Screening indicators to evaluate the clinical significance of drug-drug interactions in polypharmacy among older adults with psychiatric disorders: a delphi study.

BACKGROUND: Polypharmacy is common in older adults with psychiatric disorders, but no consensus has reached about the reliable indicators evaluating the benefits and risks of drug-drug interactions (DDIs) in polypharmacy. We aimed to identify indicators suitable for evaluating the clinical significance of DDIs in polypharmacy in older adults with psychiatric disorders. METHODS: The online tools were used to distribute and collect the questionnaires. The Delphi method was applied to analyze experts' opinions. The degree of authority and coordination of experts were analyzed using the coefficient of variation, coefficient of coordination, expert's judgment factor, familiarity with the study content factor, and Kendall coordination coefficient. Statistical analysis was conducted using the IBM SPSS® Statistics Package version 26.0. RESULTS: After three rounds of expert consultation, five primary and eleven secondary indicators were identified. The primary "pharmacodynamic indicator" included "severity of adverse drug reactions", "duration of adverse drug reaction", "symptom relief", "time to onset of symptomatic relief", "number of days in hospital", and "duration of medication". The secondary "pharmacokinetic indicator" contained "dosage administered" and "dosing intervals". The primary "patient tolerance indicator" contained one secondary indicator of "patient tolerability". The primary indicator "patient adherence" contained one secondary indicator of "patient adherence to medication". The primary indicator "cost of drug combination" contained one secondary indicator of "readmission". These indicators were used to determine the clinical significance of DDIs during polypharmacy. CONCLUSIONS: The clinical significance of drug combinations should be taken into account when polypharmacy is used in the elderly. The five primary indicators and eleven secondary indicators might be preferred to evaluate their risks and benefits. Medication management in this population requires a multidisciplinary team, in which nurses play a key role. Future research should focus on how to establish efficient multidisciplinary team workflows and use functional factors to assess DDIs in polypharmacy for psychiatric disorders.

Clinical significance of potential drug-drug interactions in older adults with psychiatric disorders: a retrospective study.

BACKGROUND: Polypharmacy increases the risk of potential drug-drug interactions (pDDIs). This retrospective analysis was conducted to detect pDDIs and adverse drug reactions (ADRs) among older adults with psychiatric disorder, and identify pDDIs with clinical significance. METHODS: A retrospective analysis was carried out based on the medical records of older adults with psychiatric disorders. Data on demographic characteristics, substance abuse, medical history, and medications were extracted. The Lexi-Interact online database was used to detect pDDIs. The minimal clinically important difference (MCID) was set as the change in the Treatment Emergent Symptom Scale (TESS) score between admission and discharge. The median and interquartile ranges were used for continuous variables, and frequencies were calculated for dichotomous variables. Poisson regression was implemented to determine the factors influencing the number of ADR types. The influencing factors of each ADR and the clinical significance of the severity of the ADR were analysed using binary logistic regression. P < 0.05 was considered statistically significant. RESULTS: A total of 308 older adults were enrolled, 171 (55.52%) of whom had at least 1 pDDI. Thirty-six types of pDDIs that should be avoided were found, and the most frequent pDDI was the coadministration of lorazepam and olanzapine (55.5%). A total of 26 ADRs induced by pDDIs were identified, and the most common ADR was constipation (26.05%). There was a 9.4 and 10.3% increase in the number of ADR types for each extra medical diagnosis and for each extra drug, respectively. There was a 120% increase in the number of ADR types for older adults hospitalized for 18-28 days compared with those hospitalized for 3-17 days. There was an 11.1% decrease in the number of ADR types for each extra readmission. The length of hospitalization was a risk factor for abnormal liver function (P < 0.05). The use of a large number of drugs was a risk factor for gastric distress (P < 0.05) and dizziness and fainting (P < 0.05). None of the four pDDIs, including coadministrations of olanzapine and lorazepam, quetiapine and potassium chloride, quetiapine and escitalopram, and olanzapine and clonazepam, showed clinical significance of ADR severity (P > 0.05). CONCLUSIONS: pDDIs are prevalent in older adults, and the rate is increasing. However, many pDDIs may have no clinical significance in terms of ADR severity. Further research on assessing pDDIs, and possible measures to prevent serious ADRs induced by DDIs is needed to reduce the clinical significance of pDDIs.

Fenvalerate induces oxidative hepatic lesions through an overload of intracellular calcium triggered by the ERK/IKK/NF-κB pathway.

