From Xiaoke to diabetes mellitus: a review of the research progress in traditional Chinese medicine for diabetes mellitus treatment.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia resulting from insulin secretion defects or insulin resistance. The global incidence of DM has been gradually increasing due to improvements in living standards and changes in dietary habits, making it a major non-communicable disease that poses a significant threat to human health and life. The pathogenesis of DM remains incompletely understood till now, and current pharmacotherapeutic interventions are largely inadequate, resulting in relapses and severe adverse reactions. Although DM is not explicitly mentioned in traditional Chinese medicine (TCM) theory and clinical practice, it is often classified as "Xiaoke" due to similarities in etiology, pathogenesis, and symptoms. With its overall regulation, multiple targets, and personalized medication approach, TCM treatment can effectively alleviate the clinical manifestations of DM and prevent or treat its complications. Furthermore, TCM exhibits desirable therapeutic effects with minimal side effects and a favorable safety profile. This paper provides a comprehensive comparison and contrast of Xiaoke and DM by examining the involvement of TCM in their etiology, pathogenesis, treatment guidelines, and other relevant aspects based on classical literature and research reports. The current TCM experimental research on the treatment of DM by lowering blood glucose levels also be generalized. This innovative focus not only illuminates the role of TCM in DM treatment, but also underscores the potential of TCM in DM management.

[Effects of Rehmanniae Radix and Rehmanniae Radix Praeparata on proteomics and autophagy in mice with type 2 diabetes mellitus induced by high-fat diet coupled with streptozotocin].

To compare the pancreatic proteomics and autophagy between Rehmanniae Radix-and Rehmanniae Radix Praeparata-treated mice with type 2 diabetes mellitus(T2DM). The T2DM mouse model was established by high-fat diet coupled with streptozotocin(STZ, intraperitoneal injection, 100 mg·kg~(-1), once a day for three consecutive days). The mice were then randomly assigned into a control group, low-(5 g·kg~(-1)) and high-dose(15 g·kg~(-1)) Rehmanniae Radix groups, low-(150 mg·kg~(-1)) and high-dose(300 mg·kg~(-1)) catalpol groups, low-(5 g·kg~(-1)) and high-dose(15 g·kg~(-1)) Rehmanniae Radix Praeparata groups, low-(150 mg·kg~(-1)) and high-dose(300 mg·kg~(-1)) 5-hydroxymethyl furfuraldehyde(5-HMF) groups, and a metformin(250 mg·kg~(-1)) group. In addition, a normal group was also set and each group included 8 mice. The pancreas was collected after four weeks of administration and proteomics tools were employed to study the effects of Rehmanniae Radix and Rehmanniae Radix Praeparata on protein expression in the pancreas of T2DM mice. The expression levels of proteins involved in autophagy, inflammation, and oxidative stress response in the pancreatic tissues of T2DM mice were determined by western blotting, immunohistochemical assay, and transmission electron microscopy. The results showed that the differential proteins between the model group and Rehmanniae Radix/Rehmanniae Radix Prae-parata group were enriched in 7 KEGG pathways, such as autophagy-animal, which indicated that the 7 pathways may be associated with T2DM. Compared with the control group, drug administration significantly up-regulated the expression levels of beclin1 and phosphorylated mammalian target of rapamycin(p-mTOR)/mTOR and down-regulated those of the inflammation indicators, Toll-like receptor-4(TLR4) and Nod-like receptor protein 3(NLRP3), in the pancreas of T2DM mice, and Rehmanniae Radix showed better performance. In addition, the expression levels of inducible nitric oxide synthase(iNOS), nuclear factor erythroid 2-related factor 2(Nrf2), and heine oxygenase-1(HO-1) in the pancreas of T2DM mice were down-regulated after drug administration, and Rehmanniae Radix Praeparata demonstrated better performance. The results indicate that both Rehmanniae Radix and Rehmanniae Radix Praeparata can alleviate the inflammatory symptoms, reduce oxidative stress response, and increase the autophagy level in the pancreas of T2DM mice, while they exert the effect on different autophagy pathways.

