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Background: Observational studies have showed an association between schizophrenia and risk of psoriasis and vice versa. However, whether schizophrenia is causally associated with psoriasis is unclear. Method s : A two‐sample bidirectional Mendelian randomization (MR) analysis was performed with publicly available genome‐wide association study data including schizophrenia (n = 77 096) and psoriasis (n = 462 933). The inverse‐variance weighted method was performed as the main analysis, with a complementary with the other two analyses: MR‐Egger and weighted median method. A series of sensitivity analyses were also conducted to evaluate the robustness of the results. Results: MR analyses indicated that genetically predicted schizophrenia was significantly associated with an increased risk of psoriasis [OR: 1.001, 95% confidence interval (CI): 1.000–1.002, p = 0.012]. However, no causal effect of genetically predicted psoriasis on schizophrenia (OR: 0.221, 95% CI: 0.029–1.682, p = 0.145) was detected. No pleiotropy or heterogeneity was detected in sensitivity analysis (all p > 0.05). Conclusions: Our study provides genetic evidence for the causal association between schizophrenia and psoriasis. [ABSTRACT FROM AUTHOR]

NHHR (non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio) is a new lipid parameter used to assess the risk of cardiovascular disease. However, the association between NHHR and the risk of depression has not been studied before. We conducted a cross-sectional study using datasets from the National Health and Nutrition Examination Survey (NHANES) 2005–2016. The PHQ-9 questionnaire was used to evaluate depression. A weighted multivariable logistic regression model and a restricted cubic spline (RCS) model were applied to investigate the association between NHHR and depression risk. Additionally, subgroup and sensitivity analyses were conducted to test the robustness of the results. In the total population, compared with the lowest reference group of NHHR, participants in the fourth quartile had a significantly increased risk of depression after full adjustments (OR: 1.61, 95%CI: 1.05–2.49). A linear dose-response relationship existed between NHHR and depression risk (P non-linearity = 0.264). The association remained significant in several subgroup analyses. The cross-sectional design and use of self-reported scales. NHHR was significantly associated with a higher risk of depression in U.S. adults. Additional research on NHHR would help in depression prevention and treatment. • Previous evidence about the association between lipids profile and depression risk is controversial. • Little is known about the association between NHHR and the risk of depression. • Higher NHHR is associated with a significantly increased risk of depression. [ABSTRACT FROM AUTHOR]

Sanguinarine (SAG) is the most abundant constituent of Macleaya cordata (Willd.) R. Br. (Popaceae). SAG has shown antimammary and colorectal metastatic effects in mice in vivo, suggesting its potential for cancer chemotherapy. To determine the antimetastatic effect and underlying molecular mechanisms of SAG on melanoma. CCK8 assay was used to determine the inhibition of SAG on the proliferation of A375 and A2058 cells. Network pharmacology analysis was applied to construct a compound-target network and select potential therapeutic targets of SAG against melanoma. Molecular docking simulation was conducted for further analysis of the selected targets. In vitro migration/invasion/western blot assay with 1, 1.5, 2 μM SAG and in vivo effect of 2, 4, 8 mg/kg SAG in xenotransplantation model in nude mice. The key targets of SAG treatment for melanoma were mainly enriched in PI3K-AKT pathway, and the binding energy of SAG to PI3K, AKT, and mTOR were −6.33, −6.31, and −6.07 kcal/mol, respectively. SAG treatment inhibited the proliferation, migration, and invasion ability of A375 and A2058 cells (p < 0.05) with IC50 values of 2.378 μM and 2.719 μM, respectively. It also decreased the phosphorylation levels of FAK, PI3K, AKT, mTOR and protein expression levels of MMP2 and ICAM-2. In the nude mouse xenograft model, 2, 4, 8 mg/kg SAG was shown to be effective in inhibiting tumour growth. Our research offered a theoretical foundation for the clinical antitumor properties of SAG, further suggesting its potential application in the clinic. [ABSTRACT FROM AUTHOR]

