (SER), on depression-like symptoms in CRS- and CUMS-co-treated mice. Our results revealed that β-HgS promoted the antidepressant effect of SER on depression-like behavior in mice, and enhanced its effects on promoting glucocorticoid receptor (GR) expression and neuronal proliferation in key hippocampal subregions, as well as increasing interleukin 10 (IL-10) levels and decreasing malondialdehyde levels in the sera of stress-stimulated mice. As for IMI, β-HgS enhanced its effects on preventing atrophy and severe structural damage in the hippocampus, as well as in promoting hippocampal GR levels and neuronal proliferation and serum IL-10 and superoxide dismutase (SOD) levels. Additionally, combination therapy resulted in the increased diversity of important intestinal microbiota compared to that of monotherapy, which may help sustain the health of the digestive tract and reduce inflammation to further enhance the antidepressant effects of IMI and SER in mice.
, Zeling Zhong, Kuangmin Lin, Xinhe Liu, Zhichao Wu, Zitian Liu, Yongming Li
Published: 30 August 2022
Frontiers in Pharmacology, Volume 13; https://doi.org/10.3389/fphar.2022.967608

Abstract:
Realgar- and cinnabar-containing AnGongNiuHuang Pill (AGNHP) is widely used for treating encephalopathy syndrome. However, it raises great safety concerns due to the adverse effects reported by arsenic or mercury poisoning. Although AGNHP has been generally recognized, little is known about the metabolism of arsenic and mercury and their resulting potential health risk in vivo. Thus, comparative pharmacokinetics and urinary excretion of arsenic and mercury were conducted in rats after oral administration of realgar, cinnabar and AGNHP, respectively. The contents of arsenic and mercury in rat blood and urine were determined by hydride-generation atomic fluorescence spectrometry (HG-AFS) after wet digestion. AGNHP significantly reduced the absorption of arsenic in blood and promoted urinary arsenic excretion. Whereas, it increased the blood mercury absorption and reduced urinary mercury excretion. No significant toxicity was observed in the clinical dose range of AGNHP. However, excessive exposure to arsenic and mercury may still pose risks especially by long-term or excessive medication. The results are helpful for the rational clinical applications of realgar- and cinnabar-containing TCMs.
Mingyi Sun, Yaolei Li, Ying Wang, Huimin Wu, Jing Liu, Longtai You, Hulinyue Peng, Huating Huang, Hongyu Jin, Xiaoxu Dong, et al.
Evidence-Based Complementary and Alternative Medicine, Volume 2022, pp 1-10; https://doi.org/10.1155/2022/1026672

Abstract:
At present, several experiments have been carried out to study the changes in total arsenic content of realgar and its prescription, but few researches on its form and valence. We evaluated the change in arsenic species concentration in realgar from the perspective of absorption by using an in vitro dissolution study, an in vivo unidirectional intestinal perfusion study, transmembrane transport in Caco-2 cells, and a pharmacokinetic study in rats. In the gastrointestinal tract, arsenic species are mainly present inorganic forms of AsIII and AsV. The cumulative dissolution rates of soluble arsenic in 4 h artificial gastric fluid and 8 h artificial intestinal fluid were 21.99% and 59.20%, respectively. The Papp values of soluble arsenic in realgar in the duodenum, jejunum, and ileum of rats were 5.4 × 10−3, 6.1 × 10−3 and 5.8 × 10−3 cm/min, respectively. In the process of small intestine perfusion, the AsIII of realgar was partially converted into AsV in the duodenum and jejunum. As the transport time increased, the transmembrane transport rate and Papp value of soluble arsenic in realgar were increased in Caco-2 cells, and it also suggested that arsenic species may be passively transported across the Caco-2 cell monolayer. The Cmax and AUC (0-24) of AsIII, AsV, and DMA in plasma of realgar were 41.26 ng L−1/343.977 ng h mL−1, 21.626 ng L−1/47.310 ng h mL−1, and 2.372 ng L−1/30.429 ng h mL−1, respectively. Tmax and MRT (0-∞) of AsIII, AsV, and DMA were 2.571 h/9.649 h, 0.393 h/2.790 h, and 3.143 h/23.145 h, respectively. It is hoped to provide a basis for clarifying the arsenic species in realgar.
Sheng Zhang, Shuai Cao, Heng Zhou, Limin Li, Qing Hu, Xiuhong Mao, Shen Ji
Published: 22 July 2022
Journal of Applied Toxicology; https://doi.org/10.1002/jat.4362

Jing Shen, Yan-Ze Li, Sai Yao, Zhou-Wei Zhu, Xiang Wang, Hui-Hui Sun, Wei-Feng Ji
Published: 18 July 2022
Frontiers in Pharmacology, Volume 13; https://doi.org/10.3389/fphar.2022.952696

Abstract:
Hu’po Anshen decoction (HPASD) is a traditional Chinese medicine formula comprising five herbal medicines for the treatment of concussion and fracture healing, but its pharmacological mechanism is still unclear. Ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC/Q-TOF MS) was used to analyze the main active components of HPASD. Rats were randomly assigned to fracture group, fracture combined with traumatic brain injury (TBI) group (FBI) and FBI combined with HPASD treatment group (FBIH). Rats in the FBIH group were given oral doses of HPASD (2.4 g/kg, 4.8 g/kg and 9.6 g/kg) for 14 or 21 consecutive days. The fracture callus formation and fracture sites were determined by radiographic analysis and micron-scale computed tomography (micro-CT) analysis. Hematoxylin and eosin (H&E) staining and a three-point bending test were applied to assess histological lesions and biomechanical properties, respectively. The levels of cytokines-/protein-related to bone formation and differentiation as well as PI3K/AKT pathway-related proteins were determined by Enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription-polymerase chain reaction (qRT-PCR), or western blot assays, respectively. UPLC-Q/TOF-MS-based serum metabolomic analysis was also performed to investigate the therapeutic effects of HPASD in the treatment of FBI. UPLC/Q-TOF MS analysis showed the chemical components in HPASD, including flavonoids, amino acids, saponins, and phenylpropanoid constituents, etc. HPASD dose-dependently promoted callus formation, increased bone density, improved mechanical parameters and morphological scores, and facilitated the expressions of VEGF, PDGF, bFGF, VEGFA, CoL1A1, RUNX2, BMP2, and Aggrecan, inhibited the expression of MMP13, and activated PI3K/AKT pathway. Metabolomics analysis revealed abnormalities of malate-aspartate shuttle and glucose-alanine. HPASD accelerates fracture healing by promoting bone formation and regulating the malate-aspartate shuttle and glucose-alanine cycle, which might be associated with the activation of the PI3K/AKT pathway.
Published: 19 May 2022
by MDPI
International Journal of Molecular Sciences, Volume 23; https://doi.org/10.3390/ijms23105697