Bioactive Dimeric Diterpenoids from Taiwania cryptomerioides (Hayata) and Their Biological Activities.

Taiwania cryptomerioides Hayata is an endangered relict plant belonging to Taxodiaceae, and it is also an endemic plant to China. The decay-resistant of Taiwania timber can provide highly quality wood for building and furniture. Plenty of regenerative of leaves of T. cryptomerioides also has been used as a resource for the discovery of new dimeric diterpenoids. In a search for structurally diverse dimeric diterpenoids and potent bioactive isolates, ten new heterodimeric diterpenoids, taiwaniadducts K-T (1-4, 6, 8-11, and 14), along with five known ones (5, 7, 12, 13, and 15), were isolated from the leaves of T. cryptomerioides. These new compounds were defined by comprehensive spectroscopic analyses, putative biosynthetic pathways, and the values of optical. Biologically, anti-multidrug resistance (MDR) activities of compounds were evaluated. Compounds 4 and 10 exerted a 9.18-fold potentiation effect on bortezmib (BTZ) susceptibility at a tested concentration (20 µM) better than the positive control verapamil. The research of the leaves of T. cryptomerioides not only added the new data to the structural diversity and activities of dimeric diterpenoids but also could provide support for the medical and industrial application of the leaves of this endangered relict plant.

The mechanism of ginger and its processed products in the treatment of estradiol valerate coupled with oxytocin-induced dysmenorrhea in mice via regulating the TRP ion channel-mediated ERK1/2/NF-κB signaling pathway.

Ginger (Rhizoma zingiberis, RZ) has been used as a food, spice, supplement, flavoring agent, and as an edible herbal medicine. It is characterized by its pungency and aroma, and is rich in nutrients with remarkable pharmacological effects. It is used in traditional medicine clinics to treat diseases and symptoms, such as colds, headache, and primary dysmenorrhea (PD). In China, a variety of processed products of RZ are used as herbal medicines, such as baked ginger (BG) or ginger charcoal (GC) to treat different diseases and symptoms. However, the molecular mechanism of the therapeutic effect of RZ and its processed products (RZPPs, including BG or GC) against PD has not been well characterized. Moreover, whether the transient receptor potential (TRP) ion channels are involved in this process is not clear. In the present study, UHPLC-Q-TOF MS was adopted to analyse the differential quality markers (DQMs) between RZ and RZPPs. In addition, differential metabolomics (DMs) was acquired between RZ- and RZPPs-treated estradiol valerate coupled with an oxytocin-induced PD mouse uterus using untargeted metabolomics (UM). A correlation analysis between DQMs and DMs was also conducted. Benzenoids, lipids, and lipid-like molecules were the main DQMs between RZ and RZPPs. RZ and RZPPs were found to improve the pathological status of the uterus of a PD mouse, with significantly decreased serum levels of E2, PGF2α, TXB2 and remarkably increased levels of PROG and 6-keto-PGF1α. Moreover, RZ and RZPPs alleviated PD in mice via regulating the TRP ion channel-mediated ERK1/2/NF-κB signaling pathway. Our results indicate that the therapeutic effect of RZ and RZPPs against PD may be mediated by regulating the TRP ion channel-mediated ERK1/2/NF-κB signaling pathway, and provide a reference for the development of new dietary supplements or medicines.

