The causal association between artificial sweeteners and the risk of cancer: a Mendelian randomization study.

Artificial sweeteners (ASs) have been widely added to food and beverages because of their properties of low calories and sweet taste. However, whether the consumption of ASs is causally associated with cancer risk is not clear. Here, we utilized the two-sample Mendelian randomization (MR) method to study the potential causal association. Genetic variants like single-nucleotide polymorphisms (SNPs) associated with exposure (AS consumption) were extracted from a genome-wide association study (GWAS) database including 64 949 Europeans and the influence of confounding was removed. The outcome was from 98 GWAS data and included several types of cancers like lung cancer, colorectal cancer, stomach cancer, breast cancer, and so on. The exposure-outcome SNPs were harmonized and then MR analysis was performed. The inverse-variance weighted (IVW) with random effects was used as the main analytical method accompanied by four complementary methods: MR Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses consisted of heterogeneity, pleiotropy, and leave-one-out analysis. Our results demonstrated that ASs added to coffee had a positive association with high-grade and low-grade serous ovarian cancer; ASs added to tea had a positive association with oral cavity and pharyngeal cancers, but a negative association with malignant neoplasm of the bronchus and lungs. No other cancers had a genetic causal association with AS consumption. Our MR study revealed that AS consumption had no genetic causal association with major cancers. Larger MR studies or RCTs are needed to investigate small effects and support this conclusion.

Low-frequency electroacupuncture exerts antinociceptive effects through activation of POMC neural circuit induced endorphinergic input to the periaqueductal gray from the arcuate nucleus.

It has been widely recognized that electroacupuncture (EA) inducing the release of ß-endorphin represents a crucial mechanism of EA analgesia. The arcuate nucleus (ARC) in the hypothalamus is a vital component of the endogenous opioid peptide system. Serving as an integration center, the periaqueductal gray (PAG) receives neural fiber projections from the frontal cortex, insular cortex, and ARC. However, the specific mechanisms how EA facilitates the release of ß-endorphin within the ARC, eliciting analgesic effects are yet to be elucidated. In this study, we conducted in vivo and in vitro experiments by transcriptomics, microdialysis, photogenetics, chemical genetics, and calcium imaging, combined with transgenic animals. Firstly, we detected 2 Hz EA at the Zusanli (ST36) increased the level of ß-endorphin and transcriptional level of proopiomelanocortin (POMC). Our transcriptomics profiling demonstrated that 2 Hz EA at the ST36 modulates the expression of c-Fos and Jun B in ARC brain nuclear cluster, and the transcriptional regulation of 2 Hz EA mainly occur in POMC neurons by Immunofluorescence staining verification. Meaning while, 2 Hz EA specifically activated the cAMP-PKA-CREB signaling pathway in ARC which mediating the c-Fos and Jun B transcription, and 2 Hz EA analgesia is dependent on the activation of cAMP-PKA-CREB signaling pathway in ARC. In order to investigate how the ß-endorphin produced in ARC transfer to integration center PAG, transneuronal tracing technology was used to observe the 2 Hz EA promoted the neural projection from ARC to PAG compared to 100 Hz EA and sham mice. Inhibited PAGGABA neurons, the transfer of ß-endorphin from the ARC nucleus to the PAG nucleus through the ARCPOMC-PAGGABA neural circuit. Furthermore, by manipulating the excitability of POMC neurons from ARCPOMC to PAGGABA using inhibitory chemogenetics and optogenetics, we found that this inhibition significantly reduced transfer of ß-endorphin from the ARC nucleus to the PAG nucleus and the effectiveness of 2 Hz EA analgesia in neurological POMC cyclization recombination enzyme (Cre) mice and C57BL/6J mice, which indicates that the transfer of ß-endorphin depends on the activation of POMC neurons prefect from ARCPOMC to PAGGABA. These findings contribute to our understanding of the neural circuitry underlying the EA pain-relieving effects and maybe provide valuable insights for optimizing EA stimulation parameters in clinical pain treatment using the in vivo dynamic visual investigating the central analgesic mechanism.

Immunosuppression by opioids: Mechanisms of action on innate and adaptive immunity.

Opioids are excellent analgesics for the clinical treatment of various types of acute and chronic pain, particularly cancer-related pain. Nevertheless, it is well known that opioids have some nasty side effects, including immunosuppression, which is commonly overlooked. As a result, the incidence of opportunistic bacterial and viral infections increases in patients with long-term opioid use. Nowadays, there are no effective medications to alleviate opioid-induced immunosuppression. Understanding the underlying molecular mechanism of opioids in immunosuppression can enable researchers to devise effective therapeutic interventions. This review comprehensively summarized the exogenous opioids-induced immunosuppressive effects and their underlying mechanisms, the regulatory roles of endogenous opioids on the immune system, the potential link between opioid immunosuppressive effect and the function of the central nervous system (CNS), and the future perspectives in this field.

Normalization of the H3K9me2/H3K14ac-ΔFosB pathway in the nucleus accumbens underlying the reversal of morphine-induced behavioural and synaptic plasticity by Compound 511.

