Angelicin: A leading culprit involved in fructus Psoraleae liver injury via inhibition of VKORC1.

ETHNOPHARMACOLOGICAL RELEVANCE: The adverse effects of Fructus Psoraleae (FP), especially liver injury, have attracted wide attention in recent years. AIM OF THE STUDY: To establish a system to explore potential hepatotoxic targets and the chief culprit of liver injury based on clinical experience, network pharmacological method, molecular docking, and in vitro and in vivo experiments. MATERIALS AND METHODS: Clinical applications and adverse reactions to FP were obtained from public literatures. Components absorbed in the blood were selected as candidates to search for potential active targets (PATs) of FP. Subsequently, potential pharmacological core targets (PPCTs) were screened through the "drug targets-disease targets" network. Non-drug active targets (NPATs) were obtained by subtracting the PPCTs from the PATs. The potential hepatotoxic targets (PHTs) of FP were the intersection targets obtained from Venn analysis using NPATs, hepatotoxic targets, and adverse drug reaction (ADR) targets provided by the databases. Then, potential hepatotoxic components and targets were obtained using the "NPATS-component" network relationship. Molecular docking and in vitro and in vivo hepatotoxicity experiments were performed to verify the targets and related components. RESULTS: Overall, 234 NPATs were acquired from our analysis, and 6 targets were identified as PHTs. Results from molecular docking and in vitro and in vivo experiments showed that angelicin is the leading cause of liver injury in FP, and VKORC1 plays an important role. CONCLUSION: The results indicate that six targets, especially VKORC1, are associated with the PHTs of FP, and angelicin is the leading culprit involved in FP liver injury via inhibition of VKORC1.

Ameliorative effect of cheqianzi decoction on hyperuricemia and kidney injury and underlying mechanism in rats.

Cheqianzi Decoction (CQD) is a Traditional Chinese Medicine (TCM) formula comprising four herbs and is recorded in the Ancient Materia Medica "Shengji Zonglu". Individually, these four herbs have been shown to reduce uric acid (UA) levels, to treat hyperuricemia (HUA), and alleviate kidney damage. However, the therapeutic efficacy of the CQD and related mechanism are not yet clear. In this study, high performance liquid chromatography (HPLC) analysis confirmed that the contents of the chemical components of the four herbal medicines were in accordance with the provisions of the Chinese Pharmacopoeia. A total of 99 potential targets were identified in the network pharmacology analysis of CQD, indicating its involvement in the regulation of inflammatory and apoptotic signaling pathways, and potential value for treating HUA and alleviating kidney injury. In vivo pharmacodynamic studies showed that compared with the Model group, significantly decreased levels of serum uric acid (SUA), serum creatinine (SCr), blood urea nitrogen (BUN) (all P < 0.05), and inflammatory factors (P < 0.01) were detected in the CQD group. Quantitative real-time PCR and Western blot analyses showed that compared with the Model group, adenosine triphosphate (ATP)-binding cassette efflux transporter G2 (ABCG2) expression in the CQD group was significantly upregulated (P < 0.01) at both the mRNA and protein levels, while mRNA expression of Caspase3 and NOD-like receptor family member 3 (NLRP3) (P < 0.05) and protein expression of NLRP3 (P < 0.01) were significantly downregulated. In conclusion, CQD promotes UA excretion by activating ABCG2, and induces inflammasome NLRP3-mediated reduction in inflammatory and apoptotic factors to achieve renal protection. Thus, our findings indicate the therapeutic potential of CQD in HUA with kidney injury.

Study on the difference and correlation between the contents and toxicity of aristolochic acid analogues in Aristolochia plants.

