Polysaccharides from Lentinus edodes prevent acquired drug resistance to docetaxel in prostate cancer cells by decreasing the TGF-ß1 secretion of cancer-associated fibroblasts.

Prostate cancer is one of the most prevalent lethal diseases among men globally. In the treatment of prostate cancer, the limited therapeutic efficacy of the standard non-hormonal systemic therapy docetaxel (DTX) represents an important challenge. Cancer-associated fibroblasts (CAFs) play a crucial role in resistance to therapy because of their prevalence and functional pleiotropy in tumor environments. Our previous research revealed that MPSSS, a novel polysaccharide extracted from Lentinus edodes, could significantly attenuate the immunosuppressive function of myeloid suppressor cells and CAFs. In this study, we investigated whether MPSSS could potentiate the efficacy of DTX against prostate cancer by inhibiting CAF-induced chemoresistance and elucidated its underlying mechanisms. The sensitivity of PC-3 prostate cancer cells cultured with conditioned medium derived from CAFs (CAF-CM) to DTX was assessed. The resistance effect induced by CAF-CM was abolished when CAFs were pretreated with MPSSS. Bioinformatic analysis of datasets from the Gene Expression Omnibus database revealed the activation of the transforming growth factor ß1 (TGF-ß1) signaling pathway in DTX-resistant cells. Based on this finding, we demonstrated that treatment with the TGF-ß1 receptor inhibitor SB525334 reversed DTX resistance in CAFs, suggesting that TGF-ß1 secreted by CAFs was a crucial intermediary in the development of DTX resistance in PC3 cells. Further research revealed that MPSSS decreases the secretion of TGF-ß1 by inhibiting the JAK2/STAT3 pathway via Toll-like receptor 4 in CAFs. Overall, MPSSS might be a potential adjuvant treatment for DTX resistance in prostate cancer.

Sustained release of levobupivacaine from temperature-sensitive injectable hydrogel for long-term local anesthesia in postoperative pain management.

Postoperative pain is a major concern for most of the surgical patients, and an inadequate postoperative pain control may cause a series of complications. With an effective pain control and lesser side effects, local anesthetics are preferred for use in postoperative pain management. However, the action duration of current local anesthetics is too short to meet the requirements of postoperative analgesia. In this study, an injectable levobupivacaine (LB)-loaded thermo-sensitive hydrogel system based on biodegradable poly(D,L-lactide)-poly(ethylene glycol)-poly(D,L-lactide) (PLEL) was developed for long-acting local anesthetic, in which the soluble charged cation form of LB (LB HCl) was partly alkalified to the poorly soluble base form (LB base). This hybrid LB loaded PLEL system (hLB/PLEL) is a free flowable liquid at room temperature and changes into a semi-solid hydrogel once injection in response to the physiological temperature. Then, the dissolved LB HCl could release firstly from the hydrogel contributing to a quick work, and the insoluble LB base dissolved and released gradually as the decrease of the pH during the biodegradation of PLEL hydrogel, resulting in a long-term LB release in local. The drug release behavior, pharmacokinetic, and biocompatibility of the thermo-sensitive hLB/PLEL were studied in vitro and in vivo. The anesthetic effects of hLB/PLEL system were evaluated in the rat models of sciatic nerve block, subcutaneous infiltration anesthesia and postoperative pain as well. This hLB/PLEL system generated a significantly prolonged analgesic effect in rat models, which produced approximately 7 times longer duration than 0.75% LB HCl and effectively relieved the spontaneous pain for 3 days. In general, the presented hLB/PLEL system can not only achieve a fast-acting but also sustainably release LB to block the nerve and significantly extend the effect of local analgesia, which means a promising candidate for long-acting postoperative pain management.

Quantifying the Contributions of Environmental Factors to Prostate Cancer and Detecting Risk-Related Diet Metrics and Racial Disparities.