Biothiols, including homocysteine (Hcy), cysteine (Cys) and reduced glutathione (GSH), play various roles in physiological and pathological processes. Because these biothiols possess similar in structures, it is difficult to discriminate Hcy, Cys and GSH from one another. In this work, a novel fluorescent probe, 4-BrCP , based on coumarin as a fluorophore to discriminate GSH from Hcy and Cys was rationally designed and synthesized in three steps with good total yield. The benzothiazol ring played the role of a fluorescent emission wavelength adjuster, while the ester part served as a fluorescent quencher and reactive sites with Hcy, Cys and GSH. The results of responsive experiment indicated that the probe could discriminate GSH from Hcy and Cys distinctly and exhibited a relatively high fluorescence quantum yield (0.84) and low detection limit (9.8 nM). In addition, the probe 4-BrCP also showed good stability and low toxicity. The reaction mechanism of 4-BrCP with GSH was speculated on according to the LC-MS data. Most importantly, because of the length of the skeletons of Hcy, Cys and GSH, different dynamic fluorescent phenomena were observed. Furthermore, imaging experiments suggested that the probe could be used to monitor GSH in living cells and organisms. [Display omitted] • A novel fluorescent probe based on coumarin was rationally designed and synthesized. • The probe could selectively discriminate GSH from Hcy, Cys, or Hcy/Cys/GSH coexisting condition. • The probe showed a good quantum yield (0.84) and low detection limit (9.8 nM). • The probe could trace endogenous GSH in living cells and organisms. [ABSTRACT FROM AUTHOR]

Previous studies have shown that microRNAs (miRNAs) are closely related to many viral infections. However, the molecular mechanism of how miRNAs regulate porcine epidemic diarrhea virus (PEDV) infection remains unclear. In this study, we first constructed a PEDV-infected IPEC-J2 cytopathic model to validate the relationship between miR-129a-3p expression levels and PEDV resistance. Secondly, we explored the effect of miR-129a-3p on PEDV infection by targeting the 3′UTR region of the ligand ectodysplasin (EDA) gene. Finally, transcriptome sequencing was used to analyze the downstream regulatory mechanism of EDA. The results showed that after 48 h of PEDV infection, IPEC-J2 cells showed obvious pathological changes, and miR-129a-3p expression was significantly downregulated (p < 0.01). Overexpression of miR-129a-3p mimics inhibited PEDV replication in IPEC-J2 cells; silencing endogenous miR-129a-3p can promote viral replication. A dual luciferase assay showed that miR-129a-3p could bind to the 3′UTR region of the EDA gene, which significantly reduced the expression level of EDA (p < 0.01). Functional verification showed that upregulation of EDA gene expression significantly promoted PEDV replication in IPEC-J2 cells. Overexpression of miR-129a-3p can activate the caspase activation and recruitment domain 11 (CARD11) mediated NF-κB pathway, thus inhibiting PEDV replication. The above results suggest that miR-129a-3p inhibits PEDV replication in IPEC-J2 cells by activating the NF-κB pathway by binding to the EDA 3′UTR region. Our results have laid the foundation for in-depth study of the mechanism of miR-129a-3p resistance and its application in porcine epidemic diarrhea disease-resistance breeding. [ABSTRACT FROM AUTHOR]

[Display omitted] • Paeoniflorin (PF) depressed T cell activation and promoted its apoptosis in vitro. • PF attenuated the ACD response by inhibiting NF-κB/IκBα/IFN-γ pathway in T cell. • PF may be a promising T cell targeted drug for the treatment of ACD. Paeoniflorin (PF) has been demonstrated to have an anti-allergic and anti-inflammatory effect in the treatment of allergic contact dermatitis (ACD). However, its clinical application is hampered by the lacking of comprehensive mechanical explanation. This research aimed to study the effect of PF on the proliferation, apoptosis and cytokines secretion as well as the expression of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways of T lymphocytes activation in vitro and in vivo. We found that PF depressed human T lymphocytes activation via inhibition of interferon-gamma (IFN-γ) production and NF-κB/IκBα and p38 MAPK signaling pathway in vitro , also PF could attenuate such ACD responses by inhibiting the production of IFN-γ and NF-κB/IκBα pathway in T lymphocytes of ACD mouse model, suggesting that PF might be useful for the treatment of T cell-mediated allergic inflammatory disorders such as ACD. This would make PF a promising T cell-targeted drug candidate for further study because of its immunosuppressive and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Compared with coumarin, 7-hydroxycoumarin could serve as a better hit for developing CYP2A6 inhibitors. In this study, a series of 7-hydroxycoumarin and its structural analogues were collected to study their structure-activity relationship (SAR) and isoform selectivity for inhibiting CYP2A6. All tested coumarins except a C4 phenyl derivative (11) showed higher inhibitory activities for CYP2A6 over the other CYP isoforms, including CYP1A2, CYP2D6, CYP2E1, CYP3A4, CYP2C8, and CYP2C9. Of these coumarins, 6,7-dihydroxycoumarin (1) and 7,8-dihydroxycoumarin (9) were found to be potent inhibitors of CYP2A6 with IC 50 / K i value of 0.39/0.25 and 4.61/3.02 μM, respectively, compared to methoxalen as positive control (IC 50 / K i = 0.43/0.26 μM). In contrast, other coumarins showed low or decreased CYP2A6-inhibiting activities. SAR analysis showed that hydroxy groups might be important for CYP2A6 inhibition, and the rank order of sites for hydroxy substitution was C6 > C7 > C8. In addition, either hydrophobic or hydrophilic substituents introduced into C4, C6 and C8 led to a reduction in CYP2A6-inhibiting activity, and the degree of influence was dependent on the size and electrical charge of substituents. Furthermore, inhibition kinetic analysis and docking simulations demonstrated that the 8- O -glucosylated coumarin derivative (17) exhibited noncompetitive inhibition against CYP2A6, while competitive inhibition patterns were noted for the other tested coumarins. The mechanisms underlying the inhibitors binding to CYP2A6 were further investigated by molecular docking study. The findings presented herein are very helpful for developing highly selective and more potent CYP2A6 inhibitors. Unlabelled Image [ABSTRACT FROM AUTHOR]