BACKGROUND: Although opioid agonist-based treatments are considered the first-line treatment for opioid use disorders, nonopioid alternatives are urgently needed to combat the inevitable high relapse rates. Compound 511 is a formula derived from ancient traditional Chinese medical literature on opiate rehabilitation. Previously, we observed that Compound 511 could effectively prevent the acquisition of conditioned place preference (CPP) during early morphine exposure. However, its effects on drug-induced reinstatement remain unclear. PURPOSE: This study aims to estimate the potential of Compound 511 for the therapeutic intervention of opioid relapse in rodent models and explore the potential mechanisms underlying the observed actions. STUDY DESIGN/METHODS: The CPP and locomotor sensitization paradigm were established to evaluate the therapeutic effect of Compound 511 treatment on morphine-induced neuroadaptations, followed by immunofluorescence and western blot (WB) analysis of the synaptic markers PSD-95 and Syn-1. Furthermore, several addiction-associated transcription factors and epigenetic marks were examined by qPCR and WB, respectively. Furthermore, the key active ingredients and targets of Compound 511 were further excavated by network pharmacology approach and experimental validation. RESULTS: The results proved that Compound 511 treatment during abstinence blunted both the reinstatement of morphine-evoked CPP and locomotor sensitization, accompanied by the normalization of morphine-induced postsynaptic plasticity in the nucleus accumbens (NAc). Additionally, Compound 511 was shown to exert a selectively repressive influence on morphine-induced hyperacetylation at H3K14 and a reduction in H3K9 dimethylation as well as ΔFosB activation and accumulation in the NAc. Finally, two herbal ingredients of Compound 511 and six putative targets involved in the regulation of histone modification were identified. CONCLUSION: Our findings indicated that Compound 511 could block CPP reinstatement and locomotor sensitization predominantly via the reversal of morphine-induced postsynaptic plasticity through epigenetic mechanisms. Additionally, 1-methoxy-2,3-methylenedioxyxanthone and 1,7-dimethoxyxanthone may serve as key ingredients of Compound 511 by targeting specific epigenetic enzymes. This study provided an efficient nonopioid treatment against opioid addiction.

Compound 511 ameliorates MRSA-induced lung injury by attenuating morphine-induced immunosuppression in mice via PI3K/AKT/mTOR pathway.

BACKGROUND: Opioids are widely used in clinical practice. However, their long-term administration causes respiratory depression, addiction, tolerance, and severe immunosuppression. Traditional Chinese medicine (TCM) can alleviate opioid-induced adverse effects. Compound 511 is particularly developed for treating opioid addiction, based on Jiumi Liangfang, an ancient Chinese drug treatment and rehabilitation monograph completed in 1833 A.D. It is an herbal formula containing eight plants, each of them contributing to the overall pharmacological effect of the product: Panax ginseng C. A. Meyer (8.8%), Astragalus membranaceus (Fisch.) (18.2%), Datura metel Linn. (10.95%), Corydalis yanhusuo W. T. Wang (14.6%), Acanthopanar gracilistµlus W. W. Smith (10.95%), Ophiopogon japonicus (Linn. f.) Ker-Gawl. (10.95%), Gynostemma pentaphyllum (Thunb.) Makino (10.95%), Polygala arvensis Willd. (14.6%). This formula effectively ameliorates opioid-induced immunosuppression. However, the underlying mechanism remains unclear. PURPOSE: To reveal the effects of Compound 511 on the immune response of morphine-induced immunosuppressive mice and their potential underlying molecular mechanism. This study provides information for a better clinical approach and scientific use of opioids. METHODS: Immunosuppression was induced in mice by repeated morphine administration. Th1/Th2/Th17/Treg cell levels were measured using flow cytometry. Splenic transcription factors of Th1/Th2/Th17/Treg and outputs of the regulatory PI3K/AKT/mTOR signaling pathway were determined. Subsequently, methicillin-resistant Staphylococcus aureus (MRSA) was administered intranasally to morphine-induced immunosuppressive mice pretreated with Compound 511. Their lung inflammatory status was assessed using micro-computer tomography (CT), hematoxylin and eosin (H&E) staining, and enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared to morphine, Compound 511 significantly decreased the immune organ indexes of mice, corrected the Th1/Th2 and Treg/Th17 imbalance in the immune organs and peripheral blood, reduced the mRNA levels of FOXP3 and GATA3, and increased those of STAT3 and T-bet in the spleen. It improved immune function and reduced MRSA-induced lung inflammation. CONCLUSION: Compound 511 ameliorates opioid-induced immunosuppression by regulating the balance of Th1/Th2 and Th17/Treg via PI3K/AKT/mTOR signaling pathway. Thus, it effectively reduces susceptibility of morphine-induced immunosuppressive mice to MRSA infection.

Influence of psychological stress and coping styles in the professional identity of undergraduate nursing students after the outbreak of COVID-19: A cross-sectional study in China.