The relevance of nongenetic factors to prostate cancer (PCa) has been elusive. We aimed to quantify the contributions of environmental factors to PCa and identify risk-related diet metrics and relevant racial disparities. We performed a unique analysis of the Diet History Questionnaire data of 41 830 European Americans (EAs) and 1282 African Americans (AAs) in the PLCO project. The independent variables in the regression models consisted of age at trial entry, race, family history of prostate cancer (PCa-fh), diabetes history, body mass index (BMI), lifestyle (smoking and coffee consumption), marital status, and a specific nutrient/food factor (X). P < .05 and a 95% confidence interval excluding zero were adopted as the criteria for determining a significant difference (effect). We established a priority ranking among PCa risk-related genetic and environmental factors according to the deviances explained by them in the multivariate Cox-PH regression analysis: age > PCa-fh > diabetes ⩾ race > lifestyle ⩾marital-status ⩾BMI > X. We confirmed previous studies showing that (1) high protein and saturated fat levels in diet were related to increased PCa risk, (2) high-level supplementary selenium intake was harmful rather than beneficial for preventing PCa, and (3) supplementary vitamin B6 was beneficial for preventing benign PCa. We obtained the following novel findings: high-level organ meat intake was an independent predictor for increased aggressive PCa risk; supplementary iron, copper and magnesium increased benign PCa risk; and the AA diet was "healthy" in terms of the relatively lower protein and fat levels and was "unhealthy" in that it more commonly contained organ meat. In conclusion, we established a priority ranking among the contributing factors for PCa and identified several risk-related diet metrics and the racial disparities. Our findings suggested some new approaches to prevent PCa such as restriction of organ meat intake and supplementary microminerals.

Tiao-Bu-Fei-Shen Formula Improves Glucocorticoid Resistance of Chronic Obstructive Pulmonary Disease via Downregulating the PI3K-Akt Signaling Pathway and Promoting GRα Expression.

Objective: To predict and determine the mechanism through which Tiao-Bu-Fei-Shen (TBFS) formula improves glucocorticoid resistance in chronic obstructive pulmonary disease (COPD), using network pharmacology, molecular docking technology, and in vitro studies. Methods: The main active components and associated targets of TBFS were screened using the systems pharmacology database of traditional Chinese medicine database (TCMSP). The main COPD targets were retrieved from the Human Gene (GeneCards) and DrugBank databases. A protein-protein interaction (PPI) network was constructed using the protein interaction platform STRING and Cytoscape 3.6.1. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genome Pathway (KEGG) analyses were performed using the biological information annotation database Metascape. Molecular docking was performed using the AutoDock Vina software. THP-1 monocytes were treated with TBFS-containing serum and cigarette smoke extract (CSE) for 48 h, and cell proliferation in each group was determined using cell counting kit-8 (CCK-8). A COPD cell model was constructed by stimulating THP-1 monocytes with CSE for 12 h. A lentivirus vector for RNA interference of histone deacetylase 2 (HDAC2) gene was constructed and transfected into the THP-1 monocytes, and the transfection efficiency was verified using quantitative polymerase chain reaction (qPCR) and western blotting (WB). The expression of HDAC2 in each group of cells was detected using qPCR, and the expression of HDAC2, phosphoinositide-3 kinase (PI3K) p85α, glucocorticoid receptor α (GRα), and P-AKT1 in each group of cells was detected through WB. Results: A total of 344 TBFS active components, 249 related drug targets, 1,171 COPD target proteins, and 138 drug and disease intersection targets were obtained. Visual analysis of the PPI network map revealed that the core COPD targets of TBFS were AKT1, IL-6, TNF, TP53, and IL1-ß. KEGG pathway enrichment analysis resulted in the identification of 20 signaling pathways as the main pathways involved in the action of TBFS against COPD, including the PI3K-Akt, TNF, and IL-17 signaling pathways. Molecular docking experiments revealed a strong binding capacity of kaempferol, luteolin, and quercetin to the ATK1 protein in TBFS, with quercetin performing the best. PCR results showed that treatment with TBFS significantly increased the expression levels of HDAC2 in the COPD model. WB results showed that TBFS treatment significantly increased the expression levels of GRα and HDAC2 in the COPD model, while reducing the expression levels of P-AKT1. Conclusion: TBFS treatment improves glucocorticoid resistance observed in COPD through downregulation of the PI3K-Akt signaling pathway and promotion of GRα expression.

