Effects of electroacupuncture of different intensities and durations on PERK/ATF4/CHOP signaling pathway in liver of non-alcoholic fatty liver disease rats. / ä¸åŒå¼ºåº¦åŠæ—¶ç¨‹ç”µé’ˆå¹²é¢„å¯¹éžé ’ç²¾æ€§è„‚è‚ªè‚ç— å¤§é¼ è‚è„PERK/ATF4/CHOP通路的影响.

OBJECTIVES: To analyze the effects of electroacupuncture (EA) at "Fenglong" (ST40) and "Zusanli" (ST36) of different intensities and durations on rats with non-alcoholic fatty liver disease (NAFLD) based on the protein kinase R-like endoplasmic reticulum kinase (PERK)-activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP) signaling pathway, so as to explore its mechanism underlying improvement of NAFLD. METHODS: SD rats were randomly divided into normal diet group, high-fat model group, sham EA group, strong stimulation EA (SEA) group, and weak stimulation EA (WEA) group, with 15 rats in each group. Each group was further divided into 2, 3, and 4-week subgroups. NAFLD rat model was established by feeding a high-fat diet. After successful modeling, rats in the SEA and WEA groups received EA at bilateral ST40 and ST36 with dense and sparse waves (4 Hz/20 Hz) at current intensities of 4 mA (SEA group) and 2 mA (WEA group), lasting for 20 minutes, once a day, 5 days a week with 2 days of rest. The sham EA group only had the EA apparatus connected without electricity. Different duration subgroups were intervened for 2, 3, and 4 weeks. After the intervention, the contents of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in rats were detected by an automatic biochemical analyzer；liver morphological changes were observed by Oil Red O staining；real-time fluorescence quantitative PCR and Western blot were used to detect the expression of PERK, ATF4, and CHOP mRNAs and proteins in the rat liver tissue. RESULTS: In the high-fat model group, there was a significant accumulation of red lipid droplets in the liver cells, which was reduced significantly in the SEA group at the 4th week. Compared with the normal diet group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs and proteins in the liver tissue were elevated (P<0.01) in the high-fat model group . Compared with the high-fat model group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, CHOP mRNAs and proteins in the liver tissue were decreased (P<0.01, P<0.05) in the SEA and WEA groups. Compared with the sham EA group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs were decreased (P<0.01, P<0.05) in the SEA and WEA groups, the expression of PERK, ATF4, and CHOP proteins in the liver tissue was decreased (P<0.01) in the SEA group at the 2nd, 3rd, and 4th week, the expression of PERK and CHOP proteins at the 2nd, 3rd, 4th week and ATF4 protein at 2nd week in the liver tissue were decreased (P<0.01, P<0.05) in the WEA group. Compared with the SEA group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs and proteins in the liver tissue were elevated (P<0.05, P<0.01) in the WEA group. Compared with the 2-week time point within the groups, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs and PERK proteins in the liver tissue were decreased (P<0.01, P<0.05) in the SEA and WEA groups at 3rd and 4th week, the expression of ATF4 proteins in the liver tissue was decreased (P<0.01) in the SEA group at 3rd and 4th week, and the expression of CHOP proteins in the liver tissue was decreased (P<0.01) in the SEA group at 4th week and in the WEA group at 3rd and 4th week. Compared with the 3-week time point within the groups, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs were significantly decreased (P<0.05, P<0.01) in the SEA and WEA groups at 4th week, the expression of PERK and CHOP proteins in the liver tissue was decreased (P<0.01) in the SEA and WEA groups at 4th week, and the expression of ATF4 protein in the liver tissue was decreased (P<0.05) in the SEA group at 4th week. CONCLUSIONS: EA at ST40 and ST36 can significantly improve liver function in NAFLD rats, and its mechanism of action may involve inhibiting PERK expression thereby targeting the downstream ATF4/CHOP signaling pathway to suppress endoplasmic reticulum stress, exerting a liver protective effect；the optimal effect was observed with EA intensity of 4 mA for 4 weeks.

Nonextractable Polyphenols from Fu Brick Tea Alleviates Ulcerative Colitis by Controlling Colon Microbiota-Targeted Release to Inhibit Intestinal Inflammation in Mice.

