A metabolomics approach reveals the pharmacological effects and mechanisms of Cistanche tubulosa stems and its combination with fluoxetine on depression in comorbid with sexual dysfunction.

ETHNOPHARMACOLOGICAL RELEVANCE: The dried succulent stems of Cistanche tubulosa (Schenk) Wight are utilized in traditional medicine for tonifying kidney yang, which have shown to be effective in alleviating depression-like behavior or male sexual dysfunction, respectively. However, the pharmacological effects and mechanisms of C. tubulosa and its combinations in the treatment of depression in comorbid with sexual dysfunction remain unclear. AIM OF THE STUDY: This study aims to elucidate the pharmacological effects and mechanisms of C. tubulosa aqueous extract (CTE) and its combination with fluoxetine (FLX) on depression in comorbid with sexual dysfunction. MATERIALS AND METHODS: A mouse model of depression in comorbid with sexual dysfunction was created using the chronic unpredictable mild stress (CUMS) procedure. The therapeutic effects of CTE and its combination with FLX were assessed using depressive-like and mating behavior experiments, histopathological analysis, and hypothalamic pituitary gonadal (HPG) axis function evaluation. The mechanisms were explored by integrated serum and testicular metabolomics combined with network correlation analysis. RESULTS: CTE was confirmed to significantly improve depressive-like behaviors, reduce mating abilities, testicular histopathological damage, and HPG axis hormone secretion disorders in CUMS mice. Subsequently, mechanism exploration findings indicated that CTE might exert its effect by regulating potential efficacy-related biomarkers (isobutyrylglycine, citric acid, D-galactose) to improve several metabolic pathways centered around steroid hormone biosynthesis and tricarboxylic acid (TCA) cycle. Furthermore, the combination of CTE and FLX exhibited stronger antidepressant effects than FLX alone, and ameliorated the exacerbated sexual dysfunction induced by FLX. These effects were achieved through the regulation of potential efficacy-related biomarkers (17α-hydroxypregnenolone, tetrahydrodeoxy-corticosterone, sphingosine, cortol, thymine, and L-histidine), thereby improving disorders in glycerophospholipid and histidine metabolism. CONCLUSION: In conclusion, the amelioration effects of CTE and its combination with FLX on depression in comorbid with sexual dysfunction were confirmed for the first time. This key mechanism may be achieved by modulating the level of potential efficacy-related biomarkers, and then emphatically intervene in steroid hormone biosynthesis, TCA cycle, glycerophospholipid and histidine metabolism. The study offers a new perspective for the development and utilization of C. tubulosa.

[Fetal electrocardiogram signal extraction based on multi-scale residual shrinkage U-Net].

In the extraction of fetal electrocardiogram (ECG) signal, due to the unicity of the scale of the U-Net same-level convolution encoder, the size and shape difference of the ECG characteristic wave between mother and fetus are ignored, and the time information of ECG signals is not used in the threshold learning process of the encoder's residual shrinkage module. In this paper, a method of extracting fetal ECG signal based on multi-scale residual shrinkage U-Net model is proposed. First, the Inception and time domain attention were introduced into the residual shrinkage module to enhance the multi-scale feature extraction ability of the same level convolution encoder and the utilization of the time domain information of fetal ECG signal. In order to maintain more local details of ECG waveform, the maximum pooling in U-Net was replaced by Softpool. Finally, the decoder composed of the residual module and up-sampling gradually generated fetal ECG signals. In this paper, clinical ECG signals were used for experiments. The final results showed that compared with other fetal ECG extraction algorithms, the method proposed in this paper could extract clearer fetal ECG signals. The sensitivity, positive predictive value, and F1 scores in the 2013 competition data set reached 93.33%, 99.36%, and 96.09%, respectively, indicating that this method can effectively extract fetal ECG signals and has certain application values for perinatal fetal health monitoring.