ETHNOPHARMACOLOGICAL RELEVANCE: The nephrotoxicity and carcinogenicity induced by traditional Chinese medicines (TCMs) containing aristolochic acids (AAs) and related compound preparations have greatly limited their clinical application. While the toxicity of AA-I and AA-II is relatively clear, there are marked differences in the toxic effects of different types of aristolochic acid analogues (AAAs). Thus, the toxicity of TCMs containing AAAs cannot be evaluated based on the toxicity of a single compound. AIM OF THE STUDY: To systematically investigate the toxicity induced by Zhushalian (ZSL), Madouling (MDL) and Tianxianteng (TXT) as representative TCMs derived from Aristolochia. MATERIALS AND METHODS: AAA contents in ZSL, MDL and TXT were determined using HPLC. Subsequently, mice were treated for 2 weeks with high (H) and low (L) dosages of TCMs containing total AAA contents of 3 mg/kg and 1.5 mg/kg, respectively. Toxicity was evaluated using biochemical and pathological examination and was based on organ indices. Correlations between AAA contents and induced toxicity were analysed using multiple methods. RESULTS: Of the total AAA content, ZSL contained mainly AA-I and AA-II (>90%, of which AA-I accounted for 49.55%). AA-I accounted for 35.45% in MDL. TXT mainly contained AA-IVa (76.84%) and other AAAs accounted for <10%. Short-term toxicity tests indicated that ZSL and high-dose MDL induced obvious renal interstitial fibrosis and gastric injury, whereas TXT (high and low dosages) caused only slight toxicity. Correlation analysis suggested that AA-I might be the critical hazard factor for toxicity. CONCLUSIONS: The toxicity of TCMs containing AAAs cannot be generalised. The toxicity of TXT is relatively low compared with those of ZSL and MDL. The toxicity of Aristolochia depends mainly on the AA-I content; therefore, control of AA-I levels in TCMs and related compound preparations is required to reduce the risk of toxicity associated with the use of Aristolochia herbs in clinical settings.

Differences in p38-STAT3-S100A11 signaling after the administration of aristolochic acid I and IVa may account for the disparity in their nephrotoxicity.

BACKGROUND: The safety of herbs containing aristolochic acids (AAs) has become a widespread concern. Previous reports indicate that AAs are highly nephrotoxic and carcinogenic, although there are more than 170 analogues of aristolochic acid. Not all AAs have the same degree of nephrotoxicity or carcinogenicity. Previous studies have found that aristolochic acid IVa (AA-IVa), the principal component of AAs within members of the Aristolochiaceae family, especially Asarum, a commonly used herb in China, has essentially no significant nephrotoxicity. However, several studies, including ours, have shown that aristolochic acid I (AA-I) is clearly nephrotoxic. PURPOSE: The focus of the study was to elucidate the molecular mechanism responsible for the difference in nephrotoxicity between the AA-I and AA-IVa. STUDY DESIGN/METHOD: Mice were administered with AA-I or AA-IVa for 22 weeks through the oral route, followed by a 50-week recovery time. The kidney tissues of mice were extracted at the end of 22 weeks. Pathological examination and proteomic detection (tandem mass tagging (TMT) and phosphorylated proteomics) were performed on the kidney tissue to investigate the key signaling pathways and targets of AAs-induced renal interstitial fibrosis (RIF). The key signaling pathways and targets were verified by Western blot (WB), siRNA transfection, and luciferase assays. RESULTS: AA-I caused severe nephrotoxicity, high mortality, and extensive RIF. However, the same AA-IVa dosage exhibited almost no nephrotoxicity and does not trigger RIF. The activation of the p38-STAT3-S100A11 signaling pathway and upregulated expression of α smooth muscle actin (α-SMA) and Bcl2-associated agonist of cell death (Bad) proteins could be the molecular mechanism underlying AA-I-induced nephrotoxicity. On the other hand, AA-IVa did not regulate the activation of the p38-STAT3-S100A11 signaling pathway and had relatively little effect on the expression of α-SMA and Bad. Consequently, the difference in the regulation of p38-STAT3-S100A11 pathway, α-SMA, and Bad proteins between AA-I and AA-IVa may be responsible for the divergence in their level of nephrotoxicity. CONCLUSION: This is the first study to reveal the molecular mechanism underlying the difference in nephrotoxicity between AA-I and AA-IVa. Whether STAT3 is activated or not may be the key factor leading to the difference in nephrotoxicity between AA-I and AA-IVa.

Involvement of p38 MAPK/cPLA2 and arachidonic acid metabolic pathway in Shengmai injection-induced pseudo-allergic reactions.