Abstract:
Realgar, a poisonous traditional Chinese medicine, has been shown to cause liver injury when used for long periods or overdoses. However, the underlying molecular mechanisms and therapeutic targets have not been fully elucidated. The aim of this study is to explore the role of autophagy in sub-chronic realgar exposure-induced liver injury. Here, the liver injury model was established by continuously administrating mice with 1.35 g/kg realgar for 8 weeks. 3-methyladenine (3-MA) and rapamycin (RAPA) were used to regulate autophagy. The results showed that realgar induced abnormal changes in liver function, pathological morphology, expression of inflammatory cytokines, and upregulated NLRP3 inflammasome pathway in mouse livers. RAPA treatment (an inducer of autophagy) significantly improved realgar-induced liver injury and NLRP3 inflammasome activation, while 3-MA (an inhibitor of autophagy) aggravated the realgar-induced liver injury and NLRP3 inflammasome activation. Furthermore, we found that realgar-induced NLRP3 inflammasome activation in mouse livers is mediated by ROS. RAPA eliminates excessive ROS, inhibits NF-κB nuclear translocation and down-regulates the TXNIP/NLRP3 axis, consequently suppressing ROS-mediated NLRP3 inflammasome activation, which may be the underlying mechanism of the protective effect of autophagy on realgar-induced liver injury. In conclusion, the results of this study suggest that autophagy alleviates realgar-induced liver injury by inhibiting ROS-mediated NLRP3 inflammasome activation. Autophagy may represent a therapeutic target in modulating realgar-induced liver injury.
, Dulasiri Amarasiriwardena, Jet Starkings, Juan Pablo Ogalde
Archaeological and Anthropological Sciences, Volume 14, pp 1-12; https://doi.org/10.1007/s12520-022-01547-w

The publisher has not yet granted permission to display this abstract.
Jia-Jia Liu, Yan Liang, Ya Zhang, Rui-Xia Wu, Ying-Lian Song, Feng Zhang, Jing-Shan Shi, , Shang-Fu Xu, Zhang Wang
Published: 8 March 2022
Frontiers in Pharmacology, Volume 13; https://doi.org/10.3389/fphar.2022.730318

Abstract:
Background: Hua-Feng-Dan is a patent Chinese medicine for stroke recovery and various diseases. This study used GC-MS to profile its ingredients and RNA-Seq to analyze the induced adaptive response in the liver.Methods: Hua-Feng-Dan was subjected to steam distillation and solvent extraction, followed by GC-MS analysis. Mice were orally administered Hua-Feng-Dan and its “Guide drug” Yaomu for 7 days. Liver pathology was examined, and total RNA isolated for RNA-Seq, followed by bioinformatic analysis and quantitative real-time PCR (qPCR).Results: Forty-four volatile and fifty liposoluble components in Hua-Feng-Dan were profiled and analyzed by the NIST library and their concentrations quantified. The major components (>1%) in volatile (5) and liposoluble (10) were highlighted. Hua-Feng-Dan and Yaomu at hepatoprotective doses did not produce liver toxicity as evidenced by histopathology and serum enzyme activities. GO Enrichment revealed that Hua-Feng-Dan affected lipid homeostasis, protein folding, and cell adhesion. KEGG showed activated cholesterol metabolism, bile secretion, and PPAR signaling pathways. Differentially expressed genes (DEGs) were identified by DESeq2 with p < 0.05 compared to controls. Hua-Feng-Dan produced more DEGs than Yaomu. qPCR on selected genes largely verified RNA-Seq results. Ingenuity Pathways Analysis of the upstream regulator revealed activation of MAPK and adaptive responses by Hua-Feng-Dan, and Yaomu was less effective. Hua-Feng-Dan-induced DEGs were highly correlated with the Gene Expression Omnibus database of chemical-induced adaptive transcriptome changes in the liver.Conclusion: GC-MS primarily profiled volatile and liposoluble components in Hua-Feng-Dan. Hua-Feng-Dan at the hepatoprotective dose did not produce liver pathological changes but induced metabolic and signaling pathway activations. The effects of Hua-Feng-Dan on liver transcriptome changes point toward induced adaptive responses to program the liver to produce hepatoprotective effects.
Meiling Zhao, Yi Li,
Published: 2 March 2022
Frontiers in Pharmacology, Volume 13; https://doi.org/10.3389/fphar.2022.807807

Abstract:
Historically, mercury and mercury-containing preparations have been widely used in traditional Chinese medicine and applied in many clinical practices mainly in the form of mercury sulfides. The clinical application, toxicity manifestations, and symptoms of these preparations largely depend on the route of administration and the dosage form. Commonly used mercury-containing medicinal materials and preparations in traditional Chinese medicine include Cinnabar, an excellent medicine for tranquilizing the nerves; Hongsheng Dan and Baijiang Dan, which have antibacterial, anti-inflammatory, promotion of tissue repair and regeneration and other pharmacological effects. Tibetan medicine commonly uses Zaotai and Qishiwei Zhenzhu pills, which have pharmacological effects such as sedation, anti-inflammatory, anti-convulsant, and improvement of cerebral apoplexy. Menggen Wusu Shibawei pills, commonly used in Mongolian traditional medicine, have the muscle growth and astringent effects. In India and Europe, mercury is often used for treating syphilis. This article summarizes the history, clinical application, pharmacology, toxicology, and pharmacokinetics of mercury and mercury-containing preparations in traditional medicines. In terms of clinical application, it provides suggestions for the rational use and safety of mercury-containing drugs in clinical practices and in public health issues. It will further provide a reference for formulation strategies related to mercury risk assessment and management.
Xiaoqing Zhong, Zhenning Di, Yuanxin Xu, Qifan Liang, Kuanhan Feng, Yuting Zhang, ,
Published: 10 February 2022
Journal: Chinese Medicine
Chinese Medicine, Volume 17, pp 1-30; https://doi.org/10.1186/s13020-022-00577-9

Abstract:
Mineral drugs are an important constituent of traditional Chinese medicine (TCM). Taking minerals that contain heavy metals as drugs is a very national characteristic part of TCM. However, the safety and scientific nature of mineral drugs are controversial owing to their heavy metals and strong toxicity. In 2000, the Food and Drug Administration (FDA) authorized arsenic trioxide (ATO) as first-line therapy for acute promyelocytic leukemia. This makes the development and utilization of mineral drugs become a research hotspot. The development of nanomedicine has found a great prospect of mineral drugs in nano-delivery carriers. And that will hold promise to address the numerous biological barriers facing mineral drug formulations. However, the studies on mineral drugs in the delivery system are few at present. There is also a lack of a detailed description of mineral drug delivery systems. In this review, the advanced strategies of mineral drug delivery systems in tumor therapy are summarized. In addition, the therapeutic advantages and research progress of novel mineral drug delivery systems are also discussed. Here, we hope that this will provide a useful reference for the design and application of new mineral drug delivery systems. Graphical Abstract
Xuerui Wang, Xiaolong Xu, Yishan Chen, Zhenxuan Li, Mina Zhang, Chunxia Zhao, Bo Lian, Jingxia Zhao, Yuhong Guo,
Published: 28 January 2022
Frontiers in Pharmacology, Volume 12; https://doi.org/10.3389/fphar.2021.824180