Daphnes Cortex and its licorice-processed products suppress inflammation via the TLR4/NF-κB/NLRP3 signaling pathway and regulation of the metabolic profile in the treatment of rheumatoid arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Daphnes Cortex (Daphne Giraldii Nitsche, DGN) is a popular traditional Chinese herbal medicine for traumatic injuries and rheumatoid arthritis (RA) in the Shaanxi and Gansu provinces of China. Due to skin irritation caused by raw DGN (RDGN), licorice-processed DGN products are usually used in clinical practice. However, the efficacy and mechanisms of action between DGN and its licorice-processed DGN products in treating RA have not been compared. AIMS: This study compared the efficacy and elucidated the mechanisms in vitro and in vivo between RDGN and its licorice-processed DGN products in treating RA. MATERIALS AND METHODS: A collagen-induced RA rat model was established, and treated with different doses of RDGN and its licorice-processed DGN products for 4 weeks to explore the therapeutic effects. The anti-inflammatory effects were assessed in RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS). Analyses of the differential quality markers (DQMs) between DGN and its licorice-processed DGN products using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry, and non-targeted metabolomics analyses of rat synovial tissues were used to systematically explore correlations between DGN processing and its efficacy. RESULTS: Licorice-processed DGN products significantly ameliorated RA symptoms in CIA rats. Licorice-processed DGN products also regulated inflammatory cytokines, matrix metalloproteinases, and vascular endothelial growth factor in the serum and cell supernatants. Licorice-processed DGN products significantly inhibited Toll-like receptor 4/nuclear factor kappa B/NOD-like receptor family, pyrin domain containing 3 (TLR4/NF-κB/NLRP3) signaling in CIA rats and LPS-induced RAW264.7 cells. The DQMs between RDGN and its licorice-processed DGN products were identified, most of which were amino acids or energy-related metabolites present in licorice-processed DGN products. Correlations between DQMs with differential metabolites and differential metabolic pathways were established. CONCLUSIONS: Licorice-processed DGN products displayed better anti-inflammatory effects via the TLR4/NF-κB/NLRP3 signaling pathway on CIA rats and LPS-induced RAW264.7 cells, and regulation of the metabolic profile in treating RA.

[Rehmanniae Radix and Rehmanniae Radix Praeparata improve diabetes induced by high-fat diet coupled with streptozotocin in mice through AMPK-mediated NF-κB/NLRP3 signaling pathway].

This study investigated the differential mechanisms of Rehmanniae Radix and Rehmanniae Radix Praeparata in improving diabetes in mice through AMPK-mediated NF-κB/NLRP3 signaling pathway. The diabetic mouse model was established with high-fat diet coupled with streptozotocin(STZ, intraperitoneal injection, 100 mg·kg~(-1), once a day for three consecutive days), after which the mice were randomly divided into model group, low-dose(5 g·kg~(-1)) and high-dose(15 g·kg~(-1)) Rehmanniae Radix groups, low-dose(5 g·kg~(-1)) and high-dose(15 g·kg~(-1)) Rehmanniae Radix Praeparata groups, catalpol group(250 mg·kg~(-1)), 5-hydroxymethylfurfural(5-HMF) group(250 mg·kg~(-1)), metformin group(250 mg·kg~(-1)), with the normal group also set. The organ indexes of heart,liver, spleen, lung, kidney and pancreas were calculated after four weeks of administration. The pathological changes and fibrosis of pancreas, kidney and liver in mice were observed by hematoxylin-eosin(HE) staining and Masson staining. Western blot was used to determine the expression levels of Toll-like receptor-4(TLR4), nuclear factor-κB(NF-κB), Nod-like receptor protein 3(NLRP3),interleukin-1ß(IL-1ß), adenosine monophosphate-activated protein kinase(AMPK), phosphorylated AMPK(p-AMPK) in the pancreas, kidney and liver of mice. Compared with the model group, the administration groups witnessed significant decrease in the liver,spleen, kidney, pancreas and fat indexes of diabetic mice, and there was no significant difference in heart and lung indexes. The pathological states and fibrosis of pancreatic, kidney and liver tissues were significantly improved after administration. Additionally, the expression levels of TLR4, NF-κB and NLRP3 in pancreas, kidney and liver of diabetic mice were significantly lowered. The expression levels of p-AMPK/AMPK were enhanced significantly in kidney and liver of mice in Rehmanniae Radix group while in pancreas, kidney and liver in Rehmanniae Radix Praeparata group. This suggests that Rehmanniae Radix and Rehmanniae Radix Praeparata differ in the mechanism of regulating energy metabolism of multiple organs and thereby exerting anti-inflammatory effects to alleviate symptoms of diabetic mice.