Fenvalerate (FEN), a mainstream pyrethroid pesticide, was initially recommended as a low-toxicity agent for controlling agricultural and domestic pests. Despite the widespread use of FEN worldwide, little data are available on FEN-induced hepatic lesions and molecular mechanisms. In the present study, we first performed an occupational cross-sectional study on FEN factory workers and found that the levels of serum alanine aminotransferase (ALT) and total antioxidant capacity increased, whereas malondialdehyde decreased in laborers in the working areas where the levels of airborne FEN were much higher compared with the office area. The results were then confirmed by animal experiments that abnormal hepatic histology, increased ALT level, and compromised hepatic oxidative capability were observed in rats exposed to a high concentration of FEN. Furthermore, the bioinformatics analysis of gene microarray in rat liver tissue showed that FEN significantly changed the expressions of genes related to the regulation of intracellular calcium ion homeostasis and the calcium signal pathway. Finally, the functional experiments in Buffalo rat liver (BRL) cells demonstrated that FEN first activated ERK MAPK, followed by IKK and NF-κB, which triggered the transcription of genes responsible for accelerating an overload of intracellular calcium ions, prompted reactive oxygen species generation in the mitochondria, and finally, induced hepatic cellular apoptosis. The calcium signaling pathway and in particular, an overload of intracellular calcium play a critical role in this pathophysiological process via the ERK/IKK/NF-κB pathway. Our study furthers the understanding of the mechanism of FEN-induced hepatic injuries and may have implications in the prevention and control of liver diseases induced by environmental pesticides.-Qiu, L.-L., Wang, C., Yao, S., Li, N., Hu, Y., Yu, Y., Xia, R., Zhu, J., Ji, M., Zhang, Z., Wang S.-L. Fenvalerate induces oxidative hepatic lesions through an overload of intracellular calcium triggered by the ERK/IKK/NF-κB pathway.

Effects of Vitamin D3 on Intestinal Flora in a Mouse Model of Inflammatory Bowel Disease Treated with Rifaximin.

BACKGROUND Rifaximin is an antimicrobial agent used to treat inflammatory bowel disease (IBD). Vitamin D3 can control IBD due to its effects on inflammatory cytokines. The purpose of this study was to assess the effect of vitamin D3 on the intestinal flora of a dextran sulfate sodium (DSS)-induced mouse model treated with rifaximin. MATERIAL AND METHODS The mouse model of IBD was developed using DSS (4%) administered via the drinking water. Twenty-four male C57BL6 mice were divided into the control group with a normal diet (N=6), the DSS group with a normal diet (N=6), the DSS group with a normal diet treated with rifaximin (N=6), and the DSS group with a normal diet treated with rifaximin and vitamin D3 (N=6). After 14 days, the colonic tissue was studied histologically. Serum levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1ß (IL-1ß) and enzyme-linked immunosorbent assay (ELISA) were used to measure the level of IL-6 and P65, and phospho-p65 was measured by western blot. 16S rRNA gene sequencing was used to analyze fecal samples. RESULTS In the DSS mouse model of IBD, rifaximin reduced the inflammation severity of the colon and reduced the expression of phospho-p65, p65, TNF-alpha, and IL-6. In the DSS+rifaximin+vitamin D3 group, the therapeutic influences of rifaximin, in terms of weight loss and colonic disease activity, were significantly reduced, and the gut microbiota of the mice were completely changed in composition and diversity. CONCLUSIONS In a mouse model of IBD, treatment with vitamin D3 significantly increased the metabolism of rifaximin and reduced its therapeutic effects.

CYP2A13 Acts as the Main Metabolic CYP450s Enzyme for Activating Leonurine in Human Bronchial Epithelial Cells.