This study was designed to elucidate the colon microbiota-targeted release of nonextractable bound polyphenols (NEPs) derived from Fu brick tea and to further identify the possible anti-inflammatory mechanism in dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice. 1.5% DSS drinking water-induced C57BL/6J mice were fed rodent chow supplemented with or without 8% NEPs or dietary fibers (DFs) for 37 days. The bound p-hydroxybenzoic acid and quercetin in NEPs were liberated up to 590.5 ± 70.6 and 470.5 ± 51.6 mg/g by in vitro human gut microbiota-simulated fermentation, and released into the colon of the mice supplemented with NEPs by 4.4- and 1.5-fold higher than that of the mice supplemented without NEPs, respectively (p < 0.05). Supplementation with NEPs also enhanced the colonic microbiota-dependent production of SCFAs in vitro and in vivo (p < 0.05). Interestingly, Ingestion of NEPs in DSS-induced mice altered the gut microbiota composition, reflected by a dramatic increase in the relative abundance of Dubosiella and Enterorhabdus and a decrease in the relative abundance of Alistipes and Romboutsia (p < 0.05). Consumption of NEPs was demonstrated to be more effective in alleviating colonic inflammation and UC symptoms than DFs alone in DSS-treated mice (p < 0.05), in which the protective effects of NEPs against UC were highly correlated with the reconstruction of the gut microbiome, formation of SCFAs, and release of bound polyphenols. These findings suggest that NEPs as macromolecular carriers exhibit targeted delivery of bound polyphenols into the mouse colon to regulate gut microbiota and alleviate inflammation.

Mechanistic insights into the ameliorative effects of Xianglianhuazhuo formula on chronic atrophic gastritis through ferroptosis mediated by YY1/miR-320a/TFRC signal pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Xianglianhuazhuo formula (XLHZ) has a potential therapeutic effect on chronic atrophic gastritis (CAG). However, the specific molecular mechanism remains unclear. AIM OF THE STUDY: To evaluate the effect of XLHZ on CAG in vitro and in vivo and its potential mechanisms. METHODS: A rat model of CAG was established using a composite modeling method, and the pathological changes and ultrastructure of gastric mucosa were observed. YY1/miR-320a/TFRC and ferroptosis-related molecules were detected. An MNNG-induced gastric epithelial cell model was established in vitro to evaluate the inhibitory effect of XLHZ on cell ferroptosis by observing cell proliferation, migration, invasion, apoptosis, and molecules related to ferroptosis. The specific mechanism of action of XLHZ in treating CAG was elucidated by silencing or overexpression of targets. RESULTS: In vivo experiments showed that XLHZ could improve the pathological status and ultrastructure of gastric mucosa and inhibit ferroptosis by regulating the YY1/miR-320a/TFRC signaling pathway. The results in vitro demonstrated that transfection of miR-320a mimics inhibited cell proliferation, migration, and invasion while promoting cell apoptosis. MiR-320a targeted TFRC and inhibited ferroptosis. Overexpression of TFRC reversed the inhibitory effect of miR-320a overexpression on cell proliferation. The effect of XLHZ was consistent with that of miR-320a. YY1 targeted miR-320a, and its overexpression promoted ferroptosis. CONCLUSION: XLHZ inhibited ferroptosis by regulating the YY1/miR-320a/TFRC signaling pathway, ultimately impeding the progression of CAG.

Effects of reservoir construction on optical and molecular characteristics of dissolved organic matter in a typical P-contaminated river.

The source and composition characteristics of dissolved organic matter (DOM) are crucial to identify and evaluate the sources of pollution in the watershed. The construction of reservoirs changes the hydrological condition and pollutant fate of the river. However, the effects of reservoirs' construction on DOM in the watershed and the underlying mechanisms are still unclear. This study aims to examine and compare the characteristics of DOM in reservoirs and streams in the Huangbai River, a typical reservoir-affected and P-contaminated river within the Yangtze River catchment. The results showed that DOM in reservoirs was characterized by more contribution from autochthonous source, under the influence of reservoirs' construction; while, DOM in rivers was mainly originated from terrestrial input. Reservoirs had more lipid-like and protein-like compounds, while rivers contained more oxy-aromatic-like compounds. The percentage of CHOP molecules in reservoirs was significantly higher than that in rivers. The underlying mechanism is that more suitable conditions were created for plankton to grow after constructing reservoirs, which converted inorganic orthophosphate into organic phosphorus, and over time, organic phosphorus was gradually enriched in reservoirs, which exacerbated the risk of eutrophication in the reservoir water body. This study can provide theoretical support for monitoring and evaluation of water quality in reservoir-affected rivers.

Coupled Processes Involving Organic Matter and Fe Oxyhydroxides Control Geogenic Phosphorus Enrichment in Groundwater Systems: New Evidence from FT-ICR-MS and XANES.