The effect of conservative therapy combined with rehabilitation nursing on elderly compression fracture patients.

OBJECTIVE: To investigate the effect of rehabilitation nursing combined with conservative therapy on patients undergoing compression fracture surgery. METHODS: 86 patients with compression fractures admitted to our hospital for rehabilitation from November 2018 to November 2019 were recruited as the study cohort. The patients were provided with conservative traditional Chinese medicine treatment along with rehabilitation methods such as rehabilitation nursing, lumbar pillows, and the prevention and cure of complications. The post-treatment effects and related influencing factors were observed. RESULTS: A single-factor analysis showed the significant effect of the rehabilitation measures combined with the conservative treatment. Specifically, 80.23% of the patients positively responded to management with lumbar pillows, and the response rates of the other methods, including rehabilitation nursing, conservative TCM treatment, the prevention of complications, and the go-to-ground activity were 68.60%, 52.33%, 94.19%, and 73.26%, respectively. The response rates of the patients who did not undergo the combined treatment were 19.77%, 31.40%, 46.67%, 5.81%, and 26.74%, respectively. The differences were statistically significant (P < 0.05). Also, the overall response rate of the combination therapy was 69.76%. In addition, the logistic regression analysis indicated that lumbar pillows (OR = 0.488, P = 0.036), rehabilitation nursing (OR = 12.23, P = 0.017), conservative TCM treatment (OR = 1.023, P = 0.533), the prevention of complications (OR = 2.293, P = 0.026) and go-to-ground activity (OR = 2.311, P = 0.021) were independent factors in elderly compression fractures. CONCLUSION: Rehabilitation nursing combined with conservative treatment can shorten the healing period and improve functional recovery in elderly compression fracture patients.

cDNA cloning of a novel lectin that induce cell apoptosis from Artocarpus hypargyreus.

We isolated a novel lectin (AHL) from Artocarpus hypargyreusHance and showed its immunomodulatory activities. In this study, the amino acid sequence of AHL was determined by cDNA sequencing. AHL cDNA (875bp) contains a 456-bp open reading frame (ORF), which encodes a protein with 151 amino acids. AHL is a new member of jacalin-related lectin family (JRLs), which share high sequence similarities to KM+ and Morniga M, and contain the conserved carbohydrate binding domains. The antitumor activity of AHL was also explored using Jurkat T cell lines. AHL exhibits a strong binding affinity to cell membrane, which can be effectively inhibited by methyl-α-D-galactose. AHL inhibits cell proliferation in a time- and dose-dependent manner through apoptosis, evidenced by morphological changes, phosphatidylserine externalization, poly ADP-ribose polymerase (PARP) cleavage, Bad and Bax up-regulation, and caspase-3 activation. We further showed that the activation of ERK and p38 signaling pathways is involved for the pro-apoptotic effect of AHL.

Target separation and antitumor metastasis activity of sesquiterpene-based lysine-specific demethylase 1 inhibitors from zedoary turmeric oil.

Lysine-specific histone demethylase 1 (LSD1) was the first histone demethylase identified in epigenetics and has recently emerged as an attractive therapeutic target for treating tumors. To date, almost all reported LSD1 inhibitors have been chemosynthesized; however, natural products possess pharmacological and biological activity and can be sources for drug development. Here, we established a target separation countercurrent chromatography technique to isolate LSD1 inhibitors from zedoary turmeric oil. Four sesquiterpene-based LSD1 inhibitors were efficiently obtained with an inhibition ratio equal to or less than that of the positive control drug. Compound 2 showed the most potent inhibitory activity, with a half-maximal inhibitory concentration of 3.97 µM, and was further tested to determine its ability to inhibit LSD1 and its antitumor metastatic effects in MDA-MB-231 cells. These four compounds are the first sesquiterpene-based natural LSD1 inhibitors to be characterized. Our findings provide a new molecular framework for studying LSD1 inhibitors and offer a template for designing more sesquiterpene-based LSD1 inhibitors with potential antitumor activity.

