A Crosstalk Between Castration-Resistant Prostate Cancer Cells, M2 Macrophages, and NK Cells: Role of the ATM-PI3K/AKT-PD-L1 Pathway.

Castration-resistant prostate cancer (CRPC) in males is associated with a poor prognosis and a higher risk of treatment-related adverse effects, with high mortality among cancers globally. It is thus imperative to explore novel potential molecules with dual therapeutic and biomarker functions. Based on the recent research findings, the expression levels of ataxia telangiectasia mutant kinase (ATM) in prostate cancer (PC) tissues collected from CRPC patients were higher than hormone-dependent PC patients. Using CRPC cell lines (C4-2 and CWR22Rv1), the transwell chamber experiments revealed ATM promoted macrophage recruitment in CRPC cells in vitro via C-X-C motif chemokine ligand 12 (CXCL12). Further in vitro investigations demonstrated that polarized macrophages prevented NK cell recruitment and reduced the immunocidal activity of NK cells against CRPC cell lines. Moreover, ATM boosted programmed death receptor ligand 1 (PD-L1) expression while inhibiting NK group 2D (NKG2D) ligand expression in selected cell lines via PI3K/AKT signaling pathway. The in vivo investigations revealed ATM induced proliferation of CRPC and macrophage recruitment, while the NK cell recruitment was found to suppress ATM expression and CRPC proliferation. In conclusion, it could be demonstrated that inhibiting ATM increased the susceptibility of CRPC to NK cell inhibitors by dampening the CXCL12 and PI3K/AKT-PD-L1 pathways, thereby offering a novel and individualized treatment protocol for treating CRPC.

Exosomes from mesenchymal stem cells expressing microribonucleic acid-125b inhibit the progression of diabetic nephropathy via the tumour necrosis factor receptor-associated factor 6/Akt axis.

Diabetic nephropathy (DN) seriously threatens the health of patients with diabetes. Moreover, it has been reported that mesenchymal stem cell (MSC)-derived exosomal miRNAs can modulate the progression of multiple diseases, including DN. It has been suggested that miR-125b is involved in DN. However, the biological functions of exosomal miRNAs, especially miR-125b, in DN are still unclear. To establish a DN model in vitro, we used a model of human embryonic kidney epithelial cells (HKCs) injury induced by high glucose (HG). Then, miR-125b was delivered to the model cells in vitro via MSC-derived exosomes (MSC-Exos), and the effect of exosomal miR-125b on HKCs apoptosis was evaluated by flow cytometry. qRT-PCR or western blotting was performed to measure miR-125b or tumour necrosis factor receptor-associated factor 6 (TRAF6) expression in HKC. The effect of MSC-Exos on HKCs apoptosis after miR-125b knockdown was determined by flow cytometry. Moreover, dual-luciferase reporter assays were used to determine the targeting relationship between miR-125b and TRAF6 in HKCs. Our data revealed that MSC-Exos increased HG-induced autophagy in HKCs and reversed HKCs apoptosis. Moreover, our study found that miR-125b was enriched in MSC-Exos and directly targeted TRAF6 in HKCs. In addition, exosomally transferred miR-125b inhibited the apoptosis of HG-treated HKCs by mediating Akt signalling. In summary, MSC-derived exosomal miR-125b induced autophagy and inhibited apoptosis in HG-treated HKCs via the downregulation of TRAF6. Therefore, our study provided a new idea for DN treatment.

Understanding the diagnosis of prostate cancer.

Prostate cancer continues to be the most commonly diagnosed cancer, and the second leading cause of cancer death among Australian men. Prostate-specific antigen testing is personalised (not dichotomous in nature) and its interpretation should take into account the patient's age, symptoms, previous results and medication (eg, 5-α reductase inhibitors such as dutasteride). Multiparametric magnetic resonance imaging of the prostate has been proven to have a 93% sensitivity for detecting clinically significant prostate cancer. It has the potential to decrease unnecessary prostate biopsies by around 27%. International Society of Urological Pathology (ISUP) grade 1 (Gleason score 6) has been shown to have very little, if any, risk of metastasis ISUP grade 1 (Gleason score 3 +3 = 6) and low percentage ISUP grade 2 (Gleason score 3 + 4 [< 10%] = 7) can be offered active surveillance. The goal of active surveillance is to defer treatment but is still curative when required. With better imaging (magnetic resonance imaging and emerging prostate-specific membrane antigen positron emission tomography-computed tomography) and transperineal prostate biopsy, more men can be offered screening after discussion of risks and benefits, knowing that overdiagnosis has been minimised and radical treatment is reserved for only the most aggressive disease.

