Morinda officinalis oligosaccharides mitigate chronic mild stress-induced inflammation and depression-like behaviour by deactivating the MyD88/PI3K pathway via E2F2.

Morinda officinalis oligosaccharides (MOs) are natural herbal extracts that have been shown to exert antidepressant effects. However, the mechanism of this effect remains unclear. Here, we explored the mechanism by which MOs improved experimental depression. Using a chronic mild stress (CMS) murine model, we examined whether MOs could protect against depressive-like behaviour. Lipopolysaccharide (LPS)- and ATP-treated BV2 cells were used to examine the potential mechanism by which MOs mediate the inflammatory response. We found that MOs prevented the CMS-induced reduction in the sucrose preference ratio in the sucrose preference test (SPT) and shortened the immobility durations in both the tail suspension test (TST) and forced swim test (FST). We also noticed that MOs suppressed inflammatory effects by deactivating the MyD88/PI3K pathway via E2F2 in CMS mice or LPS- and ATP-stimulated BV2 cells. Furthermore, overexpression of E2F2 blunted the beneficial effects of MOs in vitro. Collectively, these data showed that MOs exerted antidepressant effects in CMS mice by targeting E2F2-mediated MyD88/PI3K signalling pathway.

Euryale Small Auxin Up RNA62 promotes cell elongation and seed size by altering the distribution of indole-3-acetic acid under the light.

Euryale (Euryale ferox Salisb.) is an aquatic crop used as both food and drug in Asia, but its utilization is seriously limited due to low yield. Previously, we hypothesized that Euryale small auxin up RNAs (EuSAURs) regulate seed size, but the underlying biological functions and molecular mechanisms remain unclear. Here, we observed that the hybrid Euryale lines (HL) generate larger seeds with higher indole-3-acetic acid (IAA) concentrations than those in the North Gordon Euryale (WT). Histological analysis suggested that a larger ovary in HL is attributed to longer cells around. Overexpression of EuSAUR62 in rice (Oryza sativa L.) resulted in larger glumes and grains and increased the length of glume cells. Immunofluorescence and protein interaction assays revealed that EuSAUR62 modulates IAA accumulation around the rice ovary by interacting with the rice PIN-FORMED 9, an auxin efflux carrier protein. Euryale basic region/leucine zipper 55 (EubZIP55), which was highly expressed in HL, directly binds to the EuSAUR62 promoter and activated the expression of EuSAUR62. Constant light increased the expression of both EubZIP55 and EuSAUR62 with auxin-mediated hook curvature in HL seedlings. Overall, we proposed that EuSAUR62 is a molecular bridge between light and IAA and plays a crucial role in regulating the size of the Euryale seed.

Elucidation of the Reinforcing Spleen Effect of Jujube Fruits Based on Metabolomics and Intestinal Flora Analysis.

Jujube (Ziziphus jujuba Mill.) fruit (JF) is widely consumed as food in Asian countries due to its potential effects for human health. As a traditional Chinese medicine, JF is often used to treat anorexia, fatigue and loose stools caused by spleen deficiency syndromes in China, but the mechanism underlying this effect has not been thoroughly elucidated. In this study, a rat model of spleen deficiency syndromes was adopted to investigate the therapeutic effect of JF extract and its possible mechanism by metabolomics analyses of plasma and urine as well as the intestinal flora analysis. The results showed that the changes in plasma and urine metabolites caused by spleen deficiency were reversed after administration of JF, and these changed endogenous metabolites were mainly involved in retinol metabolism, pentose and glucuronate interconversions, nicotinate and niacinamide metabolism pathways. The 16S rDNA sequencing results showed that JF could regulate intestinal flora imbalance caused by spleen deficiency. The covariance analysis of intestinal flora structure and metabolome indicated that Aerococcus may be a candidate strain for predicting and treating the metabolic pathways of spleen deficiency and related disorders. In summary, it can be revealed that spleen deficiency, which alters metabolic profiles and the intestinal flora, could be alleviated effectively by JF extract.