A CRISPR/Cas9-Mediated, Homology-Independent Tool Developed for Targeted Genome Integration in Yarrowia lipolytica.

Yarrowia lipolytica has been extensively used to produce essential chemicals and enzymes. As in most other eukaryotes, nonhomologous end joining (NHEJ) is the major repair pathway for DNA double-strand breaks in Y. lipolytica Although numerous studies have attempted to achieve targeted genome integration through homologous recombination (HR), this process requires the construction of homologous arms, which is time-consuming. This study aimed to develop a homology-independent and CRISPR/Cas9-mediated targeted genome integration tool in Y. lipolytica Through optimization of the cleavage efficiency of Cas9, targeted integration of a hyg fragment was achieved with 12.9% efficiency, which was further improved by manipulation of the fidelity of NHEJ repair, the cell cycle, and the integration sites. Thus, the targeted integration rate reached 55% through G1 phase synchronization. This tool was successfully applied for the rapid verification of intronic promoters and iterative integration of four genes in the pathway for canthaxanthin biosynthesis. This homology-independent integration tool does not require homologous templates and selection markers and achieves one-step targeted genome integration of the 8,417-bp DNA fragment, potentially replacing current HR-dependent genome-editing methods for Y. lipolyticaIMPORTANCE This study describes the development and optimization of a homology-independent targeted genome integration tool mediated by CRISPR/Cas9 in Yarrowia lipolytica This tool does not require the construction of homologous templates and can be used to rapidly verify genetic elements and to iteratively integrate multiple-gene pathways in Y. lipolytica This tool may serve as a potential supplement to current HR-dependent genome-editing methods for eukaryotes.

New dimeric phthalides from the rhizomes of Ligusticum sinense Oliv.

Two new phthalide dimers (1 and 2) were obtained from the rhizomes of Ligusticum sinense Oliv., along with three known dimeric phthalides (3-5). Their structures were determined with the aid of the spectroscopic data, and their absolute configurations were elucidated based on the comparison of calculated and experimental electronic circular dichroism (ECD) spectra. All the compounds were evaluated in vitro for their inhibitory activities against NO production in LPS-treated RAW264.7 macrophages. Among them, compounds 1 and 3 showed potent NO prohibitive activity with IC50 values at 4.86 ± 0.29 µM and 4.87 ± 0.32 µM, respectively.

Precise separation of lysine-specific demethylase 1 inhibitors from Corydalis yanhusuo using multi-mode counter-current chromatography guided by virtual screening.

It is significant to precisely isolate potential active compounds from medicinal herbs containing multiple compounds. Herein, a new strategy for precise separation of lysine-specific demethylase 1 (LSD1) inhibitors from the rhizome of Corydalis yanhusuo (RCY) using counter-current chromatography (CCC) guided by molecular docking and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) analysis was established. First, representative alkaloids from RCY were docked with LSD1 for screening active skeleton compounds. Simultaneously, the crude extract of RCY was preliminarily separated via pH-zone refining CCC. Subsequently, guided by LC-MS/MS analysis of the fragmentation pathways, three potential active fractions were obtained, followed by further online-storage and recycling CCC separation. Finally, three high-purity target quaternary alkaloids compound 3 (dehydrocorydaline), 7 (coptisine), and 8 (columbamine) were successfully isolated as a new class of potential natural LSD1 inhibitors by only one CCC instrument with multiple modes. Compound 3, with the highest LSD1 inhibition ratio of 2.44 µM, was tested for its ability to inhibit tumor invasion and metastasis in U2OS cells. Therefore, the CCC separation guided by virtual screening is a promising method for the targeted isolation of enzyme inhibitors from medicinal herbs.

New obovatol trimeric neolignans with NO inhibitory activity from the leaves of Magnolia officinalis var. biloba.