BACKGROUND Leonurine is an active component of the traditional Chinese medicine Leonurus japonicus. This study aimed to investigate the effects of overexpressed CYP450s on the metabolic activity of leonurine. MATERIAL AND METHODS BEAS-2B cells stably expressing CYP1A1, 1A2, 2A13, 2B6, and 3A4 were constructed. CYP450s expression was identified using reverse-transcription PCR and Western blot assay. CCK-8 assay was used to evaluate the effect of leonurine on cell activity. Leonurine was incubated in vitro with CYP1A1, 1A2, 2A13, 2B6, and 3A4 metabolic enzymes to evaluate the clearance rate of CYP450 enzymes for leonurine. UPLC-MS was used to detect changes of drug concentration and discover the main metabolic enzymes affecting leonurine. RESULTS BEAS-2B cells stably expressing CYP1A1, 1A2, 2A13, 2B6, and 3A4 were successfully constructed. According to primary mass spectra and secondary mass spectra of leonurine, the main metabolic enzymes were 312.1550 [H+] and 181.0484. Compared to the control group, residue of leonurine in CYP2A13 group was significantly reduced (F=5.307, p=0.024). Compared to the 0-min group, the clearance rate of leonurine in the CYP2A13-treated group was significantly decreased at 120 min after treatment (F=7.273, p=0.007). CCK-8 results also showed that activity of BEAS-2B cells that overexpress CYP2A13 gradually decreased with increased concentration of leonurine. Although CYP2A13 demonstrated good metabolic activity for leonurine, we found that CYP1A1, 1A2, 2B6, and 3A4 had no metabolic effects on leonurine. CONCLUSIONS Leonurine can be effectively activated through CYP2A13 enzyme metabolism, and further inhibits activity of human lung epithelial cells (BEAS-2B). Therefore, CYP2A13 is a main metabolic enzyme for leonurine in BEAS-2B cells.

CYP2C9, a Metabolic CYP450s Enzyme, Plays Critical Roles in Activating Ellagic Acid in Human Intestinal Epithelial Cells.

BACKGROUND The metabolic processing of ellagic acid (EA) by cytochrome P450s (CYP450s) expressed in the intestines is unclear. This study aimed to investigate the effects of CYP450s that are highly expressed in HIEC cells on metabolic activity of EA. MATERIAL AND METHODS HIEC cell models expressing 2B6, 2C9, 2D6, and 3A4 were generated by stably transfecting with CYP450 genes using a lentivirus system. PCR and Western blot assay were used to detect expression of CYP450s. Cell Counting Kit-8 (CCK-8) assay was used to examine the cytotoxic effect of EA on CYP450s-expressing HIEC cells. Flow cytometry was employed to evaluate apoptosis of CYP450s-expressing HIEC cells after addition of EA. Metabolic clearance rate of EA in vitro by the constructed HIEC cell models was measured using UPLC-MS method. RESULTS CYP450s expression HIEC cell models, including CYP2B6, CYP2C9, CYP2D6, and CYP3A4, were successfully established. EA treatment at different concentrations (10 µg/mL and 50 µg/mL) remarkably decreased cell viability of HIEC cells expressing CYP2C9 compared to the untreated control (p<0.01), in a concentration-dependent and time-dependent manner. Expression of CYP2C9 significantly increased the apoptosis rate of HIEC cells treated with EA compared to that in HIEC cells without any CYP450s expression (p<0.01). The clearance rate of EA in CYP2B6-expressing (p<0.05) and CYP2C9-expressing (p<0.001) HIEC cell models was remarkably reduced after 120 min. CONCLUSIONS Ellagic acid was effectively activated by CYP2C9 in HIEC cells and caused cytotoxicity and apoptosis of HIEC cells. Therefore, CYP2C9 is main metabolic enzyme of EA when compared to other CYP450 HIEC cell models.

Association between short-term exposure to particulate matter air pollution and cause-specific mortality in Changzhou, China.

BACKGROUND: Extensive studies have linked ambient particulate matter (PM) to an increased mortality burden from a wide range of causes. However, the effects of PM on mortality rates from specific causes were unclear. This study aimed to estimate the detrimental effects of PM on cause specific deaths in Changzhou, China. METHOD: Data representing daily mortality rates, weather conditions and particulate air pollution levels were obtained from government-controlled agencies of Changzhou, from January 1, 2015 to December 31, 2016. An inverse distance weighting method was used to assess the population exposure to PM and a time-series was performed to detect the detrimental effects of PM. RESULTS: Positive associations were identified between PMs and daily mortality rates from non-accidental, circulatory, hypertensive, respiratory and chronic lower respiratory causes at a lag of 0-3 days. The effects of PMs were strongest on hypertensive mortality, with an increase of 5.27% (95% confidence interval (CI): 2.43-8.19%) and 3.52% (95% CI: 1.55-5.53%), per 10 µg/m3 increment in PM2.5 and PM10 respectively. The elderly exhibited a higher mortality risk with PMs exposure. Females were more vulnerable to circulatory, hypertensive and respiratory death while males were more sensitive to chronic lower respiratory and neurodegenerative mortality. The effects were stronger in warm seasons for circulatory mortality and stronger in cold seasons for respiratory mortality. CONCLUSION: These findings indicate that PM could exert adverse influences on the outcomes of several pathological processes, especially for women and the elderly with hypertension disease.