A novel P38α MAPK activator Bruceine A exhibits potent anti-pancreatic cancer activity.

Pancreatic cancer remains one of the cancers with the poorest prognosis bearing an overall 5-year survival rate of about 5%. Efficient new chemotherapic drugs are still highly desired. Here, bruceine A, a quassinoid identified from the dried fruits of Brucea javanica (L.) Merr., displayed the most potent anti-proliferation activity against pancreatic cancer in vitro and in vivo. Phosphoproteomic analysis revealed p38α MAPK phosphorylation was involved in bruceine A's action in MIA PaCa-2 cells. Utilizing fortebio octet system and microscale thermophoresis, we found p38α MAPK had high affinity for bruceine A. Molecular docking and molecular dynamic simulations showed that bruceine A widely bound to residues (Leu171, Ala172, Met179, Thr180, Val183) in P-loop of p38α MAPK. Key determinants of bruceine A binding with P-loop of p38α MAPK were 19-C[bond, double bond]O, 22-CH3, 32-CH3, and 34-CH3. Taken together, our findings demonstrate that bruceine A binds directly to p38α MAPK, which can be used to probe the role of p38α MAPK phosphorylation in pancreatic cancer progression, and as a novel lead compound for pancreatic cancer therapy.

Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou Seed Ameliorates Insomnia in Rats by Regulating Metabolomics and Intestinal Flora Composition.

The seed of Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou (ZSS) is often used as a traditional Chinese medicine for insomnia due to its sedative and hypnotic effects, but the mechanism underlying this effect has not been thoroughly elucidated. In this study, an insomnia model induced by intraperitoneal injection of DL-4-chlorophenylalanine suspension in Sprague-Dawley rats was adopted to investigate the therapeutic effect of ZSS extract. Metabolomics analyses of plasma and urine as well as 16S rRNA gene sequencing of the intestinal flora were performed. The relationships between the plasma and urine metabolites and the intestinal flora in insomnia rats were also analyzed. The results showed that changes in plasma and urine metabolites caused by insomnia were reversed after administration of ZSS, and these changes were mainly related to amino acid metabolism, especially phenylalanine metabolism. The results of 16S rRNA gene sequencing and short-chain fatty acid determination showed that the ZSS extract could reverse the imbalance of intestinal flora caused by insomnia and increase the contents of SCFAs in feces. All of these improvements are mainly related to the regulation of inflammation. Therefore, it is concluded that insomnia, which alters metabolic profiles and the intestinal flora, could be alleviated effectively by ZSS extract.

Structural analogues in herbal medicine ginseng hit a shared target to achieve cumulative bioactivity.

By a pilot trial on investigating immunomodulatory activity and target of ginsenosides, the major bioactive components of ginseng, here we report that structural analogues in herbal medicines hit a shared target to achieve cumulative bioactivity. A ginsenoside analogues combination with definite immunomodulatory activity in vivo was designed by integrating pharmacodynamics, serum pharmacochemistry and pharmacokinetics approaches. The cumulative bioactivity of the ginsenoside analogues was validated on LPS/ATP-induced RAW264.7 macrophages. The potentially shared target NLRP3 involved in this immunomodulatory activity was predicted by systems pharmacology. The steady binding affinity between each ginsenoside and NLRP3 was defined by molecular docking and bio-layer interferometry assay. The activation of NLRP3 inflammasomes in LPS/ATP-induced RAW264.7 was significantly suppressed by the combination, but not by any individual, and the overexpression of NLRP3 counteracted the immunomodulatory activity of the combination. All these results demonstrate that the ginsenoside analogues jointly hit NLRP3 to achieve cumulative immunomodulatory activity.

Alisma orientalis Beverage Treats Atherosclerosis by Regulating Gut Microbiota in ApoE-/- Mice.