Six new obovatol trimeric neolignans, houpulignans A-F (1-6) were isolated from the leaves of Magnolia officinalis var. biloba. Their structures were determined on the basis of the interpretation of HRESIMS, NMR data, and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 are the first examples of neolignans derived from three units of obovatol bearing a rare 1,4-benzodioxepane moiety. Compound 3 possesses a benzodihydropyran ring, meanwhile three units of obovatol in 4-6 are connected by an alkyl chain. Compounds 1-3 inhibited NO production in LPS-stimulated RAW264.7 cells with IC50 values of 8.01, 20.21, and 4.05 µM, respectively.

Effects of virtual reality rehabilitation training on gait and balance in patients with Parkinson's disease: A systematic review.

OBJECTIVE: In recent years, virtual reality (VR) has been tested as a therapeutic tool in neurorehabilitation research. However, the impact effectiveness of VR technology on for Parkinson's Disease (PD) patients is still remains controversial unclear. In order to provide a more scientific basis for rehabilitation of PD patients' modality, we conducted a systematic review of VR rehabilitation training for PD patients and focused on the improvement of gait and balance. METHODS: An comprehensive search was conducted using the following databases: PubMed, Web of Science, Cochrane Library, CINHAL, Embase and CNKI (China National Knowledge Infrastructure).Articles published before 30 December 2018 and of a randomized controlled trial design to study the effects of VR for patients with PD were included. The study data were pooled and a meta-analysis was completed. This systematic review was conducted in accordance with the PRISMA guideline statement and was registered in the PROSPERO database (CRD42018110264). RESULTS: A total of sixteen articles involving 555 participants with PD were included in our analysis. VR rehabilitation training performed better than conventional or traditional rehabilitation training in three aspects: step and stride length (SMD = 0.72, 95%CI = 0.40,1.04, Z = 4.38, P<0.01), balance function (SMD = 0.22, 95%CI = 0.01,0.42, Z = 2.09, P = 0.037), and mobility(MD = -1.95, 95%CI = -2.81,-1.08, Z = 4.41, P<0.01). There was no effect on the dynamic gait index (SMD = -0.15, 95%CI = -0.50,0.19, Z = 0.86, P = 0.387), and gait speed (SMD = 0.19, 95%CI = -0.03,0.40, Z = 1.71, P = 0.088).As for the secondary outcomes, compared with the control group, VR rehabilitation training demonstrated more significant effects on the improvement of quality of life (SMD = -0.47, 95%CI = -0.73,-0.22, Z = 3.64, P<0.01), level of confidence (SMD = -0.73, 95%CI = -1.43,-0.03, Z = 2.05, P = 0.040), and neuropsychiatric symptoms (SMD = -0.96, 95%CI = -1.27,-0.65, Z = 6.07, P<0.01), while it may have similar effects on global motor function (SMD = -0.50, 95%CI = -1.48,0.48, Z = 0.99, P = 0.32), activities of daily living (SMD = 0.25, 95%CI = -0.14,0.64, Z = 1.24, P = 0.216), and cognitive function (SMD = 0.21, 95%CI = -0.28,0.69, Z = 0.84, P = 0.399).During the included interventions, four patients developed mild dizziness and one patient developed severe dizziness and vomiting. CONCLUSIONS: According to the results of this study, we found that VR rehabilitation training can not only achieve the same effect as conventional rehabilitation training. Moreover, it has better performance on gait and balance in patients with PD. Taken together, when the effect of traditional rehabilitation training on gait and balance of PD patients is not good enough, we believe that VR rehabilitation training can at least be used as an alternative therapy. More rigorous design of large-sample, multicenter randomized controlled trials are needed to provide a stronger evidence-based basis for verifying its potential advantages.

Decreased vasodilatory effect of Tanshinone â ¡A Sodium Sulfonate on mesenteric artery in hypertension.