Self-Healable Polyelectrolytes with Mechanical Enhancement for Flexible and Durable Supercapacitors.

The practical application of advanced personalized electronics is inseparable from flexible, durable, and even self-healable energy storage devices. However, the mechanical and self-healing performance of supercapacitors is still limited at present. Herein, highly transparent, stretchable, and self-healable poly(2-acrylamido-2-methyl-1-propanesulfonic acid) (PAMPSA)/poly(vinyl alcohol) (PVA)/LiCl polyelectrolytes were facilely prepared by one-step radical polymerization. The cooperation of PAMPSA and PVA significantly increased the mechanical and self-healing capacity of the polyelectrolyte, which exhibited superior stretchability of 938 %, stress of 112.68 kPa, good electrical performance (ionic conductivity up to 20.6 mS cm-1 ), and high healing efficiency of 92.68 % after 24 h. After assembly with polypyrrole-coated single-walled carbon nanotubes, the resulting as-prepared supercapacitor had excellent electrochemical properties with high areal capacitance of 297 mF cm-2 at 0.5 mA cm-2 and good rate capability (218 mF cm-2 at 5 mA cm-2 ). Besides, after cutting in two the supercapacitor recovered 99.2 % of its original specific capacitance after healing for 24 h at room temperature. The results also showed negligible change in the interior contact resistance of the supercapacitor after ten cutting/healing cycles. The present work provides a possible solution for the development of smart and durable energy storage devices with low cost for next-generation intelligent electronics.

METTL4 mediated-N6-methyladenosine promotes acute lung injury by activating ferroptosis in alveolar epithelial cells.

Sepsis-induced acute lung injury has been deemed to be an life-threatening pulmonary dysfunction caused by a dysregulated host response to infection. The modification of N6-Methyladenosine (m6A) is implicated in several biological processes, including mitochondrial transcription and ferroptosis. Ferroptosis is an iron-dependent type of programed cell death, which plays a role in sepsis-induced acute lung injury (ALI). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulator of intracellular oxidative homeostasis, linked to ferroptosis resistance. This research aims to explore the effect of m6A in ferroptosis in sepsis-induced ALI. First, we found a time-dependent dynamic alteration on pulmonary methylation level during sepsis-induced ALI. We identified METTL4 as a differentially expressed gene in ALI mice using m6A sequencing and RNA-sequencing, and revealed the methylation of several ferroptosis related genes (Nrf2). Thus, we generated METTL4 deficiency mice and found that METTL4 knockdown alleviated ferroptosis, as evidenced by lipid ROS, MDA, Fe2+, as well as alterations in GPX4 and SLC7A11 protein expression. Consistently, we found that METTL4 silencing could decrease ferroptosis sensitivity in LPS-induced TC-1 cells. Furthermore, both the dual-luciferase reporter assay and rescue experiments indicated that METTL4 mediated the N6-methyladenosine of Nrf2 3'UTR, then YTHDF2 binded with the m6A site, promoting the degradation of Nrf2. In conclusion, we revealed that METTL4 promoted alveolar epithelial cells ferroptosis in sepsis-induced lung injury via N6-methyladenosine of Nrf2, which might provide a novel approach to therapeutic strategies for sepsis-induced ALI.

The intestinal microflora diversity of aboriginal chickens in Jiangxi province, China.

Intestinal microbiota can coevolve with host to form symbiotic relationship and be participated in the regulation of host physiological function. At present, there is no clear explanation on the effect of intestinal microflora in Jiangxi aboriginal chickens. Here, we investigated the association between gut microbiota and host genome of Jiangxi local chickens using 16S rRNA sequencing and genome-wide association studies (GWAS). The results showed that the breeds and genders had important effects on the intestinal microbiota of chickens. A total of 28 SNPs in 14 regions of the chicken genome were related to the relative abundance of microorganisms in 5 genera: Clostridium_sensu_stricto_1, Enterococcus, Gallibacterium, Turicibacter, and Rikenellaceae_RC9_gut_group. A total of 17 candidate genes were identified composition of chicken microbiome and show an association between the host genome and the chicken intestinal microbiota, which also unveiled the diversity of intestinal microbes in Jiangxi chickens. Given the correlation between chicken genome and intestinal microbe found in the present study, a new idea for the protection of aboriginal chicken genetic resources in China could be provided.