Simultaneous Determination of 32 Pyrrolizidine Alkaloids in Two Traditional Chinese Medicine Preparations by UPLC-MS/MS.

Pyrrolizidine alkaloids (PAs) constitute a class of phytotoxin which demonstrates strong hepatotoxicity. In China, many plants containing PAs are used as traditional medicines or medicinal preparations, which could harm human health and safety. Xiaoyao Tablet (XYT) is an antidepressant drug registered in the European Union (EU), Compound Danshen Dropping Pills (CDDP) is a commonly used drug for coronary heart disease, and phase III clinical study is ongoing in the United States. The purpose of this study is to provide data to support the use of Chinese medicine preparations internationally and to establish analytical methods for 32 PAs in XYT and CDDP. The extraction parameters that were optimized include solid-phase extraction (SPE) cartridge, extraction method, and extraction solvent. Then ultra-performance liquid chromatography coupled with triple-quadrupole linear ion-traptandem mass spectrometry (UPLC-MS/MS) was developed to effectively and efficiently quantify the 32 PAs of the XYT and CDDP. The analytical methods for XYT and CDDP were verified respectively. For XYT, the analytical method for 32 PAs was linear, and the correlation coefficient r was greater than 0.994; the recovery (REC%) at 10-2000 µg/kg was 73.3%-118.5%, and the relative standard deviation (RSD%) was 2.1%-15.4%. The CDDP REC% was 71.8%-112.0%, and the RSD% was 2.0%-17.1%. This study provides technical and data support for the registration of Chinese patented medicines in the EU, controls quality and ensures safety, and is committed to the internationalization and standardization of Chinese patented medicines.

Traditional use and safety evaluation of combination Traditional Chinese Medicine in European registration: with XiaoYao Tablets as an example.

Mental health disorders such as stress, anxiety, depression and insomnia caused by COVID-19 have attracted worldwide attention. Traditional Chinese medicines (TCMs) have been proven to be a safe and effective option for treating mental health disorders. Recently, after assessing its efficacy and safety fully, the Netherlands Medicines Evaluation Board approved XiaoYao Tablets as a traditional herbal medicinal product (THMP), indicated for an alternative self-care for patients in Europe to relieve the symptoms of mental stress and exhaustion. Despite the fact that TCMs have gradually become one of the therapeutic choices worldwide, to-date, only a few TCMs have been successfully registered in the European Union (EU) as THMPs, and XiaoYao Tablets is the first successfully registered combination TCM from China. In this article, traditional use efficacy and clinical safety of XiaoYao Tablets in the treatment of mental health disorders were summarized and analyzed from the perspective of traditional use registration (TUR). Additionally a safety evolution pathway of combination TCMs was established. This article will not only seek to enhance our understanding about traditional use efficacy and clinical safety of XiaoYao Tablets, but also summarize the experience of XiaoYao Tablets as the first successfully registered combination TCM from China, which could serve as role model for the others to overcome registration difficulties in the EU.

3'-Methoxydaidzein exerts analgesic activity by inhibiting voltage-gated sodium channels.