Tanshinone ⅡA Sodium Sulfonate (DS-201), a derivative of traditional Chinese medicinal herb Danshen, has been clinically used for various cardiovascular diseases. Previous studies showed that DS-201 induced vascular relaxation partly due to the activation of the large conductance Ca2+-activated potassium (BKCa) channels. However, the efficacy of DS-201 on the resistant vessels in hypertension remains unknown. Mesentery arteries obtained from spontaneously hypertensive rats (SHR) and hypertension patients were used in this study. The endothelium-denuded mesenteric arteries were prepared to measure the artery tension and evaluate the vasodilatory effect of DS-201. The results showed that DS-201 had a vasodilatory effect on the mesenteric artery rings pre-contracted with either phenylephrine (PE) or thromboxane mimetic U46619 in a concentration-dependent manner. However, the vasodilatory effect of DS-201 significantly decreased in hypertension than in control arteries due to a decrease in protein level of BKCa ß1subunit. A BKCa channel blocker IbTX (200 nM) significantly inhibited the relaxant effect of DS-201 on non-hypertensive arteries, whereas the BKCa channel specific agonist NS1619 rescued the vasodilating effects of DS-201 on hypertensive vessels. These results indicate that the vasodilating effect of DS-201 is BKCa-dependent. This study demonstrated that DS-201 alone may not be effective for treating hypertension, but it may be considered as therapy combined with BKCa-agonists or methods rescuing BKCa functions.

Inhibition of Human UGT1A1-Mediated Bilirubin Glucuronidation by Polyphenolic Acids Impact Safety of Popular Salvianolic Acid A/B-Containing Drugs and Herbal Products.

Bilirubin-related adverse reactions (ADR, e.g., jaundice and hyperbilirubinemia) induced by herbs rich in certain polyphenolic acids are widely reported. However, the causes and the mechanisms underlying these ADR are not well understood. The purpose of this article is to determine the mechanism by which certain polyphenolic acids inhibit UGT1A1-mediated bilirubin glucuronidation, leading to jaundice or hyperbilirubinemia. We investigated in vitro inhibitory effects on bilirubin glucuronidation of salvianolic acid A (SAA), salvianolic acid B (SAB), danshensu (DSS), protocatechuic aldehyde (PA), and rosmarinic acid (RA), as well as two Salvia miltiorrhiza injections (DSI and CDI) rich in polyphenolic acids. The results showed that average formation rates of three bilirubin glucuronides displayed a significant difference (p < 0.05) and the formation of monoglucuronide was favored regardless if an inhibitor was present or not. SAA, SAB, DSI, and CDI, but not DSS, PA, and RA, significantly inhibited human UGT1A1-mediated bilirubin glucuronidation via a mixed-type inhibitory mechanism. Average IC50 values of SAA, SAB, DSI, and CDI-mediated inhibition of bilirubin glucuronidation were bilirubin concentration-dependent, and their values (against total bilirubin glucuronidation) were in the range 0.44 ± 0.02 to 0.86 ± 0.04 µg/mL (for SAA), 4.22 ± 0.30 to 12.50 ± 0.93 µg/mL (for SAB), 9.29 ± 0.76 to 18.82 ± 0.63 µg/mL (for DSI), and 9.18 ± 2.00 to 22.36 ± 1.39 µg/mL (for CDI), respectively. In conclusion, SAA and its analog SAB are the main ingredients responsible for inhibition of bilirubin glucuronidation by DSI and CDI, whose use is associated with many high bilirubin-related ADR.

Hyperoside ameliorates glomerulosclerosis in diabetic nephropathy by downregulating miR-21.