Vitamin D3 Is Transformed into 1,25(OH)2D3 by Triggering CYP3A11(CYP3A4) Activity and Hydrolyzing Midazolam.

BACKGROUND Vitamin D3 (VD3) is a commonly used supplement in clinical practice. Cytochrome P450 3A11 (CYP3A11) is the most important monomeric enzyme involved in metabolism of drugs. This study aimed to investigate effects of vitamin D3 (VD3) on CYP3A11 activity. MATERIAL AND METHODS Forty male Sprague-Dawley (SD) rats were randomly divided a Control group (peanut oil 0.1 ml/kg/d), a Low-VD3 group (100 IU/kg/d), a Medium-VD3 group (400 IU/kg/d), and a High-VD3 (1600 IU/kg/d) group. Blood samples were collected from the jugular vein after midazolam (MDZ) administration. CYP3A11 expressions in liver and colon were detected by Western blotting and immunohistochemistry (IHC) assay. The concentration of serum 25(OH)D3 and serum 1,25(OH)2D3 were evaluated using ELISA. Effects of different dosages of vitamin D3 on metabolism of MDZ were evaluated using high-performance liquid chromatography (HPLC). RESULTS Vitamin D3 significantly enhanced serum 25(OH)D3 and 1,25(OH)2D3 levels in rats compared to Control rats (p<0.05). Expressions of hepatic CYP3A11 were more than 10-fold higher in rats treated with vitamin D3 compared to Control rats (p<0.05). Expressions of colon CYP3A11 were 5-fold higher than in Control rats (p<0.05). CYP3A11 expressions in vitamin D3-treated groups were significantly higher compared to the Control group (p<0.05). MDZ levels were significantly higher in Vitamin D3-treated rats compared to that in Control rats (p<0.05). Concentrations of serum MDZ at every sampling point were remarkably lower in the vitamin D3-treated rats than in Control rats (p<0.05). CONCLUSIONS Vitamin D3 was transformed into 1,25(OH)2D3 by triggering CYP3A11 and CYP3A11 activity and by hydrolyzing MDZ.

Tau-TCHF Inhibits Spleenic Apoptosis via PI3K-Akt Signaling Pathway in Chickens.

Taurine plays an important role in improving immunity, regulating cell proliferation and differentiation, apoptosis and so on. Traditional Chinese herb formula (TCHF) is a wealth of medicine materials for diseases control. There are many studies on Chinese herb formula in inducing cell apoptosis, differentiation and improving animal immunity. The factors in phosphatidylinositol 3-kinase/Protein Kinase (PI3K-Akt) signaling pathway are central regulators of normal cells, which integrates extra-cellular signals into cells and activates affects cell activities including cell proliferation, differentiation and apoptosis. We find the key factors (PIK3CA, PDPK1, AKT1, MDM2, ITGA2B, ITGB1, FAK and p53) in PI3K-Akt signaling pathway by RNA-Seq analysis in our previous research. The overall goal of this study to investigate the influence of taurine TCHF (Tau-TCHF) on cell proliferation, differentiation and apoptosis by estimating the factors above. The layers were fed with normal diet plus 1% of Tau-TCHF and the control group with normal diet to 42 days old. The spleen tissue samples from individual layers were used to analyze the influence of Tau-TCHF on the factors PIK3CA, PDPK1, AKT1, MDM2, ITGA2B, ITGB1, FAK and p53 in PI3K-Akt signaling pathway. The levels of transcription and protein expression of various factors were assessed by quantitative PCR (qPCR) and Western Blot. The results showed that the transcription levels of itgb1, fak, pik3ca, akt1 and mdm2 on 42-day-old chicken spleen tissues were increased significantly in Tau-TCHF group comparing with control group (P < 0.01); the transcription levels of itga2b, pdpk1 and p53 were no significant difference (P > 0.05). The protein levels of PDPK1 and AKT (Ser437) were increased significantly (P < 0.05), but ITGA2B, ITGB1, FAK, PIK3CA, AKT1, MDM2 and p53 had no significant difference (P > 0.05). The results suggest that Tau-TCHF may influence proliferation and differentiation of chickens spleen via regulating PI3K-Akt signaling pathway. And Tau-TCHF may be provided as feed additives in improving the immunity of animals. AKT (Ser473) and PDPK1 may be considered as further targets to study mechanism of Tau-TCHF on anti-apoptosis via PI3K-Akt signaling pathway.