Observational studies have found a potential bidirectional positive association between multiple sclerosis and psoriasis, but these studies are susceptible to confounding factors. We examined the directionality of causation using Mendelian randomization and estimated the genetic correlation using the linkage disequilibrium score. We performed Mendelian randomization analysis using large-scale genome-wide association studies datasets from the International Multiple Sclerosis Genetics Consortium (IMSGC, 115,803 individuals of European ancestry) and FinnGen (252,323 individuals of European ancestry). We selected several Mendelian randomization methods including causal analysis using summary effect (CAUSE), inverse variance-weighted (IVW), and pleiotropy-robust methods. According to CAUSE and IVW the genetic liability to MS reduces the risk of psoriasis (CAUSE odds ratio [OR] 0.93, p = 0.045; IVW OR 0.93, p = 2.51 × 10–20), and vice versa (CAUSE OR 0.72, p = 0.001; IVW OR 0.71, p = 4.80 × 10–26). Pleiotropy-robust methods show the same results, with all p-values < 0.05. The linkage disequilibrium score showed no genetic correlation between psoriasis and MS (rg = − 0.071, p = 0.2852). In summary, there is genetic evidence that MS reduces the risk of psoriasis, and vice versa. [ABSTRACT FROM AUTHOR]

This study aimed to develop a novel and practical fluorescent method for GSH detection in complex biological samples. To this end, a series of coumarin-based fluorescent probes was designed and synthesized using various aliphatic halogens as the sensing group. By using a new evaluation method of GSH/Cys/Hcy coexisting conditions, the probe with chloropropionate (CBF3) showed a high selectivity, excellent sensitivity, good stability for GSH detection. The reaction mechanism is proposed as nucleophilic substitution/cyclization and intramolecular charge transfer (ICT), which was confirmed by LC-MS and NMR analysis, as well as density functional theory calculations. In addition, CBF3 was demonstrated to be competent not only for the quantitative detection of GSH in real serum samples, but also for sensing GSH changes in different oxidative stress models in living cells and nematodes. This study showed a practical strategy for constructing GSH-specific fluorescent probes, and provided a sensitive tool for real-time sensing of GSH in real biological samples. The findings would greatly facilitate further investigations on GSH-associated clinical diagnosis and biomedical studies. Image 1 • A novel SN 2 -triggered and ICT-based fluorescent probe was developed for sensing GSH. • The reaction mechanism was confirmed by experimental and theoretical investigations. • The probe selectively responded to GSH in the GSH/Cys/Hcy coexisting conditions. • The probe exhibited a low detection limit of 9.2 nM. • The probe could monitor GSH in real serum sample, and in living cells and nematodes. [ABSTRACT FROM AUTHOR]

Mucins are heavily glycosylated proteins secreted by various cell types, to protect the epithelial surface of the gastrointestinal tract from damage. Currently, increasing studies provided evidence to suggest that mucins play an essential role in regulating tumor progression. However, the role of mucins and the underpinning mechanism of how mucins drive melanoma progression remains elusive. In this study, we first demonstrated that mucin 21 (MUC21) expression was significantly upregulated in metastatic melanoma tissues, and a higher MUC21 expression resulted in poor overall survival in melanoma patients by The Cancer Genome Atlas database analysis. In vitro, MUC21 overexpression markedly promoted proliferative properties and aggressive behavior of melanoma cell A375 and A875, as assessed by Cell Counting Kit‐8 and transwell assay. In mechanism, we proved that MUC21 suppressed expression of SLITRK5, an integral membrane protein, leading to activation of prosurvival hedgehog pathway and sustained melanoma development. More importantly, we found that combination of hedgehog pathway inhibitor cyclopamine and chemotherapy revealed an improved anticancer effect in MUC21 overexpression xenograft model. Altogether, our study described a novel role of MUC21 in regulating tumor progression, which offers a promising target for melanoma diagnosis and therapy. [ABSTRACT FROM AUTHOR]