Abstract:
Alteration in airway microbiota composition and perturbations in microbe-metabolites interactions have been proposed as markers of many diseases. Liu Shen (LS) capsule, a traditional Chinese medicine, was proved as favorable in treating respiratory diseases. However, the effects of the LS capsule in terms of regulating human microorganisms and metabolite profiles are not well known. This study aimed to define and compare the respiratory microbiota composition and circulating and fecal metabolite profiles before and after LS capsule administration. A total of 30 healthy volunteers were recruited. The pharyngeal swab samples were collected for 16S rRNA gene sequencing. The serum and fecal samples were collected to analyze the non-targeted ultra-performance liquid chromatography–tandem mass spectrometry metabolomics. The airway microbial compositions were profoundly altered after LS capsule administration, as evidenced by increased microbial diversity and altered microbial taxa distribution. The increasing abundance of bacterial Bifidobacteria, and Lactobacillus characterized the after-administration groups, and the increasing of abundance bacterial Proteobacteria, Veillonella, Prevotella, Neisseria, and Actinomyces characterized the before-administration groups. Significant discriminations were observed in both serum and fecal metabolic profiles between the before- and after-administration groups. A total number of 134 and 71 significant HMDB taxonomic metabolites including glycerophospholipids, fatty acyls, and prenol lipids in the serum and fecal samples were identified respectively between the before- and after-administration groups. The integrated analysis showed that some altered airway microbiota phylum, such as Bacteroidetes and Proteobacteria, significantly correlated with metabolites in serum and fecal. Hence, our study reported the alternations in the composition and functions of the airway microbial community and the changes in circulating and fecal metabolite profiles after LS capsule administration in healthy humans, thus providing a novel insight into the mechanisms underlying the role of LS capsule treating and preventing related diseases.
Yu-Chi Wang, Sheng-Han Tsai, Ming-Hong Chen, Fu-Yu Hsieh, Yuan-Chen Chang, Fu-I Tung,
ACS Applied Materials & Interfaces, Volume 14, pp 5586-5597; https://doi.org/10.1021/acsami.1c21729

The publisher has not yet granted permission to display this abstract.
Ke Fu, Yinglian Song, Dewei Zhang, Min Xu, Ruixia Wu, Xueqing Xiong, Xianwu Liu, Lei Wu, Ya Guo, You Zhou, et al.
Evidence-Based Complementary and Alternative Medicine, Volume 2022, pp 1-10; https://doi.org/10.1155/2022/8548378

Abstract:
Qishiwei Zhenzhu pills (QSW) was first recorded in the Tibetan medicine classic Si Bu Yi Dian and has been used to treat Baimai disease, stroke, paralysis, hemiplegia, cerebral hemorrhage, and other diseases till today. This prescription contains more than 70 medicines including myrobalan, pearl, agate, opal, bezoar, coral, musk, gold, silver, and a mineral mixture Zuotai. As a result, QSW contains a large amount of mercury, copper, lead, and other trace elements. The aim of this study was to determine the 18 trace elements (lithium, beryllium, scandium, vanadium, chromium, manganese, cobalt, nickel, copper, arsenic, strontium, argentum, cadmium, cesium, barium, lead, aurum, and mercury) in 10 batches of QSW produced by 5 pharmaceutical companies (Ganlu Tibetan Medicine Co., Ltd. has 6 different batches) by direct inductively coupled plasma-mass spectrometry (ICP-MS). ICP-MS is a rapid, sensitive, accurate methodology allowing the determination of 18 elements simultaneously. The results showed that each element had an excellent linear relationship in the corresponding mass concentration range. The results showed that the rank order of the elements in QSW was copper>mercury>lead from high to low, with the mass fraction higher than 6000μg/kg; the mass fractions of argentum, arsenic, manganese, aurum, strontium, barium, chromium, and nickel were in the range of 331034μg/kg; and the mass fractions of vanadium, cobalt, lithium, beryllium, cadmium, scandium, and cesium were lower than 10μg/kg. The reproducibility from the same manufacturer (Tibet Ganlu Tibetan Medicine Co., Ltd.) was relatively high; however, the element amounts among 5 manufacturers were different, which could affect the efficacy and toxicity of QSW. All in all, ICP-MS can be used as an effective tool for the analysis of trace elements in QSW and standard quality control needs to be enforced across different manufactures.
Ting Han, Hui Zhang, Wenjuan Xu, Chunshuai Li, Min Wang, Yuying Bai, Linlin Yang, Shuyan Zhang, Zhe Jia, Xinfang Xu, et al.
Evidence-Based Complementary and Alternative Medicine, Volume 2021, pp 1-14; https://doi.org/10.1155/2021/8538287

Abstract:
Background. Realgar was usually selected as a substitute for arsenic trioxide to treat acute promyelocytic leukemia due to its higher effect without high cardiotoxicity. In traditional Chinese medicine (TCM), realgar is usually processed by the water-grinding method clinically, but the mechanism of realgar processing detoxification is still unclear. However, it is necessary to take safety and efficacy into account while evaluating a drug. Methods. Sixty male Wistar rats were divided into control group, realgar products-treated groups, and corresponding subgroups. Biochemistry analysis and histopathological examination were performed in the study, and plasma samples were collected from all the rats for metabolomics analysis. Results. No significant toxicity was observed in rats treated with 0.64 g/kg/day grinding realgar (G-r) and water-grinding realgar (WG-r). When the dose increased to 1.92 g/kg/day, the liver weight coefficients of the rats treated with G-r (HG-r: 3.65 ± 0.26%) and WG-r (HWG-r: 3.67 ± 0.14%) increased significantly and severe hepatic injury occurred in comparison to the control group (Group C: 3.00 ± 0.21%). After one week's withdrawal, the liver injury caused by the high dose of WG-r significantly recovered, while the liver damage caused by G-r was more difficult to recover. In metabolomics analysis, 14 metabolites were identified as the potential biomarkers in realgar-treated rats. These metabolites indicated that there were perturbations of the primary bile acid biosynthesis, arachidonic acid metabolism, linoleic acid metabolism, and glycerophospholipid metabolism in the realgar-treated groups. Conclusions. These results illustrate that, as a TCM processing method, water grinding had the effect of reducing toxicity, and the metabolomics method may be a valuable tool for studying the toxicity induced by TCM and the mechanism of TCM processing.
Guangzhi Liu, Yurong Song, Chenxi Li, Rui Liu, Youwen Chen, Liuchunyang Yu, Qingcai Huang, Dongjie Zhu, Cheng Lu, Xue Yu, et al.
Published: 1 October 2021
European Journal of Medicinal Chemistry, Volume 221; https://doi.org/10.1016/j.ejmech.2021.113519