BACKGROUND: Alisma orientalis beverage (AOB) is a Chinese traditional medicine formulated with a diversity of medicinal plants and used for treating metabolic syndrome and atherosclerosis (AS) since time ago. Given the current limited biological research on AOB, the mechanism by which AOB treats AS is unknown. This study investigats the role of AOB-induced gut microbiota regulation in the expansion of AS. METHODS: We established an AS model in male apolipoprotein E-deficient (ApoE-/-) mice that are fed with a high-fat diet (HFD), treated with numerous interventions, and evaluated the inflammatory cytokines and serum biochemical indices. The root of the aorta was stained with oil red O, and the proportion of the lesion area was quantified. Trimethylamine N-oxide (TMAO) and trimethylamine (TMA) levels in serum were evaluated through liquid chromatography with mass spectrometry. Flavin-containing monooxygenase 3 (FMO3) liver protein expression was assessed by Western blotting. 16S rDNA sequencing technique was adopted to establish the changes in the microbiota structure. RESULTS: After 8 weeks of HFD feeding, an inflammatory cytokine, and AS development expression were significantly decreased in mice treated with AOB; the same parameters in the mice treated with the antibiotics cocktail did not change. In the gut microbiota study, mice treated with AOB had a markedly different gut microbiota than the HFD-fed mice. Additionally, AOB also decreased serum TMAO and hepatic FMO3 expression. CONCLUSION: The antiatherosclerotic effects of AOB were found associated with changes in the content of gut microbiota and a reduction in TMAO, a gut microbiota metabolite, suggesting that AOB has potential therapeutic value in the treatment of AS.

Cordycepin Alleviates Anterior Cruciate Ligament Transection (ACLT)-Induced Knee Osteoarthritis Through Regulating TGF-ß Activity and Autophagy.

INTRODUCTION: Osteoarthritis is the most prevalent articular disease in the elderly. We aimed to explore the role of cordycepin (COR) in the progression and development of osteoarthritis and its correlation with TGF-ß activity and autophagy. METHODS: Sprague Dawley rats were induced by anterior cruciate ligament transection (ACLT) to establish knee osteoarthritis model. To investigate the role of COR in knee osteoarthritis, rats were injected with 5, 10, and 20 mg/kg of COR before joint surgery. After surgery, paw withdrawal mechanical threshold (PWMT) was performed. HE staining and Alcian blue staining were carried out to detect cartilage damage. ELISA was used to detect the level of TGFß in the serum. Protein expression was analyzed by Western blotting. RESULTS: In this study, we found that the PWMT of rats with osteoarthritis induced by ACLT was decreased significantly, accompanied by obvious histological and cartilage damage. After different doses of COR treatment, the PWMT of osteoarthritis rats induced by ACLT was increased in a dose-dependent manner. In addition, compared with the control group, COR treatment also reversed the effect of ACLT on cartilage injury in rats. Furthermore, the level of TGF-ß in serum of ACLT rats was increased significantly, which may be related to the overexpression of TGF-ß R1. However, the increase of serum TGF-ß level in ACLT rats was reversed by COR treatment in a dose-dependent manner. It is worth noting that TGF-ß overexpression reduced the proportion of autophagy-related protein LC3-II/I, thus inhibiting autophagy. In order to further confirm the effect of TGF-ß on autophagy, TGF-ß was overexpressed or the autophagy inhibitor 3-MA was applied. The results showed that TGF-ß overexpression and 3-MA treatment reversed the effect of COR on autophagy. CONCLUSION: In summary, our findings declared that COR alleviated ACLT-induced osteoarthritis pain and cartilage damage by inhibiting TGF-ß activity and inducing autophagy in rat model with knee osteoarthritis.

Psycho-social and educational interventions for enhancing adherence to dialysis in adults with end-stage renal disease: A meta-analysis.