The enrichment of geogenic phosphorus (P) in groundwater systems threatens environmental and public health worldwide. Two significant factors affecting geogenic P enrichment include organic matter (OM) and Fe (oxyhydr)oxide (FeOOH). However, due to variable reactivities of OM and FeOOH, variable strategies of their coupled influence controlling P enrichment in groundwater systems remain elusive. This research reveals that when the depositional environment is enriched in more labile aliphatic OM, its fermentation is coupled with the reductive dissolution of both amorphous and crystalline FeOOHs. When the depositional environment is enriched in more recalcitrant aromatic OM, it largely relies on crystalline FeOOH acting concurrently as electron acceptors while serving as "conduits" to help itself stimulate degradation and methanogenesis. The main source of geogenic P enriched by these two different coupled processes is different: the former is P-containing OM, which mainly contained unsaturated aliphatic compounds and highly unsaturated-low O compounds, and the latter is P associated with crystalline FeOOH. In addition, geological setting affects the deposition rate of sediments, which can alter OM degradation/preservation, and subsequently affects geochemical conditions of geogenic P occurrence. These findings provide new evidence and perspectives for understanding the hydro(bio)geochemical processes controlling geogenic P enrichment in alluvial-lacustrine aquifer systems.

"They Can't Believe They're a Tiger": Insights from pediatric speech-language pathologist mobile app users and app designers.

BACKGROUND: Children with communication disorders experience difficulty in one or more areas of articulation and speech, language, fluency, voice and social communication, and they work with speech-language pathologists (SLPs) to improve their communication. With the rise of adoption and use for mobile applications among special education and healthcare service providers, SLPs also have implemented, and for some, contributed to the design of, mobile applications (apps) during clinical practice. However, how these mobile apps are designed and implemented for clinicians to facilitate their clients' communication and learning experiences during therapy remains underinvestigated. AIMS: This qualitative research study investigated how mobile apps were designed for clinicians to target assessment and intervention goals. Additionally, it focused on how clinicians adopted these apps while integrating therapy techniques to facilitate their clients' learning. METHODS AND PROCEDURES: Informed by the Research, Practice, and Design for iPad Apps (iRPD) framework and the Consolidated Framework for Implementation Research (CFIR), semi-structured interviews were conducted with 37 licensed pediatric SLPs, including 23 SLPs who have used apps and 14 SLPs who have contributed to the design of their own mobile apps. Two rounds of qualitative coding via template analysis and thematic analysis were then used to analyse client and clinician characteristics, clinical practice, therapy tools, app characteristics, influential factors and app design and use recommendations. OUTCOMES AND RESULTS: Results showed SLPs utilise different genres of assistive, educational and recreational game apps to support children's communication development when working with children who have diverse disorders and therapy needs across different age groups. SLPs who have designed their own apps emphasised the importance of following evidence-based practice, well-researched teaching methods and learning theories. Additionally, multiple financial, sociocultural, political and ethical factors contributed to the design, adoption and implementation of mobile apps during services. CONCLUSIONS AND IMPLICATIONS: By understanding the clinician's app use practices situated in various therapy activities and techniques, we specified a list of design recommendations for app designers who are interested in creating mobile apps for supporting children's speech and language development. By bringing insights from both clinical practitioners as well as those with additional technical design backgrounds, this study contributes to the understanding of clinical practice needs and strategies and will lead to the most optimal app design and adoption practice to support the well-being of children with communication disorders. WHAT THIS PAPER ADDS: What is already known on the subject Speech language pathologist (SLPs) implement mobile apps for clients with diverse therapy needs, and their app adoption and use are influenced by multifaceted factors. Although prior studies have reported SLPs' mobile app use, additional information is still needed. For example, the research literature does not include how specific technology is used during therapy practice, or specific details about challenges and needs in implementing and utilising the technology. Additional research also needs to include influential factors (e.g., financial, sociocultural, political, ethical) that are considered when selecting, implementing, assessing and designing an app. The lack of research in these areas directly affects the understanding of clinical mobile technology practices and further hinders clinicians' abilities to advocate for better clinical and design decisions towards identifying and implementing effective mobile apps that facilitate children's communication. What this study adds to existing knowledge This qualitative study is the first known empirical research that interviewed pediatric speech-language pathologists who have used and designed mobile apps for children who receive speech-language therapy across different clinical settings. By investigating experiences from clinician stakeholders to illustrate a holistic overview of app design and development to deployment, this study reported finding on (1) how clinicians use mobile apps to help children to participate in different therapy activities, and (2) a list of recommended design and development guidelines that informs the design and use of mobile apps that best support and motivate children to engage in therapy. What are the potential or actual clinical implications of this work? This study disseminates clinician-reported practices of app design and use with pediatric clients across different speech-language disorders, and identifies gaps and needs for clinicians and researchers who are interested in understanding the role of mobile technology in relationship to human communication and interaction. Additionally, the paper demonstrates that SLPs have instrumental roles rather than passive users in influencing the design and implementation of different genres of mobile apps through evidence-based clinical practice, and call for partnerships across clinicians, special educators and technologists to support children's communication development.