Identification of 5-hydroxymethylfurfural in cigarette smoke extract as a new substrate metabolically activated by human cytochrome P450 2A13.

Cytochrome P450 2A13 (CYP2A13) is an extrahepatic enzyme mainly expressed in the human respiratory system and is reported to mediate tobacco-specific N-nitrosamines (TSNA) metabolism in cigarette smoke. This study aimed to identify other new substrates of CYP2A13 in cigarette smoke and their corresponding respiratory toxicity. Following separation by HPLC, GC-MS/MS, NMR and cytotoxicity assays in BEAS-2B cells stably expressing CYP2A13 (B-2A13), 5-Hydroxymethylfurfural (5-HMF) was screened and identified in the 4-5 min section of cigarette smoke extract (CSE). In vitro metabolism results showed that CYP2A13 mediated the fast clearance of 5-HMF and formed the metabolite 5-HMF acid (5-HMFA). CSE 5-HMF (CSE-5-HMF) showed cytotoxicity similar to that of standard 5-HMF in B-2A13 and B-2A5 cells, which was inhibited by 8-methoxypsoralen (8-MOP), a CYP enzyme inhibitor. Mouse CYP2A5, a homologous CYP enzyme to CYP2A13, shares many substrates with CYP2A13 in cigarette smoke. Thus, CYP2A5-/- mice were generated to explore the role of CYP2A5 in 5-HMF bioactivation. Compared with CYP2A5-/- mice, WT mice showed serious histological lung and nasal olfactory mucosa damage, as well as increased inflammatory cells and elevated TNF-α and IL-6 levels in bronchoalveolar lavage fluid. Besides, nasal microsomes undertook fast 5-HMFA formation in WT mice than that in CYP2A5-/- mice, which could be inhibited by 8-MOP. This study is the first to identify 5-HMF as a new toxic substrate of human CYP2A13 in cigarette smoke, it may play a potential role in cigarette smoke-induced respiratory injuries.

High-fat diet aggravates 2,2',4,4'-tetrabromodiphenyl ether-inhibited testosterone production via DAX-1 in Leydig cells in rats.

Growing evidence has revealed that a high-fat diet (HFD) could lead to disorders of glycolipid metabolism and insulin-resistant states, and HFDs have been associated with the inhibition of testicular steroidogenesis. Our previous study demonstrated that 2,2',4,4'-tetrabromodiphenyl ether (BDE47) could increase the risk of diabetes in humans and reduce testosterone production in rats. However, whether the HFD affects BDE47-inhibited testosterone production by elevating insulin levels and inducing related pathways remains unknown. In male rats treated with BDE47 by gavage for 12 weeks, the HFD significantly increased the BDE47 content of the liver and testis and increased the weight of the adipose tissue; increased macrovesicular steatosis in the liver and the levels of triglycerides, fasting glucose and insulin; further aggravated the disruption of the seminiferous epithelium; and lowered the level of testosterone, resulting in fewer sperm in the epididymis. Of note, the HFD enhanced BDE47-induced DAX-1 expression and decreased the expression levels of StAR and 3ß-HSD in the testicular interstitial compartments in rats. In isolated primary Leydig cells from rats, BDE47 or insulin increased DAX-1 expression, decreased the expression of StAR and 3ß-HSD, and reduced testosterone production, which was nearly reversed by knocking down DAX-1. These results indicated that the HFD aggravates BDE47-inhibited testosterone production through hyperinsulinemia, and the accumulation of testicular BDE47 that induces the up-regulation of DAX-1 and the subsequent down-regulation of steroidogenic proteins, i.e., StAR and 3ß-HSD, in Leydig cells.

miR-138-1* regulates aflatoxin B1-induced malignant transformation of BEAS-2B cells by targeting PDK1.