To introduce a case of removing heterotopic cervical pregnancy while preserving the normal gestational sac in the uterine cavity by hysteroscopic surgery under ultrasound guidance. Video description of the case and surgical procedure. Hospital affiliated to a university. A 35-year-old woman with G7P1A5L1 was admitted with a heterotopic cervical pregnancy 21 days after in vitro fertilization and embryo transfer (the corrected gestational age was 5+2 weeks). The serum β-human chorionic gonadotropin level was 24,530 mIU/mL at the corrected gestational age of 5+3 weeks. Ultrasound examination on the day of admission showed that there was a gestational sac in the cervical canal (1.5 × 0.8 × 0.5 cm, yolk sac visible) and another in the intrauterine cavity (1.2 × 1.2 × 1.1 cm, yolk sac visible). The pregnant woman and her partner strongly urged to remove the cervical gestational sac and continue the intrauterine pregnancy to term. After the Institutional Review Board approval was obtained, hysteroscopic surgery with bipolar resectoscope and transabdominal ultrasound guidance was used to resect the heterotopic cervical pregnancy while preserving the intrauterine gestational sac. The heterotopic cervical pregnancy was completely resected by hysteroscopy, and the normal gestational sac in the uterine cavity was successfully preserved. Ultrasound-guided hysteroscopic surgery allowed us to successfully preserve the intrauterine pregnancy while removing the cervical pregnancy completely. During the operation, the dilation pressure and the flow rate of the dilation fluid was kept as low as possible to avoid excessive intrauterine pressure and excessive dilation fluid entering the intrauterine cavity, which could have had adverse effects on the intrauterine pregnancy sac. No surgical- or anesthesia-related complications occurred. The pathological results confirmed placental villi and decidual tissue. The one-month follow-up ultrasonography showed a live single intrauterine pregnancy with cardiac activity. Hysteroscopic removal of a heterotopic cervical pregnancy under ultrasound guidance can be safely performed while successfully preserving an ongoing intrauterine pregnancy. [ABSTRACT FROM AUTHOR]

In this study, an imidazole-coumarin based fluorescent probe was developed for the selective and sensitive detection of Ag+ in aqueous solution. Using a combination of Job plot, NMR titrations, and DFT calculations, the binding properties between Ag+ and the probe were deeply investigated, and the results revealed a 1:1 binding stoichiometry between the probe and Ag+ with a binding constant of 1.02 × 106 M−1. The detection limit was found to be 150 nM, which satisfies the requirement for the quantitative detection of Ag+ in real water samples. Moreover, the new probe, Ic, was successfully applied to sense Ag+ in HeLa and HepG2 cells as well as in C. elegans, indicating that it could be a useful tool for the environmental monitoring of Ag+ pollution. These results demonstrated that Ic could serve as a high-efficiency and low-cost fluorescent probe for tracking Ag+ in an aquatic environment and biological organisms. [ABSTRACT FROM AUTHOR]

[Display omitted] • The SAR profiles of 1,4-naphthoquinones for activating XO were first investigated. • Introduction of electron-donor/acceptor units in the A/B ring improved the effect. • The effect was well predicted using the HOMO-LUMO gap and the binding free energy. • The risk of 1,4-naphthoquinones was evaluated with kinetic data and in vivo exposure. Oral intake of 1,4-naphthoquinones could be a potential risk factor for hyperuricemia and gout via activation of xanthine oxidase (XO). Herein, 1,4-naphthoquinones derived from food and food-borne pollutants were selected to investigate the structure and activity relationship (SAR) and the relative mechanism for activating XO in liver S9 fractions from humans (HLS9) and rats (RLS9). The SAR analysis showed that introduction of electron-donating substituents on the benzene ring or electron-withdrawing substituents on the quinone ring improved the XO-activating effect of 1,4-naphthoquinones. Different activation potential and kinetics behaviors were observed for activating XO by 1,4-naphthoquinones in HLS9/RLS9. Molecular docking simulation and density functional theory calculations showed a good correlation between -LogEC 50 and docking free energy or HOMO-LUMO energy gap. The risk of exposure to the 1,4-naphthoquinones was evaluated and discussed. Our findings are helpful to guide diet management in clinic and avoid adverse events attributable to exposure to food-derived 1,4-naphthoquinones. [ABSTRACT FROM AUTHOR]