AIMS AND OBJECTIVES: To examine the influence of psycho-social and educational interventions on improving adherence to dialysis for patients with end-stage renal disease. BACKGROUND: Adherence to the complex regimen is poor, contributing to avoidable hospitalisation and morbidity. Psycho-social and educational interventions may be beneficial coping strategies. DESIGN: Systematic literature review and meta-analysis were conducted. METHODS: We conducted a systematic search of 8 databases from their inceptions to 16 January 2019 to identify relevant articles. Only randomised controlled trials (RCTs) were included in the analysis. The PRISMA checklist was used. RESULTS: A total of forty RCTs were included to evaluate the effect. The aggregated results of the studies showed that psycho-social and educational interventions elevated adherence rate in both peritoneal dialysis (PD) and haemodialysis (HD) patients. For physiological and biochemical indicators, meta-analysis revealed that significant post-treatment effects were evident for interdialytic weight gain (IDWG), IDWG/dry weight, serum potassium, phosphate, creatinine and blood urea nitrogen (BUN), except for albumin. In particular, subgroup analysis indicated that only the interventions carried out individually exerted significant combined effect for lowering IDWG. As for subjective measures, meta-analysis also revealed small but significant combined effects. CONCLUSIONS: The results of this meta-analysis suggest that psycho-social and educational interventions were associated with significant effects on adherence in patients receiving dialysis regimen. RELEVANCE TO CLINICAL PRACTICE: The analysis suggests that psycho-social and educational interventions should be considered as effective strategies for enhancing adherence to dialysis in adults with end-stage renal disease. The potential utility of these interventions should focus on how best to promote individually implementation in clinical practice.

Rapid and Prolonged Antidepressant-like Effect of Crocin Is Associated with GHSR-Mediated Hippocampal Plasticity-related Proteins in Mice Exposed to Prenatal Stress.

Prenatal stress (PNS) has a prolonged and adverse effect on offspring, leading to a significantly increased vulnerability to developing depression in their later life. Traditional therapies have delayed onset and limited efficacy; thus, it remains an urgent need to find novel medications with fast-onset and high-efficacy potentials. Crocin, with its structure clearly examined, has shown antidepressant-like effects. However, few studies extensively investigated its effect especially in mice exposed to PNS. Using an established PNS model, we tested whether crocin could have a rapid and persistent antidepressant-like effect in PNS mice. Growth hormone secretagogue receptor (GHSR) and phosphoinositide 3-kinase (PI3K) inhibitors were used to test their effects in antidepressant-like effect of crocin. Hippocampal GHSR-PI3K signaling was examined both in PNS mice treated with a single dose of crocin and in combination of GHSR inhibitor. PNS mice showed depression-like behaviors at juvenile and adulthood, and crocin induced an instant and persistent antidepressant-like response in PNS mice in a dose-dependent manner. Moreover, crocin increased the expression of hippocampal synaptic plasticity-associated proteins through the restoration of GHSR-PI3K signaling. Inhibitions of both GHSR and PI3K abolished the effect of crocin in alleviating depressive-like behaviors. More importantly, GHSR inhibitor JMV2959 blocked the enhanced expression of hippocampal plasticity-related proteins induced by crocin. The present study demonstrated that crocin induced a fast-onset and prolonged antidepressant effect in PNS mice and suggested that GHSR-PI3K signaling may play a key role in crocin's effect at least partially by a restoration of hippocampal synaptic plasticity-associated proteins.

A transcranial sonography study of brainstem and its association with depression in idiopathic generalized epilepsy with tonic-clonic seizures.