Environmental carcinogens-induced lung cancer and potential mechanisms have attracted widespread attention. Currently, microRNAs (miRNAs) have been recognized as key players in development of cancer, among which guide strand of miRNA has been well documented rather than its passenger strand (miRNA*). Our previous study showed that treatment of 0.1 nM AFB1 for 50 passages could induce malignant transformation of immortalized human bronchial epithelial cells stably expressing CYP2A13 (P50 B-2A13 cells). However, the role of miRNAs in this carcinogenic proceeding is still unclear. In present study, 36 upregulated and 27 downregulated miRNAs in P50 B-2A13 cells were first identified by miRNA microarray, and miR-138-1* was selected as a candidate miRNA by RT-qPCR and pilot experiments. Functional studies revealed that miR-138-1* could inhibit proliferation, colony formation, migration and invasion of P50 B-2A13 cells. Further, target analysis and dual-luciferase reporter gene assay identified that miR-138-1(*) was consequentially paired with 3'-UTR of 3-phosphoinositide-dependent protein kinase-1 (PDK1) and decreased the luciferase activity. miR-138-1* could decrease the expressions of PDK1 and its downstream proteins in PI3K/PDK/Akt pathway but not vice versa, indicating that miR-138-1* might affect AFB1-induced malignant transformation through targeting PDK1. As predicted, interference of PDK1 showed the similar effects to miR-138-1* in the proliferation, colony formation, migration and invasion of P50 B-2A13 cells. Our study demonstrated that miR-138-1* played a critical role in AFB-induced malignant transformation of B-2A13 cells by targeting PDK1. Still, the study provides a novel insight into the roles of miRNA* during carcinogenesis, particularly airborne carcinogens-induced lung cancer.

Effect of long-term in-row branch covering on soil microorganisms in pear orchards.

Branches covering (BC) is a way to reuse the pruned branches and save the cost of ground cloth. This study investigated the effects of BC and ground-cloth covering on the soil microcosm environment by measuring the chemical properties and microbial communities at different soil depths for 6 years. The results revealed that BC significantly improved soil chemical properties, increased the abundance of bacterial microbial communities and the diversity and homogeneity of bacteria and fungi, while decreased the abundance of fungal microbial communities. There was a threshold value for the regulation of microbial communities by BC, which decreased the high-abundance communities (Proteobacteria, Ascomycota, etc.) and increased the low-abundance communities (Acidobacteriota, Basidiomycota, etc.). Fungi were more sensitive to BC than bacteria. The stability and homogeneity of microorganisms were stronger in the 15-25 cm soil layer. The bacterial phyla were dominated by Proteobacteria, with the top 10 phyla accounting for more than 80% of the relative abundance; the genera were dominated by MND1, with the top 10 genera accounting for about 10%. The fungal phyla were dominated by Ascomycota, with the top 10 phyla accounting for 50-90%; the genera were dominated by unidentified Pyronemataceae sp., with the top 10 genera accounting for 30-60%. The phyla that differed significantly between treatments were mainly Proteobacteria, Ascomycota, Acidobacteriota, and Basidiomycota. In addition, metabolism was the predominant function in bacteria, while Saprotroph was the predominant function in fungi. Bacteroidota correlated strongly with soil chemical properties and bacterial functions, while Chytridiomycota correlated strongly with soil chemical properties and Pathogen-Saprotroph-Symbiotroph. In conclusion, BC can improve soil nutrient content and optimize microbial community structure and function. Through initially assessing the effects of BC on soil nutrients and microorganisms in pear orchard rows, this study provides a reference for excavating key microorganisms and updating the soil row management model.

Evaluation of the gut microbiome alterations in healthy rats after dietary exposure to different synthetic ZnO nanoparticles.

AIMS: Although synthetic ZnO nanoparticles (Nano-ZnO) as an alternative of ZnO compounds have been extensively used such as in livestock production, the increased consuming of Nano-ZnO has raised considerable concerns in environmental pollution and public health. Because of the low digestion of Nano-ZnO, the systematic studies on their interactions with gut microbiota remain to be clarified. MATERIALS AND METHODS: Nano-ZnOs were prepared by co-precipitation (ZnO-cp) and high temperature thermal decomposition (ZnO-td) as well as the commercial type (ZnO-s). Transmission electron microscopy (TEM) was used to monitor the morphology of Nano-ZnO. CCK-8 assay was used for cytotoxicity evaluation. Total antioxidant capacity assay, total superoxide dismutase assay, and lipid peroxidation assay were used to evaluate oxidative states of rats. 16S rRNA was used to study the impact of Nano-ZnO on the rat gut microbiome. KEY FINDINGS: Both ZnO-cp and ZnO-td exhibited low cytotoxicity while ZnO-s and ZnO-td exhibited prominent antibacterial activities. After a 28-day oral feeding with 1000 mg/kg Zn at dietary dosage, ZnO-s showed slight effect on causing oxidative stress in comparison with that of ZnO-cp and ZnO-td. Results of 16S rRNA sequencing analysis indicated that ZnO-td as a promising short-term nano-supplement can increase probiotics abundances like strains belonged to the genus Lactobacillus and provide the antipathogenic effect. SIGNIFICANCE: The results of the gut microbiome alteration by synthetic Nano-ZnO not only provide solution to exposure monitoring of environmental hazard, but rationalize their large-scale manufacture as alternative additive in the food chain.