ETHNOPHARMACOLOGICAL RELEVANCE: Adverse reactions to traditional Chinese medicine injections involve pseudo-allergic reactions (PARs). However, in clinical practice, "immediate allergic reactions" and PARs in response to these injections are not often differentiated. AIM OF THE STUDY: This study aimed to clarify the type of reactions produced by Shengmai injections (SMI) and elucidate the possible mechanism. MATERIALS AND METHODS: A mouse model was used to evaluate vascular permeability. Metabolomic and arachidonic acid metabolite (AAM) analyses were performed using UPLC-MS/MS, and the p38 MAPK/cPLA2 pathway was detected by western blotting. RESULTS: The first exposure to intravenous SMI rapidly and dose-dependently induced edema and exudative reactions in the ears and lungs. These reactions were not IgE-dependent and were likely to be PARs. Metabolomic analysis showed that endogenous substances were perturbed in SMI-treated mice, in which the arachidonic acid (AA) metabolic pathway was the most affected. SMI substantially increased the levels of AAMs in lung, including prostaglandins (PGs), leukotrienes (LTs), and hydroxy-eicosatetraenoic acids (HETEs). The p38 MAPK/cPLA2 signaling pathway was activated after a single SMI dose. Inhibitors of cyclooxygenase-2 and 5-lipoxygenase enzymes reduced exudation and inflammation in the ears and lungs of mice. CONCLUSION: Production of inflammatory factors that increase vascular permeability may result in SMI-induced PARs, and p38 MAPK/cPLA2 signaling pathway and downstream AA metabolic pathway are involved in the reactions.

Long-term oral administration of Asarum heterotropoides f. mandshuricum (Maxim.) Kitag. decoction and its aristolochic acid analogs do not cause renal toxicity in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Asarum heterotropoides f. mandshuricum (Maxim.) Kitag. (AH) is widely used to treat influenza, COVID-19, allergic rhinitis, headache, toothache, rheumatoid arthritis, and peptic ulcer. However, its clinical use is controversial due to the concern of aristolochic acid nephropathy (AAN) caused by its component aristolochic acid analogs (AAs). AIM OF THE STUDY: The chronic toxicity of AH decoction and its main components AA IVa (AA-IVa) and aristolactam I (AL-I) was evaluated in mice. MATERIALS AND METHODS: AAs contents in AH were quantitated by liquid chromatography-mass spectrometry. A parallel design was employed to examine the potential chronic toxicity of AH decoction at doses equivalent to 0.5, 1.6, and 5.0 g/kg AH (approximately 10-100 times the clinical doses for humans) and its major AA components at doses equivalent to that in 5.0 g/kg AH to mice after consecutive daily oral administration for 12 and 24 weeks, and at 32 weeks after withdrawal for 8 weeks. RESULTS: AH crude herb contained 2.18 µg/g of AA-I, 48.49 µg/g of AA-IVa, and 14.0 µg/g of AL-I. AH decoction contained 5.45 µg/g of AA-IVa and 2.71 µg/g of AL-I. None of AA-II and AA-IIIa were detected in AH. After long-term administration of AH decoction and its major components AA-IVa and AL-I, mice showed no signs of illness or body weight changes. In addition, biochemical and pathohistological examinations showed that long-term administration of AH decoction and its major components AA-IVa and AL-I did not alter 1) serum levels of glutamic-pyruvic transaminase, glutamic oxalacetic transaminase, alkaline phosphatase, creatinine, and urea nitrogen, 2) renal tissue mRNA expression of kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin, and 3) pathological morphology in the mouse liver, kidney, stomach, and bladder. CONCLUSIONS: AH has no obvious toxicity to mice and is relatively safe when it is used in the form of decoction. AA-IVa and AL-I, the two major AAs in AH, are not toxic to mice at the dose equivalent to that in the high dose of AH decoction. Considering the limited toxicological data on AH, we recommend that AH decoction medication should not overdose and the duration should not be too long.