Citrate and hydroxycinnamate derivatives from Mume Fructus protect LPS-injured intestinal epithelial cells by regulating the FAK/PI3K/AKT signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Mume Fructus (MF) is processed from the near-ripe fruit of Prunus mume (Siebold) Siebold & Zucc by drying at low temperature until the color turns black. MF is often used in Chinese medicine for the treatment of chronic diarrhea and dysentery. Previous studies have shown that the active components of MF against Crohn's disease (CD) are mainly citrate and hydroxycinnamate derivatives, which can alleviate the CD-induced inflammatory response and intestinal barrier damage. However, their molecular mechanisms on CD still need further elucidation. AIM OF THE STUDY: To investigate the protective effects and underlying mechanisms of citrate and hydroxycinnamate derivatives in MF on intestinal epithelial injury. MATERIALS AND METHODS: Network pharmacology technology was used to predict the anti-CD targets and molecular mechanisms of 4 citrate and 11 hydroxycinnamate derivative prototypes and 5 hydroxycinnamate derivative metabolites in the 40% ethanol fraction of MF (MFE40), the active anti-CD ingredient group of MF. Lipopolysaccharide (LPS)-treated IEC-6 cells were used to investigate the effects of the above components on the proliferation of damaged IEC-6 cells and to verify the molecular mechanism of their regulation on the FAK/PI3K/AKT signaling pathways for the promotion of the proliferation of IEC-6 cells. RESULTS: A "compound-target-pathway" network was constructed based on network pharmacology analysis, including 20 citrate and hydroxycinnamate derivatives that target 316 core proteins and 36 CD-related pathways, of which PI3K-AKT pathway and focal adhesion were the most enriched pathways. Further cell validation experiments showed that 1 citric acid (CA) compound and 10 hydroxycinnamate derivatives, including 3-O-caffeoylquinic acid (3CQA), 4-O-caffeoylquinic acid (4CQA), 5-O-caffeoylquinic acid (5CQA), caffeic acid (CFA), p-coumaric acid (PCMA), m-coumaric acid (MCMA), ferulic acid (FUA), isoferulic acid (IFUA), 3-hydroxyphenylpropionic acid (3HPPA) and hippuric acid (HPP), could promote the proliferation of IEC-6 cells and inhibit the damage of LPS to IEC-6 cells. Ethyl caffeate (ECFA), a hydroxycinnamic acid derivative, had no effect on promoting the proliferation of IEC-6 cells and was weak in inhibiting the damage of IEC-6 cells caused by LPS. Further mechanistic verification experiments showed that 7 citrate and hydroxycinnamate derivatives (CA, CFA, 3CQA, MCMA, FUA, 3HPPA, and HPP) could upregulate the expression of p-FAK, p-PI3K, and p-AKT proteins. Among them, CA had the better effect on activating the FAK-PI3K-AKT signaling pathway. CONCLUSIONS: Citrate and hydroxycinnamate derivatives in MF can ameliorate LPS-induced intestinal epithelial cell injury to demonstrate potential for Crohn's disease alleviation. This protective effect can be achieved by upregulating FAK/PI3K/AKT pathway.

The Rational Design and Atroposelective Synthesis of Axially Chiral C2-Arylpyrrole-Derived Amino Alcohols.

Axially chiral biaryl diols have achieved great success in asymmetric catalysis. By contrast, axially chiral biaryl amino alcohols are far less developed. Herein, we have rationally designed a versatile C1 -symmetric biaryl amino alcohol scaffold 1-(1-amino-pyrrol-2-yl)naphthalen-2-ol (NPNOL) on the basis of axially chiral C2-arylpyrrole framework. For its enantioselective synthesis, the chiral phosphoric acid-catalyzed asymmetric Attanasi reaction between 1,3-dicarbonyl compounds and azoalkenes had been established. By using this practical method, a wide range of NPNOLs were readily prepared in high yields and excellent atroposelectivities (38 examples, up to 89 % yield and 99 % ee). DFT calculations were performed to reveal the reaction mechanism and the origins of the enantioselectivity. The easy transformations of NPNOL-derived products into organocatalysts/ligands and their preliminary applications in asymmetric catalytic reactions demonstrated the promising utility of NPNOL.

Anti-inflammatory effect of baicalin in rats with adjuvant arthritis and its autophagy- related mechanism.

BACKGROUND: It has been found that baicalin have anti-inflammatory effects since it reduces the elevated levels of pro-inflammatory cytokines. Meanwhile, it has also been shown that baicalin brings positive effects against rheumatoid arthritis (RA). However, little is observed on its beneficial effects on adjuvant arthritis. OBJECTIVE: To consider the anti-inflammatory influence of baicalin on adjuvant arthritis rats and its related autophagy mechanism. METHODS: In this research, there are six groups of rats, each has 10 rats in it. These groups are normal group (normal saline), model group (normal saline), dexamethasone group (0.125 mg/kg dexamethasone), low-dose baicalin group (50 mg/kg baicalin), medium-dose baicalin group (100 mg/kg baicalin) and high-dose baicalin group (200 mg/kg baicalin). The degrees of adjuvant-induced swelling in rats' feet were measured every 4 days and the arthritis scores were calculated every 7 days. The inflamed joint tissues were taken after rats were sacrificed. The rat' joints showed pathological changes, which were observed by HE staining. The relative expression levels of inflammatory factors IL-6, IL-1, IL-17, TNF-α, COX2, and COX1 in the rats' snovial tissues were detected by RT-PCR. As for the expression levels of autophagy markers Beclin1, Atg5, Atg7, Atg12, microtubule-associated protein-light chain3-II (LC3-II), Bcl-2, and Bax in the synovial tissue, they were discoverd by Western blot. RESULTS: Baicalin could significantly inhibit the inflammatory response of adjuvant arthritis rats. CONCLUSIONS: RT-PCR studies showed that the different doses of baicalin could inhibit the expression of TNF-a, IL-6, IL-1, IL-17, COX2 and COX1 in the synovial tissue (P< 0.05 or P< 0.01). Western blot studies showed that the different doses of baicalin could reduce the expression of Atg5, Atg7, Atg12, LC3-II, Beclin1 and Bcl-2 proteins, and increase the expression of Bax proteins in the synovial tissue.