The cause and effect of gut microbiota in development of inflammatory disorders of the breast.

BACKGROUND: Inflammatory disorders of the breast (IDB) damages the interests of women and children and hinders the progress of global health seriously. Several studies had offered clues between gut microbiota (GM) and inflammatory disorders of the breast (IDB). The gut-mammary gland axis also implied a possible contribution of the GM to IDB. However, the causality between them is still elusive. METHODS: The data of two-sample Mendelian randomization (MR) study related to the composition of GM (n = 18,340) and IDB (n = 177,446) were accessed from openly available genome-wide association studies (GWAS) database. As the major analytical method, inverse variance weighted (IVW) was introduced and several sensitive analytical methods were conducted to verify results. RESULTS: Inverse variance weighted revealed Eubacterium rectale group (OR = 1.87, 95% CI: 1.02-3.43, p = 4.20E-02), Olsenella (OR = 1.29, 95% CI: 1.02-1.64, p = 3.30E-02), Ruminiclostridium-6 (OR = 1.53, 95% CI: 1.08-2.14, p = 1.60E-02) had an anti-protective effect on IDB. Peptococcus (OR = 0.75, 95% CI: 0.60-0.94, p = 1.30E-02) had a protective effect on IDB. The results were credible through a series of test. CONCLUSIONS: We revealed causality between IDB and GM taxa, exactly including Ruminiclostridium-6, Eubacterium rectale group, Olsenella and Peptococcus. These genera may become novel biomarkers and supply new viewpoint for probiotic treatment. However, these findings warrant further test owing to the insufficient evidences.

Encapsulating Antibiotic and Protein-Stabilized Nanosilver into Sandwich-Structured Electrospun Nanofibrous Scaffolds for MRSA-Infected Wound Treatment.

With the increasing prevalence of microbial infections, which results in prolonged inflammation and delayed wound healing, the development of effective and safe antimicrobial wound dressings of multiple properties remains challenging for public health. Despite their various formats, the available developed dressings with limited functions may not fulfill the diverse demands involved in the complex wound healing process. In this study, multifunctional sandwich-structured electrospinning nanofiber membranes (ENMs) were fabricated. According to the structural composition, the obtained ENMs included a hydrophilic inner layer loaded with curcumin and gentamicin sulfate, an antibacterial middle layer consisting of bovine serum albumin stabilized silver oxide nanoparticles, and a hydrophobic outer layer. The prepared sandwich-structured ENMs (SNM) exhibited good biocompatibility and killing efficacy on Escherichia coli, Staphylococcus aureus, and Methicillin-resistant S. aureus (MRSA). In particular, transcriptomic analysis revealed that SNM inactivated MRSA by inhibiting its carbohydrate and energy metabolism and reduced the bacterial resistance by downregulating mecA. In the animal experiment, SNM showed improved wound healing efficiency by reducing the bacterial load and inflammation. Moreover, 16S rDNA sequencing results indicated that SNM treatment may accelerate wound healing without observed influence on the normal skin flora. Therefore, the constructed sandwich-structured ENMs exhibited promising potential as dressings to deal with the infected wound management.

5-Hydroxymethylfurfural induces mice frailty through cell senescence-associated sarcopenia caused by chronic inflammation.