Isoflavones are widely consumed by people around the world in the form of soy products, dietary supplements and drugs. Many isoflavones or related crude extracts have been reported to exert pain-relief activities, but the mechanism remains unclear. Voltage-gated sodium channels (VGSCs) play important roles in excitability of pain sensing neurons and many of them are important nociceptors. Here, we report that several isoflavones including 3'-methoxydaidzein (3MOD), genistein (GEN) and daidzein (DAI) show abilities to block VGSCs and thus to attenuate chemicals and heat induced acute pain or chronic constriction injury (CCI) induced pain hypersensitivity in mice. Especially, 3MOD shows strong analgesic potential without inducing addiction through inhibiting subtypes NaV1.7, NaV1.8 and NaV1.3 with the IC50 of 181 ± 14, 397 ± 26, and 505 ± 46 nmol·L-1, respectively, providing a promising compound or parent structure for the treatment of pain pathologies. This study reveals a pain-alleviating mechanism of dietary isoflavones and may provide a convenient avenue to alleviate pain.

Berberine Alleviates Amyloid ß-Induced Mitochondrial Dysfunction and Synaptic Loss.

Synaptic structural and functional damage is a typical pathological feature of Alzheimer's disease (AD). Normal axonal mitochondrial function and transportation are vital to synaptic function and plasticity because they are necessary for maintaining cellular energy supply and regulating calcium and redox signalling as well as synaptic transmission and vesicle release. Amyloid-ß (Aß) accumulation is another pathological hallmark of AD that mediates synaptic loss and dysfunction by targeting mitochondria. Therefore, it is important to develop strategies to protect against synaptic mitochondrial damage induced by Aß. The present study examined the beneficial effects of berberine, a natural isoquinoline alkaloid extracted from the traditional medicinal plant Coptis chinensis, on Aß-induced mitochondrial and synaptic damage in primary cultured hippocampal neurons. We demonstrate that berberine alleviates axonal mitochondrial abnormalities by preserving the mitochondrial membrane potential and preventing decreases in ATP, increasing axonal mitochondrial density and length, and improving mitochondrial motility and trafficking in cultured hippocampal neurons. Although the underlying protective mechanism remains to be elucidated, the data suggest that the effects of berberine were in part related to its potent antioxidant activity. These findings highlight the neuroprotective and specifically mitoprotective effects of berberine treatment under conditions of Aß enrichment.

[Research progress of pesticide residues in traditional Chinese medicines].

The residue of the pesticides is closely related to the quality and safety of traditional Chinese medicines(TCMs) and has attracted widespread attention at home and abroad.This article analyzed the current status of pesticide residues in TCMs by summarizing the research results of recent years.At the same time,the methods for the detection of pesticide residues in TCMs were summarized,and the domestic and foreign pesticide residue limit standards for TCMs were compared,intending to provide reference and basis for the detection and control of pesticide residues in TCMs.

Pharmacokinetic Characteristics of Steamed Notoginseng by an Efficient LC-MS/MS Method for Simultaneously Quantifying Twenty-three Triterpenoids.

Steamed Panax notoginseng (SNG) has been widely used as a restorative medicine instead of the raw one, but its pharmacokinetic profile is entirely unknown. To address this, we've developed an LC-MS/MS method with high efficiency and sensitivity for simultaneous quantification of 23 triterpenoids (notoginsenosides Fa, Fc, R1, 20( S)-R2, 20( R)-R2, ginsenosides F4, Rb1, Rg1, Rd, Re, Rb2, 20( S)-Rh1, 20( R)-Rh1, Rh4, R k1, R k3, 20( S)-Rg2, 20( S)-Rg3, 20( R)-Rg3, Rg5, C-K, 20( S)-PPT, 20( S)-PPD) from SNG in rat plasma. This validated approach exhibits great linearity, precision, accuracy, recovery, and stability for all analytes. Furthermore, we, for the first time, applied this method to the pharmacokinetic study of SNG and proposed Rb1, Fa, Rd, R k1, Rg5, R k3, Rh4, and 20( S)-PPD to be suitable pharmacokinetic markers of SNG due to their high exposure levels of systemic plasma. Hence, this developed approach would be a powerful tool for future in vivo investigation of various sources of notoginseng-related samples.

Structural characterization of a pectin-type polysaccharide from Curcuma kwangsiensis and its effects on reversing MDSC-mediated T cell suppression.

Myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing hosts and play a major role in tumor-induced immunosuppression. The potent modulatory effects of polysaccharides on the innate and adaptive immune system stimulate antitumor responses. In this study, a polysaccharide with an apparent molecular weight of 14.0 kD was isolated from Curcuma kwangsiensis and designated as CKAP-2. The polysaccharide was characterized through high-performance gel permeation chromatography, chemical derivative analyses, GC-MS, FT-IR, and NMR. Results revealed that CKAP-2 is a highly methyl-esterified pectin-type polysaccharide. It is predominantly composed of a homogalacturonan region and small amounts of type-I rhamonogalacturonan regions. Its degree of methyl-esterification is approximately 62.4%. The effect of CKAP-2 on MDSC-medicated immunosuppression was primarily tested. CKAP-2 recovered the MSC2-supressed proliferation of CD4+ and CD8+ T-cells. This finding suggested that CKAP-2 can reverse MDSC-mediated T-cell suppression and that CKAP-2 can be potentially applied in antitumor therapy.

An Asparagus polysaccharide fraction inhibits MDSCs by inducing apoptosis through toll-like receptor 4.

Despite decades of research, malignant tumors are extremely difficult to eliminate with conventional methods. Although surgical resection potentially eradicates the problem, only a few cases are suitable for operation, and other approaches often involve harmful consequences. Revolutionary methods are desperately needed to improve patient outcomes and diminish harmful side effects. Myeloid-derived suppressor cells (MDSCs), downregulators of the innate and adaptive immune systems, have been widely studied over the past 2 decades. MDSCs inhibit the antitumor immune response by suppressing T cell proliferation, cytokine production, and tumor cell killing. With MDSCs becoming novel targets in cancer therapy, our research has focused on the anti-MDSC function of Asparagus polysaccharide (AP), extracted from asparagus, a traditional Chinese herb. In this study, we have used MDSCs isolated from the spleen of mice with colon cancer as an in vitro model to assess the efficacy of AP. Treatment of MDSCs with AP significantly decreased cell proliferation and induced apoptotic cell death through a toll-like receptor 4 dependent way. Subsequent studies showed that the AP treatment enhanced the expression of Bax and Caspase-9 and inhibited the expression of Bcl-2, suggesting that AP induced apoptosis in the MDSCs via the intrinsic pathway. Altogether, the results showed that AP exhibited a significant anti-MDSC activity and attenuated suppression of the antitumor immune response, thereby indicating its potential use in cancer therapy.

Berberine modulates amyloid-ß peptide generation by activating AMP-activated protein kinase.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by memory deficits and cognitive decline. Excessive amyloid-ß (Aß) peptide aggregates and forms soluble oligomers and insoluble cerebral amyloid plaques, which is widely thought to be the underlying pathogenic mechanism of AD. Therefore, effective regulation of Aß metabolism is an important aspect of preventing and improving AD. Berberine, which is the main active component of the traditional medicinal herb Coptidis rhizoma, has a positive effect on reducing Aß levels. However, the exact mechanism involved is unclear and requires more investigation. In the present study, we examined the role of berberine in the activation of AMP-activated protein kinase (AMPK) in neuroblastoma cells and primary cultured neurons and sought to characterize the role of AMPK in the metabolism of Aß. The results indicate that berberine reduces Aß generation and decreases the expression of ß-site APP cleaving enzyme-1 (BACE1) via activating AMPK in N2a mouse neuroblastoma cells stably expressing human Swedish mutant APP695 (N2a/APP695sw), N2a cells, and primary cultured cortical neurons. Therefore, berberine reduced the accumulation of Aß, which likely contributes to its memory enhancing effect in patients with AD.

QX-OH, a QX-314 derivative agent, produces long-acting local anesthesia in rats.