Abstract:
Arsenic (As), as well as its various compounds have been widely used for nearly 4000 years either as drugs or poisons. These compounds are valuable in the treatment of various diseases ranging from dermatosis to cancer, thereby emphasizing their important roles as therapeutic agents. The ability of As compounds, especially arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL), has fundamentally altered people's understanding of the poison, and has become a major factor in the re-emergence of Western medicine candidates to treat leukemia and other solid tumors. However, long-term exposure to As has been correlated with numerous disadvantageous influences on health, particularly carcinogenesis. Importantly, accumulating evidence suggests that biotransformation of As, as a step to eliminate As from the human body, can induce alterations at the genetic and epigenetic levels, resulting in therapeutic effects or carcinogenesis. In this article, we aimed to provide a systematic overview of the primary contributions associated with As and its compounds, as well as the detailed mechanisms applied in APL cells and carcinogenic toxicology. This review may help to understand the underlying mechanisms and safe wide clinical applications of medicinal As along with its compounds.
Yuan Meng, Rui Feng, Zhao Yang, Tingting Liu, Taoguang Huo,
Published: 4 September 2021
Journal of Ethnopharmacology, Volume 282; https://doi.org/10.1016/j.jep.2021.114582

The publisher has not yet granted permission to display this abstract.
Manhuayun Zhai, Dandan Gong, Qiannan Gao, Hong Zhang, Guoxiang Sun
Published: 1 September 2021
Biomedicine & Pharmacotherapy, Volume 141; https://doi.org/10.1016/j.biopha.2021.111923

Abstract:
Although Zhusha Anshen Pill (ZSASP) is a commonly used traditional prescription for insomnia, the safety of cinnabar in the formula has always been controversial since its initial application in medical fields. Here, we developed a new prescription, Tieshuang Anshen Prescription (TSASP), by improving ZSASP with Fe2+ instead of Hg2+. Besides, TSASP was further optimized by establishing and testing the HPLC fingerprint and its sedative-hypnotic effect of formulas with different compatibility ratios and performing correlation spectrum analysis. The safety of TSASP was also evaluated by HE staining of liver and kidney. In addition, a validated and robust UHPLC-MS/MS method was established to demonstrate the pharmacokinetic characteristics of berberine, palmatine, jatrorrhizine, ligustilide, catalpol, loganin, liquiritin and liquiritigenin after oral administration of TSASP. Our study originally provides a new non-toxic prescription, TSASP, with better sedative-hypnotic effect in comparison with ZSASP, revealing that Fe2+ could replace Hg2+ to eliminate its toxicity and play a sedative role. Meanwhile, we believe that our pharmacokinetics results may contribute valuable reference to both TSASP's specific mechanism of action and its further clinical efficacy and effectiveness research.
Sheng Zhang, Chao Li, Tingting Feng, Shuai Cao, Heng Zhou, Limin Li, Qing Hu, Xiuhong Mao,
Published: 23 August 2021
Frontiers in Pharmacology, Volume 12; https://doi.org/10.3389/fphar.2021.706249

Abstract:
Realgar has been used as a type of mineral drug that contains arsenic for thousands of years. Previous studies have shown that Realgar-induced acute kidney injury is associated with abnormal metabolism, but the underlying mechanism is poorly understood. The aim of this study is to investigate the metabolic changes in serum and kidney tissues of mice exposed to Realgar by using a metabolomic approach and explore the molecular mechanisms of acute kidney injury induced by Realgar. Forty mice were randomly divided into four groups: Control group, 0.5-, 1.0, and 2.0 g/kg Realgar group. After 1 week, the body weight and kidney weight of the mice were measured. The serum and kidney samples were used for LC-MS spectroscopic metabolic profiling. Principal component analysis (PCA), correlation analysis, and pathway analysis were used to detect the nephrotoxic effects of Realgar. Body weight decreased significantly in the 2.0 g/kg group, and the kidney weight index also showed a dose-dependent increase in Realgar. The PCA score plot showed the serum and kidney tissue metabolic profile of mice exposed to 2.0 g/kg Realgar separated from the control group, while the lower-doses of 0.5 g/kg and 1.0 g/kg Realgar shown a similar view to the Control group. Thirty-three metabolites and seventeen metabolites were screened and identified in the serum and kidney of mice in a dose-dependent manner. respectively. Correlation analysis showed a strong correlation among these metabolites. Amino acid metabolism, lipid metabolism, glutathione metabolism, and purine metabolism pathways were found to be mainly associated with Realgar nephrotoxicity. This work illustrated the metabolic alterations in Realgar-induced nephrotoxic mice through a metabolomic approach.
Hong-Hong Ma, Yan-Nan Ding, Ao Wang, Xia Li, Yang Wang, Fu-Guo Shi,
Published: 29 June 2021
Biochemistry and Biophysics Reports, Volume 27; https://doi.org/10.1016/j.bbrep.2021.101055

The publisher has not yet granted permission to display this abstract.
New version
Yu Nie, Shang-Fu Xu, Yan-Liu Lu, Xiu-Rong Zhao, Cen Li, Li-Xin Wei,
Published: 24 June 2021
Journal: F1000Research
Abstract:
Background: Zuotai (mainly β-HgS)-containing 70 Wei-Zhen-Zhu-Wan (70W, Rannasangpei) is a famous Tibetan medicine for treating cardiovascular and gastrointestinal diseases. We have shown that 70W protected against CCl4 hepatotoxicity. CCl4 is metabolized via cytochrome P450 (CYP) to produce reactive metabolites. Whether 70W has any effect on CYPs is unknown and such effects should be compared with mercury compounds for safety evaluation. Methods: Mice were given clinical doses of 70W (0.15-1.5 g/kg, po), Zuotai (30 mg/kg, po), and compared to HgCl2 (33.6 mg/kg, po) and MeHg (3.1 mg/kg, po) for seven days. Liver RNA and protein were isolated for qPCR and Western-blot analysis. Results: 70W and Zuotai had no effects on hepatic mRNA expression of Cyp1a2, Cyp2b10, Cyp3a11, Cyp4a10 and Cyp7a1, and corresponding nuclear receptors [aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor-α (PPARα); farnesoid X receptor (FXR)]. In comparison, HgCl2 and MeHg increased mRNA expression of Cyp1a2, Cyp2b10, Cyp4a10 and Cyp7a1 except for Cyp3a11, and corresponding nuclear receptors except for PXR. Western-blot confirmed mRNA results, showing increases in CYP1A2, CYP2B1, CYP2E1, CYP4A and CYP7A1 by HgCl2 and MeHg only, and all treatments had no effects on CYP3A. Conclusions: Zuotai and Zuotai-containing 70W at clinical doses had minimal influence on hepatic CYPs and corresponding nuclear receptors, while HgCl2 and MeHg produced significant effects. Thus, the use of total Hg content to evaluate the safety of HgS-containing 70W is inappropriate.
Songsong Wang, Xiao Xiao, ,
Evidence-Based Complementary and Alternative Medicine, Volume 2021, pp 1-9; https://doi.org/10.1155/2021/5566078