Objective: 5-Hydroxymethylfurfural (5-HMF) is an important component of air pollution, confirmed to be a risk factor for pulmonary inflammation. However, its association with general health is unknown. This article aimed to clarify the effect and mechanism of 5-HMF in the occurrence and aggravation of frailty in mice by investigating whether exposure to 5-HMF was linked to the occurrence and aggravation of mice frailty. Methods: Twelve male C57BL/6 mice (12-month-old, 38 ± 1 g) were randomly divided into the control group and the 5-HMF group. The 5-HMF group was treated with 5-HMF (1 mg/kg/day, respiratory exposure) for 12 months, whereas the control group was treated with equal amounts of sterile water. After the intervention, the ELISA method was used to detect the serum inflammation level of the mice, and the physical performance and frail status were evaluated using a Fried physical phenotype-based assessment tool. The differences in the body compositions were calculated from their MRI images, and the pathological changes in their gastrocnemius muscle were revealed using the H&E staining. Furthermore, the senescence of skeletal muscle cells was evaluated by measuring the expression levels of senescence-related proteins by the western blotting. Results: In the 5-HMF group, serum inflammatory factors IL-6, TNF-α, and CRP levels were significantly raised (p < 0.01). Mice in this group had higher frailty scores and significantly reduced grip strength (p < 0.001), slower weight gains, less WVgastrocnemius muscle masses, and lower sarcopenia indices (SI). In addition, the cross-sectional areas of their skeletal muscles were reduced, and the levels of their cell senescence-related proteins (p53, p21, p16, SOD1, SOD2, SIRT1, SIRT3) were considerably altered (p < 0.01). Conclusion: 5-HMF may induce chronic and systemic inflammation, which in turn accelerates the progression of the frailty of mice through cell senescence.

Curcumin-stabilized silver nanoparticles encapsulated in biocompatible electrospun nanofibrous scaffold for sustained eradication of drug-resistant bacteria.

Due to the misuse of antibiotics, the emerging drug-resistance of pathogenic microbes has aroused considerable concerns for the public health, which demands the continuous search for safe and efficient antimicrobial treatment. In this study, curcumin reduced and stabilized silver nanoparticles (C-Ag NPs) were successfully encapsulated into electrospun nanofiber membranes consisted of polyvinyl alcohol (PVA) cross-linked by citric acids (CA), which exhibited desirable biocompatibility and broad-spectrum antimicrobial activities. The homogeneously distributed and sustained release of C-Ag NPs in the constructed nanofibrous scaffolds yield prominent killing effect against Escherichia coli, Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus (MRSA), which involved the reactive oxygen species (ROS) generation. Outstanding elimination of bacterial biofilms and excellent antifungal activity against Candida albicans was also identified after treated with PVA/CA/C-Ag. Transcriptomic analysis on MRSA treated by PVA/CA/C-Ag revealed the antibacterial process is related to disrupting carbohydrate and energy metabolism, as well as destroying bacterial membranes. Significant down-regulation of the expression of multidrug-resistant efflux pump gene sdrM was observed pointing to the role of PVA/CA/C-Ag to overcome the bacterial resistance. Therefore, the constructed ecofriendly and biocompatible nanofibrous scaffolds provide a robust and versatile nanoplatform of reversal potential to eradicate drug-resistant pathogenic microbe in environmental as well as healthcare applications.

Discovery of Potent DYRK2 Inhibitors with High Selectivity, Great Solubility, and Excellent Safety Properties for the Treatment of Prostate Cancer.

Prostate cancer (PCa) is a common male cancer with high incidence and mortality, and hormonal therapy as the major treatment for PCa patients is troubled by the inevitable resistance that makes us identify novel targets for PCa. Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) was found to be an effective target for the treatment of PCa, but the research on its inhibitors is rather little. In this work, a potent DYRK2 inhibitor 43 (IC50 = 0.6 nM) was acquired through virtual screening and structural optimization, which displayed high selectivity among 205 kinases; meanwhile, detailed interactions of 43 with DYRK2 were illustrated by the cocrystal. Furthermore, 43 possessed great water solubility (29.5 mg/mL), favorable safety properties (LD50 > 10,000 mg/kg), and potent anti-PCa activities, which could be used as a potential candidate in further preclinical studies.

Discovery of Potent and Wild-Type-Sparing Fourth-Generation EGFR Inhibitors for Treatment of Osimertinib-Resistance NSCLC.

Osimertinib resistance is an unmet clinical need for the treatment of non-small cell lung cancer (NSCLC), and the main mechanism is tertiary C797S mutation of epidermal growth factor receptor (EGFR). To date, there is no inhibitor approved for the treatment of Osimertinib-resistant NSCLC. Herein, we reported a series of Osimertinib derivatives as fourth-generation inhibitors which were rationally designed. Top candidate D51 potently inhibited the EGFRL858R/T790M/C797S mutant with an IC50 value of 14 nM and suppressed the proliferation of H1975-TM cells with an IC50 value of 14 nM, which show over 500-fold selectivity against wild-type forms. Moreover, D51 inhibited the EGFRdel19/T790M/C797S mutant and the proliferation of the PC9-TM cell line with IC50 values of 62 and 82 nM. D51 also exhibited favorable in vivo druggability, including PK parameters, safety properties, in vivo stability, and antitumor activity.