Enrichment of geogenic phosphorus in a coastal groundwater system: New insights from dissolved organic matter characterization.

High concentrations of geogenic phosphorus (P) in coastal aquifer systems pose a serious and continuous threat to the health of marine ecosystems. A major source for geogenic P enrichment in aquifer systems is the mineralization of P-containing organic matter. However, the mechanisms that drive the enrichment remain unclear. Therefore, our study sought to characterize the occurrence, sources, and enrichment mechanisms of geogenic P in a coastal confined aquifer system of the Pearl River Delta, southern China. To achieve this, we conducted Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and fluorescence excitation-emission-matrix spectra (EEMs) as well as hydrochemistry and stable carbon isotope analyses. Our findings indicated that intense degradation of P-containing organic matter produced up to 8.07 mg/L of geogenic P in a reducing environment with abundant organic matter. The dissolved organic matter (DOM) of high-P groundwater (P > 1 mg/L) contained more humic-like fluorophores and exhibited higher humification. Groundwater with high P concentrations contained more aliphatic compounds and highly unsaturated-low O compounds, and the enrichment of P was mostly associated with CHOP compounds in the region of aliphatic compounds and CHON2P compounds in the region of highly unsaturated-low O compounds. Different types of dissolved organic phosphorus (DOP) can be mineralized into P, and even the mineralization of phosphonates takes precedence over the more unstable phosphate esters. P produced by the metabolism of different types of DOP was assimilated by marine microorganisms (e.g., heterotrophic bacteria and archaea), and the newly synthesized organic P compounds by chemosynthesis were subsequently released into the groundwater. Over time, P continues to be enriched in the aquifer system. This study provides new insights into subsurface P cycling in coastal aquatic systems.

Fu brick tea alleviates alcoholic liver injury by modulating the gut microbiota-liver axis and inhibiting the hepatic TLR4/NF-κB signaling pathway.

This study first evaluated the protective effects of Fu brick tea water extracts (FTE) on alcoholic liver injury and its underlying mechanism in C57BL/6J mice. Oral administration of FTE by oral gavage (400 mg per kg bw) for 12 weeks significantly alleviated lipid metabolism disorder, reduced the activities of serum ALT and AST, decreased the expression of the liver CYP2E1 gene, and enhanced the antioxidant capacities of the livers in alcohol-fed mice (p < 0.05). FTE also relieved alcohol-induced gut microbiota dysbiosis by promoting the proliferation of probiotics such as Muribaculaceae and Lactobacillus, and subsequently increased the cecal levels of short-chain fatty acids (SCFAs) and decreased the tryptophan content of alcohol-fed mice (p < 0.05). Importantly, FTE was found to improve the alcohol-impaired gut barrier function by up-regulating the expression of the epithelial tight junction protein. Accordingly, FTE decreased the circulating lipopolysaccharide (LPS) and thus inhibited the hepatic TLR4/NF-κB signaling pathway to ameliorate alcoholic liver injury. Cumulatively, these findings shed light on the important role of the gut microbiota-liver axis behind the protective efficacy of FTE on alcoholic liver injury.

p-hydroxy benzaldehyde revitalizes the microenvironment of peri-infarct cortex in rats after cerebral ischemia-reperfusion.