Studies on the metabolism and mechanism of acteoside in treating chronic glomerulonephritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Acteoside (ACT) is the main ingredient derived from the leaves of Rehmannia glutinosa (Dihuangye). Dihuangye has the function of clearing heat, replenishing qi and activating blood, nourishing yin and tonifying kidney in traditional Chinese medicine. Recent studies have demonstrated that Dihuangye can be used to treat nephritis and ACT is a promising antinephritic agent. AIM OF THE STUDY: To clarify the metabolites of ACT in biological samples and investigate the renoprotective effect and mechanism of ACT in rats with chronic glomerulonephritis (CGN). MATERIALS AND METHODS: In this study, the biotransformation of ACT in rat biological samples was clarified by quadrupole time-of-flight tandem mass spectrometry. The metabolites were validated by urine samples in nephropathy model rats. The effect of ACT and its metabolites was evaluated by glomerular podocyte injury due to high glucose. Based on an analysis of the ingredients in vivo, the potential therapeutic targets in the treatment of CGN were investigated by using network pharmacological analysis and molecular docking. Then, the renoprotective effect and mechanism of ACT were determined in rats in a passive Heymann nephritis (PHN) model. RESULTS: A total of 49 metabolites of ACT were detected and identified. Meanwhile, 21 metabolites were detected in nephropathy model rats. ACT was absorbed rapidly and transferred from the kidney, and the metabolites were eliminated via urine. The whole process lasted approximately 8 h. ACT had a significant protective effect on glomerular podocytes damaged by high glucose and 3,4-dihydroxyphenylacetic acid might be the main metabolite of ACT underlying its functions in vivo. The network pharmacology and molecular docking results showed 84 ACT-CGN targets, among which MAPK1, HRAS, AKT1, EGFR, and others were a highly correlated. In the PHN rat model, ACT significantly reduced the 24-h urine protein and serum creatinine concentrations, suppressed the leukocyte CD18 expression levels, decreased the serum tumor necrosis factor α (TNF-α) levels and tended to reduce serum interleukin 6 (IL-6) levels. ACT significantly reduced the platelet aggregation rate and inhibited the proliferative activity of splenic lymphocytes in response to the mitogen concanavalin A. Meanwhile, ACT inhibited transforming growth factor-ß and fibronectin expression in renal tissues and dose-dependently inhibited TNF-α and IL-6 production in RAW264.7 mouse macrophages at doses ranging from 1.8 to 1330 µg/mL. CONCLUSIONS: ACT had therapeutic effects on PHN rats, and its mechanism might be related to the inhibition of intercellular or intercellular-matrix adhesion, suppression of inflammatory response, regulation of immune function, improvement of tissue hemodynamics and hemorheology, and relief of fibrotic lesions.

[A novel mouse allergy tested model and its application for traditional Chinese medicine injections's allergy evaluation].

When the drug induces the organism to produce a type Ⅰ allergic reaction, the combination of IgE and mast cells results in the degranulation of the mast cells. Release of vasoactive substances, increase in vascular permeability, and exudation of intravascular substances outside the blood vessels. Based on this pathophysiological mechanism, a mouse model that can objectively and quantitatively assess the allergic response to the injection has been established. ICR mice were sensitised by intraperitoneal injection of different doses of OVA once every two days for three times. 14 days after the last sensitization, a combination OVA solution of 4 times the sensitizing dose and Evans blue were injected intravenously into mice for the challenge. Compared with the normal group, OVA 0.625/2.5, 1.25/5, 2.5/10, 5/20 mg·kg~(-1) sensitized and challenged can induce allergic reactions mainly manifested by blue staining of the auricle in mice. Direct injection of OVA intravenously did not cause an auricular blue colouration reaction in mice. The passive cutaneous anaphylaxis reaction in mice was conducted with the aforementioned OVA-sensitized mouse serum, and there were obvious blue spots on the mouse's back. In addition, the content of anti-OVA-IgE in 5 mg·kg~(-1) OVA-sensitized mice was significantly increased. Ears and lungs of mice sensitized to OVA showed evident exudation inflammation. Significantly elevated inflammatory factors(VEGF and IL-10) were also detected in the serum of OVA-sensitized mice. The equivalent dose of OVA caused obvious allergic reactions in both guinea pigs and mice. Compared with nude mice, ICR and BALB/c mice are more sensitive to OVA sensitization. Injections of selected TCMI did not induce type Ⅰ allergic reactions in mice and guinea pigs, but there was a risk of inducing pseu-doallergic reactions in mice. The model is problematic and may well reflect the sensitization effect of allergens. It obtains the benefits of simple operation, accuracy, low cost, easy extension, and high repeatability. It is suitable for predicting and researching for IgE-dependent type Ⅰ allergic reactions.

[Risk assessment, safe medication and scientific supervision of traditional Chinese medicine containing aristolochic acids--toxicity is different among aristolochic acids, and detection and control of aristolochic acid â /â ¡ is critical].