QX-314 has been shown to produce long-acting local anesthesia in vivo in animals; however, translation to humans has been impeded by concerns about toxicity. We investigated whether the newly emerged QX-OH molecule could confer long-lasting anesthesia with a low local toxicity in rats. In rat sciatic nerve block model, QX-OH 25mM produced a longer sensory block than QX-314 25mM (median [25th, 75th percentiles], 5.5 [4.25, 6] h vs. 3 [3, 4] h; P=0.03). QX-OH 35mM produced a longer sensory block than QX-314 35mM (8 [6, 12] h vs. 6 [4, 6.5] h, P=0.038). QX-OH at 35 and 45mM generated longer motor blocks than QX-314, with tissue toxicity less than that of QX-314 at the same concentration. In contrast with bupivacaine, QX-OH was clearly superior in terms of sensory and motor blockade durations after a single bolus injection. There was no significant difference in tissue toxicity between QX-OH (25 and 35mM) and bupivacaine. In rat cutaneous trunci pinprick model, the QX-OH-induced pain threshold remained significantly different from baseline at 6h (25mM, P<0.0001), 10h (35mM, P<0.0001), and 12h (45mM, P<0.0001). The time required for full recovery from the subcutaneous anesthetic effect was significantly longer for QX-OH than for QX-314 and bupivacaine. So QX-OH produced concentration-dependent, reversible, and long-acting local anesthesia in animal models with a moderate local toxicity.

Geniposide ameliorates cognitive deficits by attenuating the cholinergic defect and amyloidosis in middle-aged Alzheimer model mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory deficits and cognitive decline. Amyloid-ß (Aß) deposition and cholinergic defect are widely thought to be the underlying mechanism of learning and memory impairment. Geniposide, which is the main active component of the traditional Chinese herbal Gardenia jasminoides Ellis, elicits neuroprotective effects by alleviating inflammation responses and oxidative damages. In this study, we investigated the protective effect of geniposide on levels of cholinergic markers, RAGE, RAGE-dependent signalling pathways and amyloid accumulation in the APPswe/PS1dE9 AD model mouse. Geniposide suppressed MAPK signaling over-activation mediated by Aß-RAGE interaction, resulting in reduced Aß accumulation and amelioration of cholinergic deficits in the cerebral hippocampus. Furthermore, geniposide inhibited the toxic effect of oligomeric Aß1-42 induced cholinergic deficit by increasing ChAT levels and activity but decreasing AChE activity in cultured primary hippocampal neurons. These results indicated that geniposide enhanced cholinergic neurotransmission, which likely contributes to its memory enhancing effect.

Determination of arsenic speciation and the possible source of methylated arsenic in Panax Notoginseng.

Arsenic species and a possible source of methylated arsenic in a Panax Notoginseng (PN) medicinal plant were explored to further understand the change of inorganic arsenic to the less toxic methylated form to minimize the health risks associated with its medicinal use. Arsenic speciation in PN from major planting areas was determined using high-performance liquid chromatography coupled with hydride generator-atomic fluorescence (HPLC-HG-AFS). Pot experiments were performed to explore the source of methylated arsenic in PN, and the arsenite methyltransferase (arsM) gene abundance was determined using quantitative reverse transcription PCR (q-RTPCR). Methylated arsenic (monomethylarsonic acid (MMA) + dimethylarsinic acid (DMA)) accounted for 43% ± 30% of the total arsenic in PN from planting areas, while the primary species in soil was As(V) (94% ± 0.12%). In the pot experiments, methylated arsenic accounted for 37%-49% of the total arsenic in PN, and As (V) was the primary species in soil (>98%). The four detected arsenic species in PN increased as the amount of As added to soil increased. The methylated arsenic contents in the PN root were significantly positively correlated with the ArsM gene abundance in soil, suggesting that methylated arsenic in PN is likely from the planting soil.