Brainstem raphe (BR) hypoechogenicity in transcranial sonography (TCS) has been depicted in patients with depression. But, up to date, the association of BR alterations in TCS with depression in patients with epilepsy has never been reported. This study was to investigate the possible role of BR examination via TCS in patients with idiopathic generalized epilepsy with tonic-clonic seizures (IGE-TCS) and depression. Forty-six patients with IGE-TCS and 45 healthy controls were recruited. Echogenicity of the caudate nuclei (CN), lentiform nuclei (LN), substantia nigra (SN), and BR and widths of the lateral ventricle (LV) frontal horns and the third ventricle (TV) were assessed via TCS. The determination of depression was based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV), and depression severity measured by Chinese version Neurological Disorders Depression Inventory for Epilepsy (C-NDDI-E) and Beck Depression Inventory-II (BDI-II). The width of TV in patients with epilepsy was found significantly larger than that in healthy controls (p = 0.001), but there was no significant difference in TV width between patients with IGE-TCS with and without depression. There were no significant differences between patients with IGE-TCS and healthy controls in LV frontal horn width, as well as in SN, CN, LN, and BR echogenicity. Here, it seems that patients with IGE-TCS were detected with smaller SN echogenic area compared with controls though they had no statistical significance. Patients with IGE-TCS with hypoechogenic BR had significantly higher C-NDDI-E and BDI-II scores than those with normal BR signal, and most patients with IGE-TCS with depression exhibited hypoechogenic BR, but few patients with IGE-TCS without depression exhibited hypoechogenic BR. In conclusion, BR echogenic signal alterations in TCS can be a biomarker for depression in epilepsy, but it might not be associated with epilepsy itself. The alterations of SN echogenic area and TV width in TCS may reflect a potential role of SN and diencephalon structure in the pathogenesis of epilepsy, which needs to be further elucidated.

Acute onset neurological symptoms in Wilson disease after traumatic, surgical or emotional events: A cross-sectional study.

Acute onset neurological symptoms evoked by traumatic, surgical, or emotional events in Wilson disease (WD) have never been reported and its clinical characteristics are unclear.We aimed to summarize the clinical characteristics of a special WD whose neurological symptoms acutely developed after traumatic, surgical, or emotional events.Retrospective pilot study.Thirty-one patients who had acute onset neurological symptom as an initial presentation of WD or a new presentation of hepatic WD after mild trauma, surgery, or emotional events were retrospectively studied. All patients were followed for half to 1 year after regular anti-copper treatment.The averaged latency for neurological symptom presentation was 2.79 ±â€Š1.21 hours. The most frequent neurological symptoms were tremor (74%) and basal ganglia (BG) lesions were detected on magnetic resonance imaging in all patients. Lesions in other regions were much less frequently detected. Neurological symptom score and its recovery after treatment were correlated with lesion location: BG area and BG plus other brain areas. Neurological symptoms improved in 21 patients who received timely anti-copper treatment but continued to deteriorate in 6 patients who did not accept regular anti-copper treatment for delayed diagnosis.A diagnosis of WD should be considered when adolescents or adults experience acute presentation of extrapyramidal systems after traumatic, surgical, or emotional stimulation. Timely anti-copper therapy usually gives rise to an excellent prognosis.

Ventrolateral Periaqueductal Gray Matter Neurochemical Lesion Facilitates Epileptogenesis and Enhances Pain Sensitivity in Epileptic Rats.

The ventrolateral periaqueductal gray matter (vlPAG) plays a critical role in the pathogenesis of migraine and few studies have shown that vlPAG might be involved in the pathophysiology of epilepsy. But its roles in epileptogenesis and comorbid relationship between migraine and epilepsy have never been reported. In this study, the impairments of vlPAG neuronal network during spontaneous recurrent seizure (SRS) development after status epilepticus (SE) were investigated, and the pain sensitivity as well as the SRS investigated after neurochemical lesion to vlPAG to determine the role of vlPAG in epileptogenesis and in migraine comorbidity with epilepsy. Neuronal loss and alterations of excitatory and inhibitory neural transmission within vlPAG accompanied the development of epileptogenesis induced by SE. On the other hand, neurochemical lesion to vlPAG enhanced frequency and duration of spontaneous seizure event and frequency of epileptiform inter-ictal spike discharges in electroencephalography (EEG), but decreased pain threshold in epileptic rats. This indicates an involvement of the pain regulating structure, vlPAG, in the pathogenesis of epilepsy. This may imply that vlPAG network alterations could be a possible underlying mechanism of the interactive comorbid relationship between epilepsy and migraine.