The safety problem of traditional Chinese medicine containing aristolochic acid is of great concern in China and abraod, which poses a challenge in clinical application and supervision. There are many types of aristolochic acid analogues(AAAs) and 178 have been reported. According to the structure, they are classified into aristolochic acids(AAs) and aristololactams(ALs). The toxi-city is remarkably different among AAAs of different types. For example, AA-Ⅰ has strong nephrotoxicity and carcinogenicity, and the toxicity of AA-Ⅱ is lower than that of AA-Ⅰ. Besides, AA-Ⅳa and AA-Ⅰa are considered to have no obvious nephrotoxicity and carcinogenicity. The types and content of AAAs are significantly different among traditional Chinese medicines derived from different Aristolochiaceae species. For example, Asari Radix et Rhizoma and Aristolochiae Herba mainly consist of AAAs without obvious toxicity(such as AA-Ⅳa). The content of AAAs in compound preparations is related to the proportions of the medicinals and the processing method. The content of AA-Ⅰ in some compound preparations is very low or below the detection limit. Therefore, the author concludes that AAAs of different types have different toxicity, but not all AAAs has nephrotoxicity and carcinogenicity. Moreover, the toxicity of traditional Chinese medicines containing AAAs should not be generalized and AA-Ⅰ and AA-Ⅱ should be emphasized. In this paper, it is suggested that traditional Chinese medicine containing AAAs should be used rationally and research, analysis, and toxicological study of AAAs species and content should be strengthened. In addition, limit standards of AA-Ⅰ and AA-Ⅱ should be formulated and science-based supervision should be performed.

[Compatibility for toxicity attenuation of toxic traditional Chinese medicine: a review and strategies].

Toxicity-attenuating compatibility is an effective measure to ensure the safety of Chinese medicine. Involving the origin, processing method, compatibility mode, and dosage, it faces multiple challenges, such as the uncertainty of toxic substances, toxicity latency, indefinite safe dose, complex toxicity-efficacy relationship, and individual difference. As a result, research on clinical safety of Chinese medicine is limited by the consistency at "molecular-cellular-organ-overall" levels, unclear interaction of multiple medicinals and multiple substances, the "toxicity-efficacy-compatibility-syndrome" correlation, and the "dosage-time-toxicity-efficacy" conversion law. Therefore, following the principle of "starting from the clinical practice, verifying via the theoretical basis, and finally applying in clinical practice", we verified the toxicity at "molecular-cellular-organ-overall" levels, revealed the interaction of multiple medicinals and substances, collected evidence at multiple levels, clarified the "dosage-time-toxicity-efficacy" relationship, and tested the consistency between basic and clinical biomarkers. On this basis, we studied the toxicity-alleviating and efficacy-enhancing(preserving) compatibility characteristics, the fate of one medicinal and multiple medicinals in vivo, the molecular mechanism of toxicity, the "dosage-time-toxicity-efficacy" conversion law, and the clinical characteristics of toxic traditional Chinese medicine based on disease and syndrome. The three mechanisms of toxicity-attenuating compatibility reflect the seven-reaction theory in Chinese medicine compatibility. Finally, the strategies for safe use of Chinese medicine were proposed.

Clinical features of adverse events associated with Xiyanping-Ribavirin combination: A systematic review.

ETHNOPHARMACOLOGICAL RELEVANCE: In China, Xiyanping (XYP) has been widely used in combination with Ribavirin (RB) for the treatment of infectious diseases. It has been found that this combination may change the severity of XYP-associated adverse events (AEs). AIM: To provide a comprehensive review about the clinal features of AEs of XYP-RB combination from randomized controlled trials, cohort studies, case-control studies, case reports, case series, and data from the National Adverse Drug Reaction Monitoring Information System (NADRMIS). MATERIALS AND METHODS: Seven electronic databases were searched in March 2021. Articles on AEs associated with XYP published from January 2004 to December 2020 in the NADRMIS were included. Data on the incidence of AEs, distribution of AEs, occurrence time of AEs, type and possible signal of AEs, primary diseases, allergic history, family history of allergies, dosage, and combination interval were extracted. RESULTS: We included 228 cases of AEs with XYP-RB combination (63 cases from randomized controlled trials, 1 from a cohort study, and 164 from the NADRMIS). The most common primary disease was hand-foot-and-mouth disease. The main age distribution was 0-6 years (118 cases, 72%) and 8 cases (6.8%) experienced serious AEs. The combination group showed a significant reduction than the RB group in the incidence of AEs in those with hand-foot-and-mouth disease (risk ratio = 0.54, 95% confidence interval = 0.38-0.78, P = 0.0008) and children with viral pneumonia (risk ratio = 0.36, 95% confidence interval = 0.14-0.95, P = 0.04). Allergic history and infusion interval were not described in the randomized controlled trials. AEs were reported in 57.9% of cases in the first combination (XYP-RB were combined for the first time) (NADRMIS), 56.4% of which were skin and appendage reactions, and the risk signal of skin and appendage reactions was a maximum (Information Component = 6.21). CONCLUSION: The major AE associated with XYP-RB combination was skin and appendage reactions. Most of the combination AEs were pseudo-allergic reactions. These findings suggest that we should increase awareness about the safety of XYP-RB combination treatment and standardize medication protocol, especially for children. Unless absolutely necessary, children should avoid combination therapy. More rigorous high-quality studies are needed to obtain more evidence.