BACKGROUND: The formation of glial scar around the ischemic core following cerebral blood interruption exerts a protective effect in the subacute phase but impedes neurorepair in the chronic phase. Therefore, the present study aimed to explore whether p-hydroxy benzaldehyde (p-HBA), a phenolic compound isolated from Gastrodia elata Blume, can cut the Gordian knot of glial scar and promote brain repair after cerebral ischemia. METHODS: The effects of p-HBA on neurorepair were evaluated using a rat model of transient middle cerebral artery occlusion (tMCAO). The motor functions were evaluated by neurobehavioral tests, the pathophysiological processes in the peri-infarct cortex (PIC) were detected by viral-based lineage tracking or immunofluorescence staining, and the putative signaling pathway was analyzed by western blot. RESULTS: Administration of p-HBA in the acute stage after stroke onset alleviated the motor impairment in tMCAO rats in a time-dependent manner. The corresponding cellular events were inhibition of astrogliosis, facilitating the conversion of reactive astrocytes (RAs) into neurons, and prompting angiogenesis in PIC, thereby protecting the structure of the neurovascular unit (NVU). One of the underlying molecular mechanisms is the activation of the neurogenic switch of the Wnt/ß-catenin signaling pathway. Notably, p-HBA only promotes astrocyte-to-neuron conversion in the PIC, and only partial RAs were converted to neurons. This pattern of conversion ensures that the brain structure remains unaltered, and the beneficial role of glial scarring is preserved during the subacute phase after ischemia. CONCLUSIONS: These results provided a potential approach to address the dilemma of glial scarring after brain injury, i.e., the pharmacological promotion of astrocyte-to-neuron conversion in the PIC without interfering with normal brain tissue, which mitigates but does not eliminate the glial scar. Subsequently, the neuron rescue-unfriendly environment is switched to a beneficial reconstruction milieu in PIC, which is conducive to neurorepair. Moreover, p-HBA could be a candidate for pharmacological intervention.

Artemisinin Alleviates Intestinal Inflammation and Metabolic Disturbance in Ulcerative Colitis Rats Induced by DSS.

Objective: This study is aimed to reveal the possible mechanisms of artemisinin in the treatment of ulcerative colitis (UC) through bioinformatics analysis and experimental verification in UC model rats. Methods: Firstly, we searched two microarray data of the Gene Expression Omnibus (GEO) database to explore the differentially expressed genes (DEGs) between UC samples and normal samples. Then, we selected DEGs for gene ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The acute UC model of rats was established by using 3.5% dextran sulfate sodium (DSS) for 10 days to verify the core pathway. Finally, we evaluated the therapeutic effect of artemisinin at the molecular level and used metabonomics to study the endogenous metabolites in the rat serum. Results: We screened in the GEO database and selected two eligible microarray datasets, GSE36807 and GSE9452. We performed GO function and KEGG pathway enrichment analyses of DEGs and found that these DEGs were mainly enriched in the inflammatory response, immune response, and IL-17 and NF-κB signaling pathways. Finally, we verified the IL-17 signaling pathway and key cytokines, and ELISA and immunohistochemical results showed that artemisinin could downregulate the expression of proinflammatory cytokines such as IL-1ß and IL-17 in the IL-17 signaling pathway and upregulate the expression of the anti-inflammatory cytokine PPAR-γ. Metabolomics analysis showed that 33 differential metabolites were identified in the artemisinin group (AG) compared to the model group (MG). Differential metabolites were mainly involved in alanine, aspartate, and glutamate metabolism and synthesis and degradation of ketone bodies. Conclusion: In this study, we found that artemisinin can significantly inhibit the inflammatory response in UC rats and regulate metabolites and related metabolic pathways. This study provides a foundation for further research on the mechanism of artemisinin in the treatment of UC.

Population pharmacokinetics and dosage optimisation of tacrolimus coadministration with Wuzhi capsule in adult liver transplant patients.

This study aimed to establish a population pharmacokinetic model of tacrolimus coadministration with Wuzhi capsule and optimise the dosage regimen in adult liver transplant patients.Totally 1327 tacrolimus trough concentrations from 116 adult liver transplant patients were obtained for model development. A one-compartment model with first-order absorption and elimination was used to analyse the data, and the final model was internally verified using a goodness-of-fit diagnostic plot, bootstrap methods, and visual prediction test. A total of 29 patients with 250 tacrolimus trough concentrations were used for external validation via prediction-based diagnostics. Additionally, the simulation was used to optimise the recommended dose of tacrolimus and Wuzhi capsules.The estimated apparent clearance and volume of the distribution of tacrolimus were 15.4 L/h and 1210 L, respectively. The tacrolimus daily dose, Wuzhi capsule daily dose, postoperative time, alanine transaminase, haemoglobin, total bilirubin, direct bilirubin, estimated glomerular filtration rate, and urea, concomitant with voriconazole and fluconazole, were identified as significant covariates affecting the pharmacokinetic parameters. Internal and external validation showed that the final model was stable and reliable for predicting performance.The final model could provide guidance for dosage optimisation of tacrolimus coadministered with Wuzhi capsules in adult liver transplantation patients.

Phosphorus cycling in freshwater lake sediments: Influence of seasonal water level fluctuations.