Abstract:
An-Gong-Niu-Huang Wan (AGNH) has been a well-known cinnabar- and realgar-containing compound recipe for cerebral diseases. Unfortunately, its clinical practice is often restrained by the specific hepatorenal toxicity of cinnabar and realgar (C+R). In previous research studies, we have found that the antioxidative and anti-inflammatory effects of its herbal constituents could mitigate the risks from the toxicity. The underlying detoxification mechanisms are still unsolved. The present study investigated the protective effects of AGNHs herbal constituents on hepatorenal injury induced by C+R. For the mice treated with C+R, the increased expression levels of sensitive biomarkers of metal exposure and hepatorenal toxicity, including metallothionein (MT) in both hepatorenal tissues and kidney induced molecule-1 (KIM-1) in the kidney, were simultaneously reduced when C+R coadministered with other herbal medicines. In addition, the contents of trivalent As (AsIII), pentavalent As (Asv), and mercury (Hg) in hepatorenal tissues of mice were also significantly reduced benefiting from the herbal constituents in AGNH. Further mechanism studies showed that the herbal constituents in AGNH could downregulate the expressions of uptake transporters (AQP9 and OAT1) and upregulate the expressions of efflux transporters (P-gp, MRP2, and MRP4) in mice intoxicated by C+R. Our results suggested that AGNHs herbal constituents protect the body against C+R-induced hepatorenal toxicity and accumulations of Hg and As, which could be associated with the reestablishment of heavy metal homeostasis and the detoxification system.
Kannan N, Shanmuga Sundar S, , ,
Published: 1 April 2021
Colloids and Surfaces B: Biointerfaces, Volume 200; https://doi.org/10.1016/j.colsurfb.2021.111607

Abstract:
The study aims to characterize and understand the toxicological effects of colloidal mercuric formulation. The physiochemical characterization was carried out using Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), Energy dispersive X-ray microanalysis system (EDS), Inductively coupled plasma optical emission spectrometry (ICP-OES), X-ray diffraction (XRD), Zeta potential, Brunauer-Emmett-Teller (BET) and electron microscopy. Based on the physiochemical characterizations, the pairwise relationship between the parameters such as size, surface area, surface charge, reactivity and band gap energy were described. The biological effects of the sample were studied by both in vitro and in vivo assays. The in vitro cytotoxicity assay confirmed that the colloidal mercuric formulation was effective against cancer cells (MCF-7) and less toxic to normal cells (Hek 293). The formulation was effective against MCF-7 with more than 85% of apoptotic and necrotic cells, positive for PI staining when treated with 100 μg/mL. The inflammatory response on the macrophage cell lines was studied. The colloidal mercuric formulation upregulated the expression of TGF-β, IL-6 and TNF-α, due to the presence of arsenic and other organic compounds such as piperine. The in vivo developmental toxicity was observed in Zebrafish hampered growth and survival in a dose and time dependent manner. The formulation was safe at lower concentration and exhibit a dose and time dependent toxicity. Based on the results obtained, it is confirmed that the selective toxicity towards MCF-7 cells is promising to develop an effective formulation for the treatment of cancer, provided more such proofs obtained from in vivo experiments.
Yu Nie, Shang-Fu Xu, Yan-Liu Lu, Xiu-Rong Zhao, Cen Li, Li-Xin Wei,
Published: 11 March 2021
Journal: F1000Research
Abstract:
Background: Zuotai (mainly β-HgS)-containing 70 Wei-Zhen-Zhu-Wan (70W, Rannasangpei) is a famous Tibetan medicine for treating cardiovascular and gastrointestinal diseases. We have shown that 70W protected against CCl4 hepatotoxicity. CCl4 is metabolized via cytochrome P450 (CYP) to produce reactive metabolites. Whether 70W has any effect on CYPs is unknown and such effects should be compared with mercury compounds for safety evaluation. Methods: Mice were given clinical doses of 70W (0.15-1.5 g/kg, po), Zuotai (30 mg/kg, po), and compared to HgCl2 (33.6 mg/kg, po) and MeHg (3.1 mg/kg, po) for seven days. Liver RNA and protein were isolated for qPCR and Western-blot analysis. Results: 70W and Zuotai had no effects on hepatic mRNA expression of Cyp1a2, Cyp2b10, Cyp3a11, Cyp4a10 and Cyp7a1, and corresponding nuclear receptors [aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor-α (PPARα); farnesoid X receptor (FXR)]. In comparison, HgCl2 and MeHg increased mRNA expression of Cyp1a2, Cyp2b10, Cyp4a10 and Cyp7a1 except for Cyp3a11, and corresponding nuclear receptors except for PXR. Western-blot confirmed mRNA results, showing increases in CYP1A2, CYP2B1, CYP2E1, CYP4A and CYP7A1 by HgCl2 and MeHg only, and all treatments had no effects on CYP3A. Conclusions: Zuotai and Zuotai-containing 70W at clinical doses had minimal influence on hepatic CYPs and corresponding nuclear receptors, while HgCl2 and MeHg produced significant effects. Thus, the use of total Hg content to evaluate the safety of HgS-containing 70W is inappropriate.
Jieyu Zuo, Chulhun Park, Janice Yu Chen Kung, Nádia Araci Bou-Chacra, Michael Doschak,
Published: 18 February 2021
Pharmaceutical Research, Volume 38, pp 199-211; https://doi.org/10.1007/s11095-021-03007-x

Abstract:
Currently, the use of Traditional Chinese Medicine (TCM) for healthy living in daily practice is widely accepted across the world. However, not much attention has been paid to the particular characteristics of TCM “pills”, one of the classic dosage forms in TCM. For a better understanding, this review was undertaken to provide a modern pharmaceutical overview of pills. Over many centuries, pills have been developed in different types (honeyed pill, water-honeyed pill, watered pill, pasted pill, waxed pill, concentrated pill, and dripping pill) to achieve varying intended TCM release patterns. It suggests that knowledge relating to the impact of binders and excipients on drug release from TCM pills can be traced back to before dissolution testing was invented. Therefore, although Pills may be considered as an ancient and outdated dosage form compared to current drug delivery systems, they have surprisingly modern pharmaceutical properties that is highlighted in this article. In addition, this review found that the quality control standards for TCM pill are globally substantially different. Hence, greater effort should be taken to establish an internationally harmonized and proper standard to safeguard the quality of this dosage form and to ensure the alignment with TCM use.
Ping Yang, Haifeng He, Shangfu Xu, ,
Evidence-Based Complementary and Alternative Medicine, Volume 2020, pp 1-12; https://doi.org/10.1155/2020/8872593