Hypoechogenicity of brainstem raphe correlates with depression in migraine patients.

BACKGROUND: Brainstem raphe (BR) hypoechogenicity in transcranial sonography (TCS) has been depicted in patients with major depression (MD) and in depressed patients with different neurodegenerative diseases. But, up to date, the association of BR alterations in TCS with depression in migraineurs has never been reported. This study was to investigate the possible role of BR examination via TCS in migraineurs with depression. METHODS: Forty two migraine without aura (MwoA) patients and 40 healthy controls were recruited. Echogenicity of lentiform nuclei (LN), caudate nuclei (CN), substantia nigra (SN) and brainstem raphe (BR) and width of the frontal horns of the lateral ventricles and the third ventricle were assessed with TCS. The diagnosis of depression was based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders IV (DSM -IV), and the severity of depression was measured by Hamilton Rating Scale for Depression (HAM-D) and Hospital Anxiety and Depression Scale depression subscale (HADS-D). RESULTS: There were no significant differences between migraineurs and controls in the width of frontal horn of the lateral ventricle (p = 0.955), width of third ventricle (p = 0.129) as well as in the echogenicity of SN (p = 0.942), CN (p = 0.053), LN (p = 0.052) and BR (p = 0.677). Here, it seems that more migraineurs were detected with increased echogenecity of CN and LN compared with controls (33.3% versus 15.0% for CN, 19.0% versus 5.0% for LN) though they had no statistical significance. Patients with hypoechogenic BR had significantly higher HAM-D and HADS-D scores than those with normal BR signal (p = 0.000 for both HAM-D and HADS-D), and most (83.33%) migraineurs with depression exhibited hypoechogenic raphe but none (0.00%) of the migraineurs without depression exhibited hypoechogenic raphe (p = 0.000). CONLUSIONS: TCS signal alteration of BR can be a biomarker for depression in migraine but it is not associated with migraine headache itself. LN and CN alterations in TCS may reflect a potential role of them in the pathogenesis of migraine, which needs to be further elucidated.

[Incompatibility mechanism of Crotonis Semen Pulveratum and Glycyrrhizae Radix et Rhizoma based on diuretic effect and intestinal flora structure].

Based on the toxic characteristics caused by the compatibility between "Zaoji Suiyuan" and Glycyrrhizae Radix et Rhizoma, which was found in the previous studies, the expanded study was carried out on the incompatibility mechanism between Crotonis Semen Pulveratum(CT) and Glycyrrhizae Radix et Rhizoma(GU) with the diuretic effect and intestinal flora as the characteristic indexes. The results showed that GU could slow down the rapid diuretic effect of CT, which suggested a tendency of decreasing the efficacy. Both the high and low dose of CT could significantly induce the intestinal injury and change the intestinal bacteria structure of mice. Low dose CT combined with GU could significantly increase the levels of Streptococcus and Rikenellaceae＿ukn. The relative abundance of Desulfovibrio and Streptococcaceae＿ukn were increased after the combined application of high dose CT and GU. It also suggested that there was a risk of inflammation in the liver and intestines when combined application of these two herbs. The results revealed that the combination of CT and GU has a tendency to reduce the clinical effect and increase the toxicity from the aspects of its traditional efficacy and its effect on intestinal microflora structure, which could provide the data for the clinical use of CT.

Incompatibility assessment of Genkwa Flos and Glycyrrhizae Radix et Rhizoma with biochemical, histopathological and metabonomic approach.