Freshwater lakes experience drastic water level fluctuations because of climate change and human activities. However, the influence of such fluctuations on phosphorus cycling in sediments has rarely been investigated. We conducted a geochemical investigation on the phosphorus cycle in a shallow freshwater lake, Dongting Lake; under the influence of human activities and climate change, its water regime undergoes drastic changes. Irrespective of the permanent inundation zone (PIZ) or seasonal inundation zone (SIZ), the phosphorus cycle in sediments was found to be dominated by the reductive dissolution of iron (Fe) (oxyhydr)oxides, degradation of organic matters, and conversion between authigenic phosphorus (Ca-P) and detrital phosphorus in individual seasons. From winter to summer, with increasing water level, the content of Fe-bound phosphorus and organic phosphorus increase due to the deposition of suspended matter, thus increasing total phosphorus in PIZ. Moreover, the rising water level also reduces the dissolved oxygen content and promotes the reductive dissolution of Fe (oxyhydr)oxides. The mineralization of increased organic matter can release CO2 and reduce pH in the vicinity, which can further result in the acidic dissolution of detrital apatite. In turn, most of the released phosphorus can be adsorbed or co-precipitated with calcium minerals, resulting in the significant increase of Ca-P. The mechanisms of phosphorus transformation in SIZ are similar to those in PIZ, but most of the increased organic matter and total P in a core from SIZ are attributable to the decomposition of plant matter. Therefore, the water level rise not only changes the conservative speciation of phosphorus in sediments to active speciation, but also triggers the release of phosphorus adsorbed to oxides and further increases the risk of phosphorus release from sediments to overlying water. Thus, our findings have major implications for freshwater shallow lakes and their P-driven productivity.

Associations between medication use and phthalate metabolites in urine and follicular fluid among women undergoing in vitro fertilization.

BACKGROUND: Phthalates, which are used as excipients of drugs, have been related to adverse reproductive outcomes. However, the relationships between medication use and phthalate exposure among women undergoing in vitro fertilization (IVF) have not been studied. OBJECTIVE: To investigate the associations between the medication intake and phthalate metabolites in urine and follicular fluid (FF). METHOD: Eight phthalate metabolites were measured in urine and FF samples from 274 women undergoing IVF using liquid chromatography-tandem mass spectrometry. Information on recent medication intake was obtained via interview by trained staff. We constructed generalized linear regression models to examine the associations of medication intake with phthalate metabolite concentrations and dose-response relationships between the number of medicines used and metabolite concentrations in two matrices. RESULTS: Four of 10 drugs were used by more than 10% of the participants, including vitamins (23.0%), traditional Chinese medicine (TCM, 22.3%), antioxidants (12.4%) and amoxicillin (10.2%). Participants who had used TCM had 26.0% (95% CI: 0.0, 58.8%), 32.6% (95% CI: 4.2, 68.8%) and 32.3% (95% CI: 2.6, 70.6%) higher urinary mono-n-butyl phthalate (MBP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) concentrations, respectively, than those who had not. Antioxidant intake was associated with a 30.6% (95% CI: -48.5, -6.6%) decrease in the urinary MBP concentration. Compared with non-users, women who reported the use of medicines had 53.2% (95% CI: 2.7, 128.5%) higher concentrations of MMP and a 37.7% (95% CI: -60.7, -1.5%) lower level of MBP in FF, respectively. CONCLUSION: Our data suggest that the intake of some medications may increase phthalate exposure among women undergoing IVF.

Costunolide alleviates HKSA-induced acute lung injury via inhibition of macrophage activation.

Staphylococcus aureus (S. aureus) infection leads to a severe inflammatory response and causes acute lung injury (ALI), eventually threatening human life. Therefore, it is of importance to find an agent to inhibit inflammation and reduce ALI. Here, we found that costunolide, a sesquiterpene lactone, displays anti-inflammatory effects and ameliorates heat-killed S. aureus (HKSA)-induced pneumonia. Costunolide treatment attenuated HKSA-induced murine ALI in which pulmonary neutrophil infiltration was inhibited, lung edema was decreased, and the production of pro-inflammatory cytokines was significantly reduced. In addition, costunolide dose-dependently inhibited the generation of IL-6, TNF-α, IL-1ß, and keratinocyte-derived cytokine (KC), as well as the expression of iNOS, in HKSA-induced macrophages. Furthermore, costunolide attenuated the phosphorylation of p38 MAPK and cAMP response element-binding protein (CREB). Collectively, our findings suggested that costunolide is a promising agent for alleviating bacterial-induced ALI via the inhibition of the MAPK signaling pathways.