Pharmacological effects and safety of Andrographis paniculata (Burm.f.) Nees.

Andrographis paniculata (Burm.f.) Nees (AP) is widely used in most Asian and some Western countries. However, its main effects and underlying pharmacological mechanism have not been thoroughly characterized, and its safety has not been sufficiently investigated. The present study aimed to predict and visualize the potential targets and pathways, clarify the main pharmacological effects, and investigate the toxicological properties of AP extract (APE). First, ingenuity pathway analysis (IPA) was performed to directly predict AP's therapeutic targets and pathways; main pharmacological effects of AP were speculated based on IPA results and confirmed by pharmacodynamics experiments. Rodent toxicity studies were then performed through administration of a single dose of 10 g/kg or daily doses of 2, 1, or 0.5 g/kg for 8 weeks to evaluate the safety of APE, and a similar repeated-dose study was performed using dogs with doses equal to half of the above-mentioned doses. Thus, repeated-dose toxicity studies were performed with both rodents and nonrodents. The IPA analysis and confirmatory pharmacodynamics experiments revealed that the main pharmacological effect of APE was anti-inflammation, which might be achieved by influencing various targets (e.g., AR, AKT, and BAX) and pathways (IL-8). In the single-dose toxicity test, no death or abnormal consequences were observed, and maximum tolerated dose of APE was 10 g/kg. Results from the repeated-dose toxicity tests did not reveal any obvious toxic effects from the repeated daily intragastric administration of APE at 1 g/kg for 8 weeks. In conclusion, APE at a dose of 1 g/kg did not exert any adverse effects, and administration of APE could be beneficial for the inflammatory diseases' treatment. PRACTICAL APPLICATION: Andrographis paniculata (Burm.f.) Nees is a plant that exerts clearing and detoxification effects and is widely used around the world, but a comprehensive analysis of its efficacy and safety is needed.

A review of the ethnopharmacology, phytochemistry, pharmacology and toxicology of Fructus Gardeniae (Zhi-zi).

ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Gardeniae (FG) is the dried fruit of Gardenia jasminoides Ellis (GjE), which belongs to the family Rubiaceae. FG has a long history of use as a herb, and was originally recorded in Sheng Nong's herbal classic. FG has also been widely used as both medicine and food. AIM OF STUDY: This review aimed to provide a systematic and comprehensive analysis of the current research progress of FG in terms of ethnopharmacology, phytochemistry, pharmacology and toxicity, to provide new insights and extensive field of view for subsequent studies. METHODS: Scientific databases, including CNKI, VIP (Chinese literature), PubMed, Science Direct, Elsevier and Google Scholar (English literatures) were searched to gather data about FG and its main active ingredients such as geniposide and genipin (only regarding toxicity). RESULTS: Many chemical constituents have been identified from the fruit of GjE, including iridoids, terpenoids, flavonoids, organic acids, volatile oils and others. The constituents of different parts of FG and processed FG are different from those of whole FG. FG extract and its main active constituents have been reported to have pharmacological properties such as hepatoprotective, choleretic, anti-inflammatory, antioxidant, neuroprotective, anti-diabetic, anti-apoptotic and antitumor activities. However, an increasing number of studies have shown that FG induces multiple organ injury, especially causing hepatotoxicity and nephrotoxicity, which could increase the risk during clinical use. The available literature shows that geniposide, a major active component of FG and a critical marker for its quality, is associated with the pharmacology and toxicity of FG. CONCLUSION: Although a large number of studies examining FG have been published, issues remain. In the aspect of FG's pharmacology, the traditional efficacy and modern pharmacological effects of FG should be combined, which to broadens clinical application prospects. In addition, few studies have assessed the toxicity of FG. Toxicity assessment of FG should tackle various aspects, including compatibility, processing and the symptom-based prescription theory, in addition to over-dosage or long-term use, for a reasonable clinical use.