The purpose of this study was to investigate the therapeutic effects of hyperoside (Hyp) on glomerulosclerosis in diabetic nephropathy and its underlying mechanisms. Blood glucose, kidney mass, and renal function of mice were measured. Renal morphology was observed using hematoxylin and eosin, periodic acid - Schiff's, and Masson's trichrome stain. Fibronectin (FN) and collagen IV (COL IV) in kidney were determined by Western blot and immunohistochemical studies. Matrix metalloproteinases (MMP)-2 and -9 and tissue inhibitors of metalloproteinase (TIMP)-1 in renal tissues were detected on both the mRNA and protein levels. miRNA expression and artificial alterations by miRNA agomir transfection were evaluated to investigate the protective mechanism of Hyp in mesangial cells. Hyp effectively improved renal function and physiologic features of db/db mice. Hyp also ameliorated glomerulosclerosis by suppressing FN, COL IV, and TIMP-1 expressions and promoting MMP-9 and MMP-2 expressions. The change in MMP-9 mRNA expression was inconsistent with that in protein levels in kidney, indicating that there was a post-transcriptional regulation. Further exploration in vitro showed that miR-21 was downregulated by Hyp, increasing expression of its target, MMP-9. These results suggest that Hyp can ameliorate glomerulosclerosis in diabetic nephropathy by downregulating miR-21 to increase expression of its target, MMP-9.

A multi-residue method for simultaneous determination of 74 pesticides in Chinese material medica using modified QuEChERS sample preparation procedure and gas chromatography tandem mass spectrometry.

The present study is focused on the development of an analytical method for the simultaneous analysis of seventy-four pesticides belonging to different chemical classes (organochlorines, organophosphates, pyrethroids, dinitroanilines, dicarboximides, triazoles, etc.) in Chinese material medica. The samples were extracted according to the acetate QuEChERS protocol. To reduce the amount of co-extracted compounds, n-hexane instead of acetonitrile was employed as the extraction solvent. To improve the overall recoveries of problematic basic and base-sensitive compounds, sodium acetate was used to adjust the pH to a neutral condition, and florisil combined with octadecyl-modified silica (C18) were utilized in the cleanup step. The samples were analysed by GC-MS/MS, and quantified by matrix-matched calibration. The validation study was carried out on two representative herbs, Chuanxiong Rhizoma and Angelica Sinensis Radix. In two matrices, the linearity of the calibration was good between 5 and 250 ng/mL concentration ranges, and the limits of quantification (LOQs) less than 0.01 mg/kg for most pesticides. At the LOQs and ten times the LOQs, the mean recoveries of almost all pesticides were within 70-120%, with relative standard deviations (RSDs) lower than 10%. The method was applied on twenty real samples. Seven batches of Chuanxiong and five batches of Danggui were found to contain the residues. The combination of modified QuEChERS and GC-MS/MS offers low cost of analysis as well as excellent accuracy and sensitivity. This method could be especially useful for trace analysis of pesticide residues in complex matrices.

Association of prenatal exposure to acetaminophen and coffee with childhood asthma.

PURPOSE: Some studies have suggested that maternal acetaminophen use during pregnancy is associated with asthma in the offspring, and coffee consumption may modify the toxicity of acetaminophen. We aim to examine whether pregnancy maternal acetaminophen use increases the risk for offspring asthma, and whether such a potential association could be modified by maternal coffee consumption. METHODS: We included 63,652 live-born singletons enrolled in the Danish National Birth Cohort. Maternal acetaminophen use and coffee consumption during pregnancy were assessed prospectively via the enrolment questionnaire and three computer-assisted telephone interviews. Asthma cases were identified by using the Danish National Patient Register and the Danish National Prescription Registry. We estimated the hazard ratios (HRs) for asthma according to prenatal acetaminophen and coffee exposure using Cox proportional hazards regression model. RESULTS: After adjusting for potential confounders, acetaminophen use during pregnancy was associated with an increased risk of offspring asthma (HR = 1.16, 95% confidence interval (CI): 1.11-1.22). Coffee drinking during pregnancy was associated with a slightly decreased risk (HR = 0.94, 95%CI: 0.90-0.99). But there was no strong evidence of effect measure modification of acetaminophen use on offspring asthma by coffee consumption. CONCLUSIONS: Acetaminophen use during pregnancy was associated with a modest increased risk for offspring asthma, which was not modified by coffee consumption.