ETHNOPHARMACOLOGICAL RELEVANCE: As recorded in traditional Chinese medicine (TCM) theory, Genkwa Flos (YH) and Glycyrrhizae Radix et Rhizoma (GC) compose one herbal pair of the so-called "eighteen incompatible medicaments", which indicate pairs of herbs that are mutually incompatible and that theoretically should not be applied simultaneously. However, the theory has been called into question due to a lack of evidence. AIMS OF STUDY: In this study, the incompatibility of YH and GC was investigated based on an assessment of the toxic effects of their combination by traditional safety methods and a modern metabonomic approach. MATERIALS AND METHODS: Sprague-Dawley rats were used to evaluate the subacute toxicity of YH and YH-GC. The serum, urine, and several tissues were collected for biochemical analysis, histopathological examination, and metabonomic analysis. RESULTS: Rats exposed to a dose of 1.0 g/kg YH (3 times of the Chinese Pharmacopoeia maximum dose) exhibited toxicity of the heart, liver, kidney and testes, and rats exposed to a YH-GC combination (1.0 g/kg YH + 1.0 g/kg GC) exhibited similar hepatotoxicity, which aggravated renal and reproductive toxicity. Following this, a metabonomic study tentatively identified 14 potential biomarkers in the YH group and 10 potential biomarkers in the YH-GC group, and metabolic pathways were then constructed. YH disturbed the pathways of glycerophospholipid metabolism, primary bile acid biosynthesis, and sphingolipid metabolism, while YH-GC combination induced disruptions in phenylalanine, tyrosine and tryptophan biosynthesis, tyrosine metabolism, and glycerophospholipid metabolism. CONCLUSION: The toxicities of YH and YH-GC combination above the Chinese Pharmacopoeia dose were obvious but different. Metabonomics combined with biochemical and histopathological methods can be applied to elucidate the toxicity mechanism of the YH-GC combination that caused liver, kidney and reproductive injuries in rats.

Elucidating the interaction of kansui and licorice by comparative plasma/tissue metabolomics and a heatmap with relative fold change.

Although compatibility is highly advocated in traditional Chinese medicine (TCM), inappropriate combination of some herbs may reduce the therapeutic action and even produce toxic effects. Kansui and licorice, one of TCM "Eighteen Incompatible Medicaments", are the most representative cases of improper herbal combination, which may still be applied simultaneously under given conditions. However, the potential mechanism of their compatibility and incompatibility is unclear. In the present study, two different ratios of kansui and licorice, representing their compatibility and incompatibility respectively, were designed to elucidate their interaction by comparative plasma/tissue metabolomics and a heatmap with relative fold change. As a result, glycocholic acid, prostaglandin F2a, dihydroceramide and sphinganine were screened out as the principal alternative biomarkers of compatibility group; sphinganine, dihydroceramide, arachidonic acid, leukotriene B4, acetoacetic acid and linoleic acid were those of incompatibility group. Based on the values of biomarkers in each tissue, the liver was identified as the compatible target organ, while the heart, liver, and kidney were the incompatible target organs. Furthermore, important pathways for compatibility and incompatibility were also constructed. These results help us to better understand and utilize the two herbs, and the study was the first to reveal some innate characters of herbs related to TCM "Eighteen Incompatible Medicaments".

[Incompatible mechanism of compatibility of Chinese medicines based on Qianjinzi and Gancao effect on intestinal flora/barrier system].

The study was based on the toxic characteristics of the compatibility between "Zaojisuiyuan" and Gancao, with intestinal tract and intestinal bacteria as subject. From the angle of intestinal barrier function, motor function, steady state of intestinal flora and metabolism genes, the toxic and side effects of the compatibility between Qianjinzi and Gancao with similar properties, bases and chemical composition and types were further explored. The results showed that the combined application of Qianjinzi and Gancao enhanced intestinal mucosa damage, and led to abnormal changes in intestinal bacteria structure and metabolic function. It improved the degradation functions of mucus and aromatic amino acids on intestinal bacteria, which may increase the risk of disease and derived from intestinal urotoxin and other toxic substances. This study considered intestinal bacteria as an important target to study the interactions of traditional Chinese medicine. The "drug-intestinal bacteria-metabolism-toxicity" was applied in the experiment. Meanwhile, it provides ideas for exploring incompatible mechanism of traditional Chinese medicines.