The Diagnosis and Management of Allergic Reactions Caused by Chinese Materia Medica.

Traditional Chinese medicines (TCM) have been used in China for thousands of years. Although TCM has been generally perceived to be safe, adverse reactions to Chinese materia medica (CMM) have been reported. Most of the adverse reactions are allergic in nature, but other mechanisms may play a role. This review focuses on the mechanism and clinical presentation of these allergic reactions. Allergic reactions can occur as a result of the active and inactive ingredients of CMM. Impurities and chemicals generated during the production process can also lead to allergic or adverse reactions. Environmental factors such as temperature, humidity, and light can cause changes in the allergenicity of drugs. Human error in formulating CMM drugs also contributes to adverse drug reactions. The management of allergic reactions to CMM includes taking a good history, avoidance of medications in the same class as those which caused prior reactions, the proper training of staff, adherence to manufacturer guidelines and expiration dates, evaluation of benefit and risk balance, and the formulation of a risk management strategy for the use of CMM. A small test dose of a considered drug before using, improvements in drug purification technology, and proper storage and clinical administration help reduce allergic reactions due to CMM.

Target-Based In Silico Screening for Phytoactive Compounds Targeting SARS-CoV-2.

Coronavirus disease 2019 (COVID-19), resulting from infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause severe and fatal pneumonia along with other life-threatening complications. The COVID-19 pandemic has taken a heavy toll on the healthcare system globally and has hit the economy hard in all affected countries. As a result, there is an unmet medical need for both the prevention and treatment of COVID-19 infection. Several herbal remedies have claimed to show promising clinical results, but the mechanisms of action are not clear. We set out to identify the anti-viral natural products of these herbal remedies that presumably inhibit the life cycle of SARS-CoV-2. Particularly we chose four key SARS-CoV-2 viral enzymes as targets: Papain-like protease, Main protease, RNA dependent RNA polymerase, and 2'-O-ribose methyltransferase, which were subjected to an unbiased in silico screening against a small molecule library of 33,765 compounds originating from herbs and medicinal plants. The small molecules were then ranked based on their free energy of fitting into the "druggable" pockets on the surface of each target protein. We have analyzed the best "fit" molecules and annotated them according to their plant sources and pharmacokinetic properties. Here we present a list of potential anti-viral ingredients of herbal remedies targeting SARS-CoV-2 and explore the potential mechanisms of action of these compounds as a framework for further development of chemoprophylaxis agents against COVID-19.

Quantitative Determination and Toxicity Evaluation of Aristolochic Acid Analogues in Asarum heterotropoides F. Schmidt (Xixin) and Traditional Chinese Patent Medicines.

Asarum (Xixin), which contains analogues of aristolochic acid (AA), is the only species of the genus Aristolochia included in the Chinese Pharmacopoeia 2020. However, the contents and nephrotoxic effects of AA analogs in Asarum (Xixin) and its formulations have not been clarified. An automatic, effective solid phase extraction process and UPLC-MS/MS method were established for the pretreatment and quantitative detection of AA analogues in commercially available traditional Chinese patent medicines. The cytotoxicity and DNA damage induced by five analogues of AA were evaluated by CCK8 using human kidney cells (HK-2) and comet assays. HPLC was used to detect the analogues of AA in Asarum heterotropoides F. Schmidt (Xixin). The results showed that the contents of AA I, AA II, and AA IIIa were below the detection limit, while AA IVa and AL I presented relatively high contents of Asarum heterotropoides F. Schmidt (Xixin), within the range of 66.50-121.03 µg/g and 19.73-43.75 µg/g, respectively. The levels of AA analogues were in the nanogram-per-gram level in the main traditional Chinese patent medicines. AA I and AL I exhibited relatively high cytotoxicity at 48 h in CCK8 assays, while AA II, AA IIIa, and AA IVa showed weak cytotoxicity even at 800-1,000 µM. AA I induced significant pathological alterations and direct DNA damage at 40 mg/kg and 20 mg/kg, respectively. No distinct nephrotoxicity or hepatotoxicity was observed in mice treated with AA II, AA IIIa, AA IVa, or AL I at 40 mg/kg in this study. Consumption of Asarum heterotropoides F. Schmidt (Xixin) with controlled doses and periods is relatively safe as the contents of AA analogues in Asarum heterotropoides F. Schmidt (Xixin) and its formulations were far below those causing acute toxicity in this study. But, the long-term toxicity of Asarum heterotropoides F. Schmidt (Xixin) still needs further study.