Ginsenoside Re reduces Aß production by activating PPARγ to inhibit BACE1 in N2a/APP695 cells.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by ß-amyloid protein (Aß) deposition. Reducing the Aß load may be a new perspective for AD treatment. Ginsenoside Re is an extract from Panax notoginseng, which is a well-known traditional Chinese medicine that has been used for the treatment of various diseases for years. Ginsenoside Re has been reported to decrease Aß in Alzheimer's disease animal models, but the mechanism has not been fully elucidated. In the present study, we investigated the mechanism of ginsenoside Re. Our results showed that ginsenoside Re decreased the Aß levels in N2a/APP695 cells. Aß peptides are generated by ß-secretase (ß-site amyloid precursor protein cleaving enzyme 1 (BACE1)) and γ-secretase. We found that ginsenoside Re decreased the BACE1 mRNA and protein levels and inhibited BACE1 activity in the N2a/APP695 cells. Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor that regulates the activity of the BACE1 promoter, and activating PPARγ can inhibit BACE1. The results also showed that ginsenoside Re significantly increased the PPARγ protein and mRNA levels. These effects of ginsenoside Re on BACE1 could be effectively inhibited by the PPARγ antagonist GW9662. These findings indicate that ginsenoside Re inhibits BACE1 through activation of PPARγ, which ultimately reduces the generation of Aß1-40 and Aß1-42. Therefore, ginsenoside Re may be a promising agent for the modulation of Aß-related pathology in AD.

Partial Activation and Inhibition of TRPV1 Channels by Evodiamine and Rutaecarpine, Two Major Components of the Fruits of Evodia rutaecarpa.

Evodiamine (1) and rutaecarpine (2) are the two major components of Evodia rutaecarpa, which has long been used in traditional medicine for the treatment of many diseases. Using transient receptor potential vanilloid 1 (TRPV1)-expressing HEK293 cells and patch-clamp recording, the inhibitory actions of 1 and 2 against TRPV1 channels were investigated. The effects of these compounds against capsaicin- or proton-activated TRPV1 activities were evaluated. The results showed that, although 1 and 2 can activate TRPV1, the maximum response was 3.5- or 9-fold lower than that of capsaicin, respectively, suggesting partial agonism. In comparison to capsaicin, coadministration of 1 and capsaicin increased the half-maximal effective concentration (EC50) of capsaicin-activated TRPV1 currents as shown by a right shift in the dose-response curve, whereas coadministration of 1 with protons failed to inhibit the proton-induced current. Moreover, preadministration of 1, but not 2, inhibited both capsaicin- and proton-induced TRPV1 currents, which might involve channel desensitization. Taken together, 1 and 2 may share the same binding site with capsaicin and act as partial agonists (antagonists) of TRPV1. Evodiamine (1), but not rutaecarpine (2), can desensitize or competitively inhibit the activity of TRPV1.

Cadmium accumulation in Panax notoginseng: levels, affecting factors and the non-carcinogenic health risk.

Cadmium (Cd) contamination has been reported to be a problem for the safe usage of Panax notoginseng (Sanchi); thus, it is necessary to elucidate the Cd accumulation in Sanchi and to assess its associated health risk. Samples were collected from major producing areas in Yunnan, China. The average concentration of Cd in Sanchi was 0.43 mg/kg, which exceeds the standard level for herbal medicine in China (0.3 mg/kg). A stepwise regression analysis showed that zinc and the pH were the related factors that most significantly impacted Cd in Sanchi roots. The hazard quotient values were estimated as 0.0010 (men) and 0.0012 (women) for consumers taking preparations and were 0.011 (men) and 0.013 (women) for consumers taking health products, implying that there is no non-carcinogenic hazard associated with Sanchi consumption. However, a Monte Carlo simulation showed that approximately 0.80 % of male and 1.02 % of female consumers via drug consumption and 36.28 % of male and 41.87 % of female consumers via health product consumption had an exposure exceeding the acceptable daily intake (ADI) of Cd from drugs (1 % of the total oral ADI as suggested by the World Health Organization). These people should control their oral Cd intake from both Sanchi consumption and diet as a whole.