Early growth response-1 negative feedback regulates skeletal muscle postprandial insulin sensitivity via activating Ptp1b transcription.

Postprandial insulin desensitization plays a critical role in maintaining whole-body glucose homeostasis by avoiding the excessive absorption of blood glucose; however, the detailed mechanisms that underlie how the major player, skeletal muscle, desensitizes insulin action remain to be elucidated. Herein, we report that early growth response gene-1 ( Egr-1) is activated by insulin in skeletal muscle and provides feedback inhibition that regulates insulin sensitivity after a meal. The inhibition of the transcriptional activity of Egr-1 enhanced the phosphorylation of the insulin receptor (InsR) and Akt, thus increasing glucose uptake in L6 myotubes after insulin stimulation, whereas overexpression of Egr-1 decreased insulin sensitivity. Furthermore, deletion of Egr-1 in the skeletal muscle improved systemic insulin sensitivity and glucose tolerance, which resulted in lower blood glucose levels after refeeding. Mechanistic analysis demonstrated that EGR-1 inhibited InsR phosphorylation and glucose uptake in skeletal muscle by binding to the proximal promoter region of protein tyrosine phosphatase-1B (PTP1B) and directly activating transcription. PTP1B knockdown largely restored insulin sensitivity and enhanced glucose uptake, even under conditions of EGR-1 overexpression. Our results indicate that EGR-1/PTP1B signaling negatively regulates postprandial insulin sensitivity and suggest a potential therapeutic target for the prevention and treatment of excessive glucose absorption.-Wu, J., Tao, W.-W., Chong, D.-Y., Lai, S.-S., Wang, C., Liu, Q., Zhang, T.-Y., Xue, B., Li, C.-J. Early growth response-1 negative feedback regulates skeletal muscle postprandial insulin sensitivity via activating Ptp1b transcription.

Comparative metabolomics analysis for the compatibility and incompatibility of kansui and licorice with different ratios by UHPLC-QTOF/MS and multivariate data analysis.

Kansui, the root of Euphorbia kansui T.N. Liou ex T.P. Wang (Euphorbiaceae), is a well-known poisonous traditional Chinese medicine (TCM). However, many monographs of TCM indicated that it cannot be co-used with licorice, as kansui-licorice is a typical "eighteen incompatible" medicaments. Our previous studies have indicated that kansui was effective in treating malignant pleural effusion (MPE), and the efficacy could be weakened by the co-use of licorice, even causing serious toxicity at the given ratio. Nevertheless, the actual mechanisms of their dosage-toxicity-efficacy relationship need to be well clarified. The present study aimed to investigate the effect of individual and combined use of kansui and licorice on MPE rats, and explain the underlying mechanisms from a metabolomic perspective. Urine samples were analyzed by ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). Partial least-squares discriminate analysis (PLS-DA) models were built to evaluate the interaction between kansui and licorice. Seven potential biomarkers contribute to the separation of model group and control group were tentatively identified. And selenoamino acid metabolism and nicotinate and nicotinamide metabolism with the impact-value 0.31 and 0.24, respectively, were filtered out as the most important metabolic pathways. Kansui and kansui-licorice at a ratio of 4:1 can treat MPE rats by adjusting abnormal metabolic pathways to the normal state, while it may have opposite result with kansui-licorice 1:4. The different influences to the two metabolic pathways may partially explain the dosage-toxicity-efficacy relationship of kansui-licorice with different ratios. The results could offer valuable insights into the compatibility property changes for the two herbs.