Abstract:
Objective. Hua-Feng-Dan (HFD) is a Chinese medicine for stroke. This study is to predict and verify potential molecular targets and pathways of HFD against stroke using network pharmacology. Methods. The TCMSP database and TCMID were used to search for the active ingredients of HFD, and GeneCards and DrugBank databases were used to search for stroke-related target genes to construct the “component-target-disease” by Cytoscape 3.7.1, which was further filtered by MCODE to build a core network. The STRING database was used to obtain interrelationships by topology and to construct a protein-protein interaction network. GO and KEGG were carried out through DAVID Bioinformatics. Autodock 4.2 was used for molecular docking. BaseSpace was used to correlate target genes with the GEO database. Results. Based on OB ≥ 30% and DL ≥ 0.18, 42 active ingredients were extracted from HFD, and 107 associated targets were obtained. PPI network and Cytoscape analysis identified 22 key targets. GO analysis suggested 51 cellular biological processes, and KEGG suggested that 60 pathways were related to the antistroke mechanism of HFD, with p53, PI3K-Akt, and apoptosis signaling pathways being most important for HFD effects. Molecular docking verified interactions between the core target (CASP8, CASP9, MDM2, CYCS, RELA, and CCND1) and the active ingredients (beta-sitosterol, luteolin, baicalein, and wogonin). The identified gene targets were highly correlated with the GEO biosets, and the stroke-protection effects of Xuesaitong in the database were verified by identified targets. Conclusion. HFD could regulate the symptoms of stroke through signaling pathways with core targets. This work provided a bioinformatic method to clarify the antistroke mechanism of HFD, and the identified core targets could be valuable to evaluate the antistroke effects of traditional Chinese medicines.
, Shanshan Zhang, Wenqing Jiang, Shuo Xu,
Evidence-Based Complementary and Alternative Medicine, Volume 2020, pp 1-7; https://doi.org/10.1155/2020/8380473

Abstract:
Objective. To investigate the influence of gut microbiota on arsenic accumulation of realgar in mice. Methods. Mice were treated with antibiotics to form a mouse model of gut microbial disruption. Antibiotic-treated and normally raised mice were given 15 mg/kg, 150 mg/kg, and 750 mg/kg realgar by gavage and 0.2 mg/kg and 1 mg/kg arsenic solution by subcutaneous injection for 7 days. The concentration of arsenic in mice whole blood was determined by inductively coupled plasma mass spectrometry (ICP-MS). Arsenic accumulation in antibiotic-treated mice and normally raised mice was compared. Results. After exposure to low dose (15 mg/kg) and middle dose (150 mg/kg) of realgar, significantly, more arsenic was accumulated in the whole blood of antibiotic-treated mice compared to normally raised counterparts, which indicated that the disruption of gut microbiota could lead to higher arsenic load of realgar in mice. The homeostasis of gut microbiota was supposed to be disrupted by high dose (750 mg/kg) of realgar because after exposure to high dose of realgar, there was no significant difference in arsenic accumulation between antibiotic-treated and normally raised mice. Furthermore, arsenic solution was administered by subcutaneous injection to mice to investigate the influence of gut microbial differences on arsenic accumulation in addition to the absorption process, and there was no significant difference in arsenic accumulation between mice with these two different statuses of gut microbiota. Conclusions. Gut microbiota disruption could increase arsenic accumulation of realgar in mice.
Lujing Geng, Zhenghua Xia, Lu Yuan, Cen Li, Ming Zhang, Yuzhi Du, Lixin Wei,
Published: 8 July 2020
Journal: Metallomics
Metallomics, Volume 12, pp 1389-1399; https://doi.org/10.1039/d0mt00088d

Abstract:
Traditional Tibetan medicines containing β-HgS have been used to treat chronic ailments for thousands of years. However, there has recently been speculation regarding the safety of these medicines due to their high mercury content. Although the toxic effect of β-HgS has been previously investigated in vivo, the mechanism underlying the toxicity of this compound remains unclear. In this study, we investigate the mechanism of β-HgS cytotoxicity via experiments performed on rat adrenal gland tumor cells (PC-12). Specifically, we analyze the viability and intracellular oxidative stress state of PC-12 cells treated with varying concentrations of β-HgS. For comparison purposes, the effects of MeHgCl and HgCl2, two Hg-based compounds, on ROS generation and MDA, GSH/GSSG, Nrf2, NQO-1, and HO-1 levels are also determined. It should be noted that we used the small-molecule thiols of cell culture medium, such as cysteine, to increase the solubility of β-HgS and prepare a β-HgS solution to treat PC-12 cells. The obtained results show that β-HgS inhibits cell viability at concentrations of 200–1000 ng Hg mL−1 (48 h treatment). In the concentration range of 200–600 ng Hg mL−1 (24 h treatment), the inhibitory effect of β-HgS is stronger than that of MeHgCl; however, this trend is reversed at higher concentrations (800–1000 ng mL−1) and longer exposure times (48 h). Moreover, β-HgS significantly promotes MDA, but has no appreciable influence on cell apoptosis and ROS generation in PC-12 cells, which suggests that its inhibitory effect on cell viability might be related to the stimulation of ROS-independent oxidative stress. Notably, β-HgS and HgCl2 significantly increase the GSH content, GSH/GSSG ratio, NQO-1 mRNA expression, and HO-1 protein expression in PC-12 cells, indicating that the antioxidant protection against these compounds is triggered by Nrf2 activation. HPLC-AFS analysis shows that in β-HgS and HgCl2 solutions, mercury exists in the same form of Hg2+, but the cytotoxicity of the former is greater. This is probably due to the additional oxidative damage induced by the S2− ion in β-HgS. In conclusion, β-HgS induces ROS-independent oxidative stress in PC-12 cells, and thus, is obviously cytotoxic. At the same time, it promotes the antioxidant capacity of cells by activating the Nrf2 pathway.
Dan Zhang, Bing Zhang, Jin-Tao Lv, Ri-Na Sa, Xiao-Meng Zhang, Zhi-Jian Lin
Published: 5 May 2020
Pharmacological Research, Volume 157, pp 104882-104882; https://doi.org/10.1016/j.phrs.2020.104882

Abstract:
The outbreak of emerging infectious pneumonia caused by 2019 Novel Coronavirus (2019-nCoV) has posed an enormous threat to public health, and traditional Chinese medicine (TCM) have made vast contribution to the prevention, treatment and rehabilitation of coronavirus disease 19 (COVID-19) among Chinese population. As an indispensable part of TCM, Chinese patent medicines (CPMs) are highly valued and critically acclaimed in their campaign to contain and tackle the epidemic, they can achieve considerable effects for both suspected cases under medical observation period, and confirmed individuals with serious underlying diseases or critical conditions. Given this, based on the Guideline on Diagnosis and Treatment of Coronavirus Disease 2019 in China, the present review summarized the basic information, clinical evidence and published literatures of recommended CPMs against COVID-19. The details were thoroughly introduced involving compositions, therapeutic effects, clinical indications, medication history of CPMs and the profiles of corresponding research. With regard to infected patients with different stages and syndrome, the preferable potentials and therapeutic mechanism of CPMs were addressed through the comprehensive collection of relevant literatures and on-going clinical trials. This study could provide an insight into clinical application and underlying mechanism of recommended CPMs against COVID-19, with the aim to share the Chinese experience in clinical practice and facilitate scientific development of TCM, especially CPMs in the fierce battle of COVID-19.
Mimi Yang, Lichao Wang, Tao Zhang, An Zhu, Yuqing Sun, Jingwei Zhao, Dan Liu, ,
Published: 1 May 2020
Journal of Ethnopharmacology, Volume 253; https://doi.org/10.1016/j.jep.2020.112668