The differences in catalytic mechanism and domain between the soluble (S-COMT) and membrane-bound catechol- O -methyltransferase (MB-COMT) are poorly documented due to the unavailable crystal structure of MB-COMT. Considering the enzymatic nature of S-COMT and MB-COMT, the challenge could be solvable by probing the interactions between the enzymes with the ligands with minor differences in structures. Herein, isomeric shikonin and alkannin bearing a R/S -OH group in side chain at the C2 position were used for domain profiling of COMTs. Human and rat liver-derived COMTs showed the differences in inhibitory response (human's IC 50 and K i values for S-COMT < rat's, 5.80–19.56 vs. 19.56–37.47 μM; human's IC 50 and K i values for MB-COMT > rat's) and mechanism (uncompetition vs. noncompetition) towards the two isomers. The inhibition of the two isomers against human and rat S-COMTs was stronger than those for MB-COMTs (S-COMT's IC 50 and K i values < MB-COMT's, 5.80–37.47 vs. 40.01–111.8 μM). Additionally, the inhibition response of alkannin was higher than those of shikonin in no matter human and rat COMTs. Molecular docking stimulation was used for analysis. The inhibitory effects observed in in vitro and in silico tests were confirmed in vivo. These findings would facilitate further COMT-associated basic and applied research. [Display omitted] • The catalytic mechanism and domain of S-COMT and MB-COMT were probed using isomeric shikonin and alkannin. • S-COMT is more subject to inhibition by shikonin and alkannin compared with MB-COMT. • Alkannin has a higher inhibitory potency towards COMTs than that of shikonin. • The tendency mentioned above was investigated using inhibition kinetics and molecular docking, and further validated in vivo. • Species difference in inhibiting human and rat COMTs by shikonin and alkannin was studied and discussed mechanistically. [ABSTRACT FROM AUTHOR]

Objective Chondrocytes express many kinds of hormone receptors. The function of Follicle stimulating hormone (FSH) in the ovary is mediated by FSH receptor (FSHR). FSH receptor (FSHR) is found in many non-ovarian tissues, however it has been unclear if chondrocytes express FSHR. The purpose of this study is to determine it. Methods Mouse primary chondrocytes and human articular cartilage tissues were examined. The expression and sequence of FSHR mRNA by reverse transcription polymerase chain reaction (RT-PCR) and sequenced, respectively, and its protein expression was tested using western blotting and location was observed under immunofluorescence microscopy. Ovarian tissue was as a positive control. After FSH stimulated mouse chondrocytes, intracellular cAMP levels were assessed by ELISA, and gene expression relative to Mouse WNT Signaling Pathway was tested by RT 2 Profiler PCR Arrays. Results FSHR was detected at the transcriptional level and confirmed to have the same sequence as that of ovary-derived mRNA of FSHR. FSHR proteins presented at the same line as the positive proteins of ovary, in mouse chondrocytes and human cartilage tissue, respectively. FSHR proteins were located at the cell membrane. Intracellular cAMP contents were significantly elevated up to 7-fold in mouse chondrocytes by forskolin (100 mM) (P < 0.001); however, different doses of FSH did not change the cAMP contents in mouse primary chondrocytes. RT 2 Profiler PCR Arrays demonstrated that FSH could cause changes in gene expression among the 84 preordained genes, such as Fosl1, Rhou, and Dkk1, in mouse chondrocytes relative to the control. Conclusion Mouse chondrocytes and human articular cartilage express functional FSHR. Moreover, FSH can act on chondrocytes and cause genetic changes. [ABSTRACT FROM AUTHOR]

A novel two-photon pH probe, 3-benzimidazole-7-hydroxycoumarin (BHC), was designed and synthesized based on the structures of hydroxycoumarin and benzimidazole. BHC showed good linearity in the pH ranges of 3.30–5.40 (pKa = 4.20) and 6.50–8.30 (pKa = 7.20) at a maximum emission wavelength of 480 nm. BHC in acidic and alkaline media could be distinguished by an obvious spectral shift of the maximum absorption wavelength from 390 nm to 420 nm. In addition, BHC was well localized to mitochondria and successfully applied to one-photon and two-photon imaging of pH changes in the mitochondria of HeLa cells. The findings presented herein suggest that BHC can serve as an excellent fluorescent probe for selectively sensing mitochondrial pH changes with remarkable photostability and low cytotoxicity. Unlabelled Image • A new fluorescent probe for one- and two-photon sensing of pH was developed. • The probe responded sensitively and selectively to pH changes within 3.0–6.0 (pKa = 4.20) and 6.0–9.0 (pKa = 7.20). • The probe was successfully applied for monitoring and imaging of mitochondrial pH in living cells. [ABSTRACT FROM AUTHOR]