[Study on synergistic effect of Qingkailing Injection and Shengmai Injection on organ injury in endotoxemia rats].

As a dangerous disease with rapid progression, endotoxemia is easy to induce the damage to multiple organs. However, its specific and efficient treatment methods are still lacking at present. Both Qingkailing Injection(QKLI) and Shengmai Injection(SMI) have been proved effective in anti-inflammation, anti-endotoxin and organ protection. In this study, carrageenan and endotoxin were injected successively into rats to establish an endotoxemia model. Different doses of QKLI and SMI were administered to the endotoxemia rats by intraperitoneal injection separately or in combination. Then the count of white blood cells, the number of platelets, the content of cytokines, biochemical indexes, organ coefficient and pathological changes of main organs in the rats were detected. The results showed that the rats in the model group had obvious symptoms of endotoxemia, i.e., leucopenia, thrombocytopenia, increase in cytokines(IL-6 and TNF-α) and biochemical indexes of liver and kidney function as well as pathological damage to liver, kidney and lung. QKLI alone can alleviate the above symptoms of endotoxemia and the organ injury. SMI alone is less effective in improving disseminated intravascular coagulation(DIC) and cytokine secretion complicated with endotoxemia, but capable of reducing the inflammation degree of the lung, liver and kidney. The combination of QKLI and SMI remarkably increased the number of platelets in the peripheral blood, improved the liver and kidney function and reduced inflammatory factors, with lung, liver, kidney and other organ structures protected well. Moreover, the improvement effect of the combination of QKLI and SMI was stronger than those of the two injections alone at fixed doses, indicative of a synergistic effect.

[Research progress on adverse reactions and pseudo-allergic reactions of traditional Chinese medicine injections].

Since the safety re-evaluation of traditional Chinese medicine(TCM) injections began in 2009, some TCM injection companies and research institutes have done a lot of work. And with the increase of drug development and drug production technology levels in China, the safety of some TCM injections has been greatly improved. There are safety risks in TCM injections, which are mainly reflected in unclear basis of medicinal materials, simple production process, poor controllability of quality standards, nonstan-dard drug instructions and irrational medication in the use process. This paper describes the research progress of the above-mentioned aspects of TCM injections. In addition, the author team found that adverse reactions of TCM injections are mainly pseudo-allergic reactions. Therefore, a lot of work has been done in detection of pseudo-allergic reactions, mechanism research and risk control. This part of the work is also described in this article.

Shuxuening injection, derived from Ginkgo biloba leaf, induced pseudo-allergic reactions through hyperactivation of mTOR.

Context: Shuxuening injection (SXNI), derived from the leaf of Ginkgo biloba L. (Ginkgoaceae), is widely used to treat cardio-cerebral vascular system related disease due to the efficacy of dilating the blood vessels and improving the function of microcirculation. Nevertheless, SXNI induces immediate hypersensitivity reactions in clinics and the molecular mechanisms are unknown.Objective: The present study investigates the molecular mechanism of SXNI mediated hypersensitivity reactions.Materials and methods: Naive male ICR mice (n = 10) were administered (i.v.) with negative control combined with Evans blue (EB) (CTL-EB), SXNI (14 or 70 mg/kg) combined with EB (SXNI/1-EB or SXNI/4-EB), vascular leakage was evaluated, ears and lungs were collected for histopathological analysis. In vitro, TSC1 was knockdown in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated with SXNI, and the alterations of endothelial cell permeability were observed. Rapamycin (mTOR inbibitor) was used to investigate SXNI-induced hypersensitivity reactions both in mice and HUVECs.Results: SXNI (70 mg/kg) induced vascular leakage in mice. Slight oedema and microvascular dilation in the ears, and broaden of alveolar septal and monocyte infiltration in the lungs were observed in SXNI (70 mg/kg) treated mice. mTOR inhibitor alleviates SXNI mediated vascular endothelial hyperpermeability both in vitro and in vivo.Discussion and conclusions: SXNI stimulates pseudo-allergic reactions through hyperactivation of mTOR signalling pathway. Our work provides the new molecular mechanism of drug related pseudo-allergic reactions, and a potential drug to prevent and treat SXNI mediated hypersensitivity reactions.