Schisandrin C targets Keap1 and attenuates oxidative stress by activating Nrf2 pathway in Ang II-challenged vascular endothelium.

Vascular endothelial dysfunction plays a crucial role in the pathogenesis of cardiovascular diseases. Oxidative stress is a key pathophysiological mechanism underpinning endothelial dysfunction. Schisandrin C (Sch C), a dibenzocyclooctadiene derivative of Schisandra chinensis, has antioxidative properties. Here, we report the use of Sch C as a novel therapeutic for the treatment of angiotensin II (Ang II)-induced endothelial deficits and explore the underlying mechanisms and the target of Sch C. Our results demonstrated that Sch C treatment prevents aorta oxidative stress and improves relaxation in mice, challenged with subcutaneous infusion of Ang II. In addition, Sch C significantly ameliorates Ang II-induced oxidative stress in rat aortic endothelial cells. We then discovered that these antioxidative effects of Sch C are mediated through the induction of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Using an expression plasmid and molecular docking, we identified that Kelch-like ECH-associated protein-1 (Keap1), a negative regulator of Nrf2, is a target of Sch C. These findings provide evidence for the potential use of Sch C as an antioxidative agent for treatment of vascular endothelial deficits.

The effects of ultraviolet supplementation to the artificial lighting on rats' bone metabolism, bone mineral density, and skin.

Working and living under artificial lighting environment for a long duration do not allow sufficient sunlight exposure, resulting in an adverse effect on bone. Common artificial light source, white LED light, does not include ultraviolet irradiation that plays an important role in bone metabolism. Ultraviolet supplementation in artificial lighting environment can be used to simulate the effect of sunlight irradiation on bone metabolism. In this paper, we report the effects of long-term exposure of low-dose ultraviolet irradiation on the rats' bones and skin. We studied the changes in body weight, bone metabolism markers, bone mass content, bone mineral density, and skin of rats, under long-term exposure of low-dose ultraviolet irradiation. We found that the rats exposed to ultraviolet irradiation showed an increase in bone formation rate, decrease in bone resorption rate, and improvement in bone mass content and bone mineral density without adverse effects on skins. This paper provides an effective basis for future application of LED light to create a healthier, safer, and more comfortable indoor lighting environment.

[Protective effect and mechanism of p-hydroxybenzaldehyde on blood-brain barrier].

The disruption of blood-brain barrier(BBB) induced by oxidative stress is an important pathological reaction which results in secondary brain injury during the cerebral ischemia-reperfusion. This study was designed to investigate the protective effect and mechanism of p-hydroxybenzaldehyde (p-HBA) from Gastrodia elata on BBB. The BBB is mainly consisted of vascular endothelial cells and astrocytes, so brain microvascular endothelial cell line (bEnd.3) and astrocytes (Ast) in mice were used in this study to establish BBB model. H2O2-induced oxidative stress was employed to induct the BBB damage. The bEnd.3 cells or astrocytes were exposed to different concentrations of H2O2 (0.125, 0.25, 0.5, 0.75 mmol·L⁻¹) for 4 h, then exposed to 0.5 mmol·L⁻¹ H2O2 for different duration (1, 2, 4, 6 h) to detect the reasonable condition of oxidative injury. After intervention by different concentrations of p-HBA(12.5, 25, and 50 mg·L⁻¹), LDH leakage rate was detected for bEnd.3 and Ast cells; the expression levels of tight junction protein claudin-5 and occludin in bEnd.3 cells were determined by Western blot and immunofluorescence. Nrf2, HO-1 and NQO1 in normal bEnd.3 cells and astrocytes as well as H2O2-induced damaged in astrocytes were detected by western blot after treatment with p-HBA. The results showed that the optimal condition of H2O2 induced damage in bEnd.3 cells and astrocytes was set up as exposure the cells to 0.5 mmol·L⁻¹ H2O2 for 4 h. Different concentrations of p-HBA could decrease LDH leakage rate after bEnd.3 and Ast injury was induced by H2O2; increase the protein expression levels of claudin-5, occludin, Nrf2, HO-1 and NQO1; and increase the expression levels of Nrf2, HO-1 and NQO1 in normal and H2O2-induced damaged astrocytes. These findings indicate that the p-HBA has protective effect on the BBB, and the related mechanism seems to involve up-regulating tight junction protein of the bEnd.3 cells and enhancing endogenous antioxidant capacity by activating the Nrf2/ARE pathway in both of bEnd.3 cells and astrocytes.