AIM: To investigate the influencing factors in professional identity of undergraduate nursing students after the outbreak of COVID-19. DESIGN: Cross-sectional study. METHODS: The study covered 2,999 nursing students in six undergraduate nursing schools. Several self-report questionnaires were used to collect the general information, psychological stress, coping styles and professional identity of the undergraduate nursing students. RESULTS: The overall average score of the professional identity of nursing students (3.67 ± 0.51) has increased significantly after the outbreak of COVID-19. The professional identity of the undergraduate nursing students was negatively correlated with psychological stress (r = -0.23, p < .001), expectation (r = -0.12, p < .001) and avoidance (r = -0.16, p < .001), but was positively correlated with solving problems (r = 0.18, p < .001) and seeking support (r = 0.12, p < .001). Academic performance, positions, grades, reasons for choosing a nursing profession, parents or relatives engaged in nursing work and the risk degree of residence were the factors influencing the professional identity score of undergraduate nursing students' (p < .001).

Effects of Impurities on CaSO4 Crystallization in the Ca(H2PO4)2-H2SO4-H3PO4-H2O System.

Wet-process phosphoric acid is a fundamental process in the fertilizer industry. The influence of impurities on crystallization kinetics of CaSO4 was investigated in the Ca(H2PO4)2-H2SO4-H3PO4-H2O system using a mixed suspension mixed product removal crystallizer. Effects of Si, Al, Fe, Mg, K, and Na on crystal morphology and structure were examined in the highly acidic system through scanning electron microscopy and high-resolution transmission electron microscopy. Results show that the increase of Mg, K, and Na content facilitates crystal growth. Si, Al, and Fe are beneficial to CaSO4 crystal growth at a certain concentration range. Impurities also affect the crystal morphology, and the addition of Si, Fe, and Na promotes the formation of needle-like crystals compared with other impurities. X-ray diffraction results show that the preferred crystal growth direction is (020), and the interplanar spacing of the crystals is affected by the element radius of the impurities.

Specific recognition of bovine serum albumin using superparamagnetic molecularly imprinted nanomaterials prepared by two-stage core-shell sol-gel polymerization.

A novel type of uniform magnetic imprinted nanomaterial for the recognition of bovine serum albumin (BSA) was prepared by anchoring MIP shells on the surface of silica deposited Fe3O4 NPs via a surface imprinting process and two-stage core-shell sol-gel polymerization. The resulting magnetic nanomaterials were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, and a vibrating sample magnetometer (VSM). The measurements indicated that the as-synthesized nanospheres exhibited good dispersion, high crystallinity, and satisfactory superparamagnetic properties. Moreover, the obtained Fe3O4@BSA-MIPs had a high saturation magnetization (43.82 emu g-1), which allowed them to be easily separated from solution by means of an external magnetic field. The thickness of the imprinted polymer layer was approximately 5 nm, which would be effective for the mass transport between the solution and the surface of Fe3O4@BSA-MIPs. The kinetic adsorption experiment showed that the imprinted nanomaterials could reach equilibrium within 15 min and be well described by the second-order kinetics model, indicating chemical adsorption might be the rate-limiting step. Meanwhile, the imprinting factor and selectivity coefficient of the Fe3O4@BSA-MIPs were as high as 16.4 and 4.65, displaying excellent selectivity towards BSA. In addition, the resulting imprinted polymers were without obvious deterioration after ten adsorption-desorption cycles and different batches of which exhibited excellent reproducibility. Successful application in the selective separation and enrichment of BSA from a bovine blood sample and good recovery after a reasonably mild elution suggested that the Fe3O4@BSA-MIPs could specifically capture BSA from a real complex matrix and had potential value in practical applications.

Combination of surface imprinting and immobilized template techniques for preparation of core-shell molecularly imprinted polymers based on directly amino-modified Fe3O4 nanoparticles for specific recognition of bovine hemoglobin.

In this work, the core-shell bovine hemoglobin (BHb)-imprinted superparamagnetic nanoparticles (Fe3O4@BHb-MIPs) were synthesized by combining for the first time a surface imprinting technique and a two-step immobilized template strategy. Initially, amino-functionalized Fe3O4 nanoparticles (Fe3O4@NH2) were synthesized directly through a facile one-pot hydrothermal method. Next, BHb was immobilized on the surface of Fe3O4@NH2 through non-covalent interactions. Then, siloxane co-polymerization on the Fe3O4@NH2-protein complex surface resulted in a polymeric network molded around BHb which then became further immobilized. Finally, a thin polymer layer with specific recognition cavities for BHb was formed on the surface of Fe3O4@NH2 after the removal of the template protein. The morphology and structure property of the prepared magnetic nanoparticles were characterized by transmission electronic microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometer (XRD), and vibrating sample magnetometer (VSM). To obtain the best selectivity and binding performance, the polymerization and adsorption conditions were investigated in detail. Under the optimized conditions, the Fe3O4@BHb-MIPs exhibited fast adsorption kinetics, large binding capacity, significant selectivity, and favorable reproducibility. The resultant Fe3O4@BHb-MIPs could not only specifically extract BHb from a mixed standard protein mixture, but also selectively enriched BHb from a real bovine blood sample. In addition, the synthetic process was quite simple and the stability and regeneration of the Fe3O4@BHb-MIPs were also satisfactory.