Abstract:
Cinnabar, a traditional Chinese mineral medicine with sedative and tranquilizing effects, is known to be toxic to the neural system, but its detailed pharmacological and toxicological mechanisms are still unclear. This study aimed to explore the potential neuropharmacological and neurotoxicological mechanisms of cinnabar by investigating the differentially expressed proteins in cerebral cortices of mice exposed to therapeutic and toxic doses of cinnabar. Label-free quantitative proteomics and bioinformatics analysis were used to characterize the proteins, pathways, and potential targets associated with therapeutic (50 mg/kg) and toxic (1000 mg/kg) doses of cinnabar in cerebral cortices of mice. Proteomic analysis was verified by parallel reaction monitoring. A total of 6370 and 6299 proteins were identified in the cerebral cortices of mice after exposure to therapeutic and toxic doses of cinnabar, among which 130 and 119 proteins were differentially expressed, respectively. Functional/pathway enrichment analysis showed that both exposure doses of cinnabar could affect transport processes in the cerebral cortex through different proteins. The changes induced by the therapeutic dose included pathways involved in translation and sphingolipid metabolism. Interestingly, for the toxic dose, differentially expressed proteins were enriched for functions and pathways related to RNA splicing, transcription, synaptic plasticity regulation and developmental processes, among which RNA splicing was the most significantly affected function. ATP6V1D and CX3CL1 were shown to be possible key proteins affected by cinnabar, leading to multiple functional changes in the cerebral cortex at the therapeutic and toxic doses, respectively. Furthermore, Connectivity Map (CMap) analysis predicted LRRK2 to be a potential therapeutic target and FTase to be a potential toxic target for cinnabar. Our results suggest that the pathways and potential targets identified in the mouse cerebral cortex exposed to therapeutic and toxic doses of cinnabar are different, which provides novel insights into the potential molecular mechanisms underlying the pharmacological and toxicological effects of cinnabar.
, O. Shpotyuk, , P. Demchenko, E. Dutková, E. Tóthová, Z. Bártová
Published: 27 March 2020
Applied Nanoscience, Volume 10, pp 4651-4660; https://doi.org/10.1007/s13204-020-01345-7

The publisher has not yet granted permission to display this abstract.
, A. Martínez-Benítez, M. Meléndez-Lira, I. Ceja-Andrade, A. Chávez-Chávez, A. Pérez-Centeno, ,
Journal of Materials Science: Materials in Electronics, Volume 31, pp 4611-4617; https://doi.org/10.1007/s10854-020-03013-6

The publisher has not yet granted permission to display this abstract.
, Shuo Xu, Shanshan Zhang, Xuejun Wu,
Evidence-Based Complementary and Alternative Medicine, Volume 2019, pp 1-8; https://doi.org/10.1155/2019/8496817

Abstract:
Niuhuang Jiedu tablet (NJT), a realgar (As2S2) containing Traditional Chinese Medicine (TCM), is a well-known formula. The safety of NJT is of growing concern since arsenic (As) is considered as one of the most toxic elements. NJT was demonstrated to be safer than realgar by our previous experiments and some other studies. The toxicity of realgar has been shown to be related to the amount of soluble or bioaccessible arsenic. In this study, the influences of the other TCMs in NJT on the bioaccessibility of arsenic from realgar, and the roles of gut microbiota during this process were investigated in vitro. Results showed that Dahuang (Rhei Radix et Rhizoma), Huangqin (Scutellariae Radix), Jiegeng (Platycodonis Radix), and Gancao (Glycyrrhizae Radix et Rhizoma) could significantly reduce the bioaccessibility of arsenic from realgar in artificial gastrointestinal fluids. Gut microbiota played an important role in decreasing the bioaccessibility of realgar because it was demonstrated to be able to absorb the soluble arsenic from realgar in the incubation medium. Dahuang, Huangqin, and Jiegeng could modulate the gut microbiota to enhance its arsenic absorption activity.
Qing Wu, Xi He, Shaojun Zhou, ,
Published: 12 December 2019
Toxicology in Vitro, Volume 63; https://doi.org/10.1016/j.tiv.2019.104747

Abstract:
Cinnabar, a mercury-containing mineral medicine, has been used as an ingredient in Traditional Chinese Medicines for treatment of various diseases for thousands of years and is still widely used today. The toxicity of cinnabar is much less than other mercury-containing compounds. This study aimed to evaluate the possible role of oligopeptide transporter1 (PEPT1) in intestinal uptake of cinnabar. Thus, the Caco-2 cell model was employed to investigate the differential transport levels and the probable transporter involved in the transport of cinnabar, mercury sulfide (HgS) and mercury chloride (HgCl2). Cells were incubated with the same molar concentration of cinnabar, HgS or HgCl2 and then the inorganic mercury content of apical (AP), cellular and basolateral (BL) side of the cell was measured by ultra-high liquid chromatography-inductively coupled plasma mass spectrometry (UPLC-ICP/MS) after the treatment, respectively. Their transportation levels were also investigated when pH was changed to 5.5 in AP side to define the role of the H+ dependent transporter. Effects of cinnabar, HgS or HgCl2 on transporter mRNA and protein expression levels were assayed by RT-PCR and Western-blot method, respectively. The possible transporter involved in the transport was examined by siRNA silencing and chemical inhibition. The results showed that the levels of inorganic mercury in the BL side for cinnabar and HgS were 49.39% and 30.41% of that in HgCl2 group. The transport levels of cinnabar and HgCl2 were significantly increased when the pH was changed to 5.5 on the AP side as compared with the control group (pH 7.4). Cinnabar significantly decreased the mRNA and protein expression of PEPT1. Transport levels of cinnabar were significantly decreased by PEPT1-siRNA and chemical inhibition of PEPT1. The present study demonstrates that PEPT1 may be an important transporter in the entry of cinnabar into the intestinal epithelium, and intestinal transport levels of cinnabar and HgS was lower than that of HgCl2.
Xiao Wu, Rong Guan, Yuexin Liu, Shanhu Wu, ,
Published: 1 November 2019
Journal of Ethnopharmacology, Volume 249; https://doi.org/10.1016/j.jep.2019.112370

Abstract:
Realgar (As2S2), a mineral traditional Chinese medicine (TCM), is proved to have great therapeutic effects in clinic and has been widely used in China for hundreds of years. As one of the most popular realgar-containing TCMs, NiuHuangJieDu Tablets (NHJDT) is used as OTC (over-the-counter) drug in daily life for fever relieving, detoxicating, as well as cure of sore throat and gingival swelling. However, the safety of realgar and its-containing TCMs still remains unclear.
Ce Chen, Bin-Bin Zhang, An-Ling Hu, Huan Li, , Feng Zhang
Published: 10 October 2019
Journal of Ethnopharmacology, Volume 247; https://doi.org/10.1016/j.jep.2019.112299