The hypothalamus as the primary brain region of metabolic abnormalities in APP/PS1 transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is an amyloid-related neurodegenerative disorder and is also considered to be a metabolic disease. Thus, investigation of metabolic mechanisms of amyloid pathology progression is of substantial importance for the diagnosis, prevention and treatment of AD. In the present study, cognitive function and brain metabolism were explored in the transgenic APP/PS1 mouse model of amyloid pathology at different ages. Using an NMR-based metabolomic approach, we examined metabolic changes in six different brain regions of wild-type and APP/PS1 mice at 1, 5 and 10months of age. Learning and memory performance in mice was evaluated using the Morris water maze test. Furthermore, a generalized linear mixed model was employed to analyze the interaction effect between the mouse-type and brain region (or age) on metabolic alterations. Brain region-specific changes in energy metabolism occurred prior to a very early-stage of amyloid pathology (1month of age) in APP/PS1 mice. A hypermetabolic state was identified in the brains of APP/PS1 mice at 5months of age, and the hypothalamus was identified as the main brain region that underwent significant metabolic alterations. The cognitive function of APP/PS1 mice was impaired at 10months of age; moreover, the hypermetabolic state identified in various brain regions at 5months of age was also significantly decreased. In conclusion, our results suggest that a hypothalamic metabolism abnormality may comprise a potential indicator for the early-diagnosis and monitoring of amyloid pathology progression.

Ligand- and protein-based modeling studies of the inhibitors of human cytochrome P450 2D6 and a virtual screening for potential inhibitors from the Chinese herbal medicine, Scutellaria baicalensis (Huangqin,Baikal Skullcap).

We have previously examined the binding patterns of various substrates to human cytochrome P450 2D6 (CYP2D6) using a series of molecular modeling methods. In this study, we further explored the binding modes of various types of inhibitors to CYP2D6 using a combination of ligand- and protein-based modeling approaches. Firstly, we developed and validated a pharmacophore model for CYP2D6 inhibitors, which consisted of two hydrophobic features and one hydrogen bond acceptor feature. Secondly, we constructed and validated a quantitative structure-activity relationship (QSAR) model for CYP2D6 inhibitors which gave a poor to moderate prediction accuracy. Thirdly, a panel of CYP2D6 inhibitors were subject to molecular docking into the active site of wild-type and mutated CYP2D6 enzyme. We demonstrated that 8 residues in the active site (Leu213, Glu216, Ser217, Gln244, Asp301, Ser304, Ala305, and Phe483) played an important role in the binding to the inhibitors via hydrogen bond formation and/or π-π stacking interaction. Apparent changes in the binding modes of the inhibitors have been observed with Phe120Ile, Glu216Asp, Asp301Glu mutations in CYP2D6. Finally, we screened for potential binders/inhibitors from the Chinese herbal medicine Scutellaria baicalensis (Huangqin, Baikal Skullcap) using the established pharmacophore model for CYP2D6 inhibitors and molecular docking approach. Overall, 18 out of 40 compounds from S. baicalensis were mapped to the pharmacophore model of CYP2D6 inhibitors and most herbal compounds from S. baicalensis could be docked into the active site of CYP2D6. Our study has provided insights into the molecular mechanisms of interaction of synthetic and herbal compounds with human CYP2D6 and further benchmarking studies are needed to validate our modeling and virtual screening results.

Effects of herbal products on the metabolism and transport of anticancer agents.

IMPORTANCE OF THE FIELD: Cancer patients on chemotherapy treatment often seek herbal therapies and this may alter the clearance of anticancer drugs. AREAS COVERED IN THIS REVIEW: Many anticancer drugs are metabolized by CYPs and are substrates of P-glycoprotein, breast cancer resistance protein and multi-drug resistance proteins. CYPs and drug transporters are subject to inhibition and/or induction by the herbal medicines used by cancer patients and the metabolism and pharmacokinetics of anticancer agents may be altered by herbal products. There are increased reports on the interaction of herbal medicines with anticancer agents. A clinical study in cancer patients reported that treatment of St John's wort at 900 mg/day orally for 18 days decreased the plasma levels of the active metabolite of irinotecan, SN-38, by 42%. In healthy subjects, treatment with St John's wort for 2 weeks significantly decreased the systemic exposure of imatinib by 32%. Induction and/or inhibition of CYPs and transporters is considered an important mechanism for these interactions. WHAT THE READER WILL GAIN: Potential interactions of herbal medicines with anticancer agents have become a safety concern in cancer chemotherapy. TAKE HOME MESSAGE: Further studies are warranted to investigate the efficacy and safety profiles of herbal medicines commonly used by cancer patients.