The publisher has not yet granted permission to display this abstract.
, Songlin Wang, Chong Gao, Yunhao Luo, Wenting Li, Dan Yang, Depo Yang,
Published: 14 June 2019
Toxicology and Applied Pharmacology, Volume 377; https://doi.org/10.1016/j.taap.2019.114613

The publisher has not yet granted permission to display this abstract.
, Audrey Alderman, Ashley McKenzie, Rebecka Brasso, Alison R. Taylor, María Molina Moreno, Oscar Cambra-Moo, Armando González Martín, , , et al.
Published: 11 June 2019
Journal of Archaeological Science, Volume 108; https://doi.org/10.1016/j.jas.2019.05.005

The publisher has not yet granted permission to display this abstract.
Bin-Bin Zhang, Yong-Mei Liu, An-Ling Hu, Shang-Fu Xu, Li-Da Fan, Ming-Liang Cheng, , Li-Xin Wei,
Published: 6 June 2019
Toxicology and Applied Pharmacology, Volume 379; https://doi.org/10.1016/j.taap.2019.114615

Abstract:
Mercury (Hg) is generally considered as a toxic metal; yet the biological outcomes of Hg-containing compounds are highly dependent upon their chemical forms. We hypothesize that mercury sulfide (HgS) is different from HgCl2 and methylmercury (MeHg) in producing intestinal Hg absorption and disruption of gut microbiome. To test this hypothesis, mice were given orally with HgS (α-HgS, 30 mg/kg), Zuotai (β-HgS, 30 mg/kg), HgCl2 (33.6 mg/kg, equivalent Hg as HgS), or MeHg (3.1 mg/kg, 1/10 Hg as HgS) for 7 days. Accumulation of Hg in the duodenum and ileum after HgCl2 (30–40 fold) and MeHg (10–15 fold) was higher than HgS and Zuotai (~2-fold). HgCl2 and MeHg decreased intestinal intake peptide transporter-1 and Ost-β, and increased ileal bile acid binding protein and equilibrative nucleoside transporter-1. The efflux transporters ATP-binding cassette sub-family C member-4 (Abcc4), Abcg2, Abcg5/8, and Abcb1b were increased by HgCl2 and to a lesser extent by MeHg, while HgS and Zuotai had minimal effects. Bacterial DNA was extracted and subjected to 16S rDNA sequencing. Operational taxonomic unit (OTU) results showed that among the 10 phyla, HgS increased Firmicutes, Proteobacteria, while HgCl2 increased Bacteroidetes, Cyanobacteria and decreased Firmicutes; among the 79 families, HgS increased Rikenellaceae, Lactobacillaceae, Helicobacteraceae, and decreased Prevotellaceae, while HgCl2 increased Odoribacteraceae, Porphyromonadaceae, and decreased Lactobacillaceae; among the 232 genus/species, HgS and Zuotai affected gut microbiome quite differently from HgCl2 and MeHg. qPCR analysis with 16S rRNA confirmed sequencing results. Thus, chemical forms of mercury are a major determinant for intestinal Hg accumulation, alterations in transporters and disruption of microbiome.
Published: 18 March 2019
by MDPI
International Journal of Molecular Sciences, Volume 20; https://doi.org/10.3390/ijms20061364

Abstract:
This study aims to reveal the potential relationship between 5-HT and oxidative stress in the organism. Our in vitro experiments in RIN-14B cells showed that anoxia leads the cells to the state of oxidative stress. Administration of exogenous 5-HT exacerbated this effect, whereas the inhibition of Tph1, LP533401 alleviated the oxidative stress. Several research articles reported that Cinnabar (consists of more than 96% mercury sulfide, HgS), which is widely used in both Chinese and Indian traditional medicine prescriptions, has been involved in the regulation of 5-HT. The present research revealed that HgS relieved the level of oxidative stress of RIN-14B cells. This pharmacological activity was also observed in the prescription drug Zuotai, in which HgS accounts for 54.5%, and these effects were found to be similar to LP533401, an experimental drug to treat pulmonary hypertension. Further, our in vivo experiments revealed that the administration of cinnabar or prescription drug Zuotai in zebrafish reduced the reactive oxygen species (ROS) induced by hypoxia and cured behavioral abnormalities. Taken together, in organisms with hypoxia induced oxidative stress 5-HT levels were found to be abnormally elevated, indicating that 5-HT could regulate oxidative stress, and the decrease in the 5-HT levels, behavioral abnormalities after treatment with cinnabar and Zuotai, we may conclude that the therapeutic and pharmacologic effect of cinnabar and Zuotai may be based on the regulation of 5-HT metabolism and relief of oxidative stress. Even though they aren’t toxic at the present dosage in both cell lines and zebrafish, their dose dependent toxicities are yet to be evaluated.
, , Velagapudi Ravikanth, , ,
Evidence-Based Complementary and Alternative Medicine, Volume 2019, pp 1-13; https://doi.org/10.1155/2019/1697804

Abstract:
Minerals are alchemically processed as Bhasmas in Ayurvedic medicines or as Zuotai in Tibetan medicines. Ayurveda is a knowledge system of longevity and considers the mineral elixir made from “nature” capable of giving humans perpetual life. Herbo-metallic preparations have a long history in the treatment of various diseases in India, China, and around the world. Their disposition, pharmacology, efficacy, and safety require scientific evaluation. This review discusses the Bhasmas in Ayurvedic medicines and Zuotai in Tibetan medicines for their occurrence, bioaccessibility, therapeutic use, pharmacology, toxicity, and research perspectives. A literature search on Mineral, Bhasma, Ayurvedic medicine, Zuotai, Tibetan medicine, and Metals/metalloids from PubMed, Google and other sources was carried out, and the relevant papers on their traditional use, pharmacology, and toxicity were selected and analyzed. Minerals are processed to form Bhasma or Zuotai to alter their physiochemical properties distinguishing them from environmental metals. The metals found in Ayurveda are mainly from the intentional addition in the form of Bhasma or Zuotai. Bhasma and Zuotai are often used in combination with other herbals and/or animal-based products as mixtures. The advanced technologies are now utilized to characterize herbo-metallic preparations as Quality Assurance/Quality Control. The bioaccessibility, absorption, distribution, metabolism, and elimination of herbo-metallic preparations are different from environmental metals. The pharmacological basis of Bhasma in Ayurveda and Zuotai in Tibetan medicines and their interactions with drugs require scientific research. Although the toxic potentials of Bhasma and Zuotai differ from environmental metals, the metal poisoning case reports, especially lead (Pb), mercury (Hg), and arsenic (As) from inappropriate use of traditional medicines, are increasing, and pharmacovigilance is desired. In risk assessment, chemical forms of metals in Bhasma and Zuotai should be considered for their disposition, efficacy, and toxicity.
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