Regulation of NcRNA-protein binding in diabetic foot.

Non-coding RNA (ncRNA) is a special type of RNA transcript that makes up more than 90 % of the human genome. Although ncRNA typically does not encode proteins, it indirectly controls a wide range of biological processes, including cellular metabolism, development, proliferation, transcription, and post-transcriptional modification. NcRNAs include small interfering RNA (siRNA), PIWI-interacting RNA (piRNA), tRNA-derived small RNA (tsRNA), etc. The most researched of these are miRNA, lncRNA, and circRNA, which are crucial regulators in the onset of diabetes and the development of associated consequences. The ncRNAs indicated above are linked to numerous diabetes problems by binding proteins, including diabetic foot (DF), diabetic nephropathy, diabetic cardiomyopathy, and diabetic peripheral neuropathy. According to recent studies, Mir-146a can control the AKAP12 axis to promote the proliferation and migration of diabetic foot ulcer (DFU) cells, while lncRNA GAS5 can activate HIF1A/VEGF pathway by binding to TAF15 to promote DFU wound healing. However, there are still many unanswered questions about the mechanism of action of ncRNAs. In this study, we explored the mechanism and new progress of ncRNA-protein binding in DF, which can provide help and guidance for the application of ncRNA in the early diagnosis and potential targeted intervention of DFU.

Genomic characteristics and selection signals of Zhongshan ducks.

The Zhongshan duck (ZSP) is a duck breed indigenous to China and is known for its moderate body size, strong disease resistance, tender meat, and little subcutaneous fat. However, the genomic basis of such excellent breeding characteristics remains poorly understood. Therefore, we generated whole-genomes of 58 ZSPs and 180 other indigenous Chinese ducks (60 Jinding ducks, 60 Shan Partridge ducks, and 60 Liancheng white ducks) and identified 10 560 032 single nucleotide polymorphisms and 1 334 893 structural variants. Based on genetic diversity and population structure indices, our results confirm that the ZSP is a unique germplasm resource. In addition, three reproduction-related genes (i.e., OAZ, AMH, and RLF) were located in highly differentiated regions between the ZSP and the other three duck breeds (Jinding duck; Liancheng White duck; Shan Partridge duck), suggesting that these genes may have a strong influence on egg production. Among these genes, AMH may have introgressed from an unknown species of the Anatidae family. We also identified other significant genes in the significantly differentiated window (i.e., 1% cut-off), some of which are responsible for growth and development (SEMA5B and MIB1), metabolism (EDEM3 and Xylb), skeletal system morphogenesis (bglap and MGP), and egg shape (ITPR2). These findings highlight the genetic characteristics of the ZSP that shape an array of its morphological traits. Overall, this study should facilitate a more fine-scale approach towards improving the ZSP and other indigenous ducks in China and even all over the world.

Downregulation of pro-surfactant protein B contributes to the recurrence of early-stage non-small cell lung cancer by activating PGK1-mediated Akt signaling.

Recurrence is one of the main causes of treatment failure in early-stage non-small cell lung cancer (NSCLC). However, there are no predictors of the recurrence of early-stage NSCLC, and the molecular mechanism of its recurrence is not clear. In this study, we used clinical sample analysis to demonstrate that low levels of expression of precursor surfactant protein B (pro-SFTPB) in primary NSCLC tissue compared to their adjacent tissues are closely correlated with recurrence and poor prognosis in early-stage NSCLC patients. In vitro and in vivo experiments showed that downregulation of pro-SFTPB expression activates the Akt pathway by upregulating PGK1, which promotes metastasis and tumorigenicity in NSCLC cells. We then demonstrated that pro-SFTPB suppresses the formation of the ADRM1/hRpn2/UCH37 complex by binding to ADRM1, which inhibits PGK1 deubiquitination, thus accelerating ubiquitin-mediated PGK1 degradation. In summary, our findings indicate that low expression of pro-SFTPB in primary NSCLC compared to their adjacent tissue has potential as a predictor of recurrence and poor prognosis in early-stage NSCLC. Mechanistically, downregulation of pro-SFTPB attenuates inhibition of ADRM1-deubiquitinated PGK1, resulting in elevated levels of PGK1 protein; this activates the Akt pathway, ultimately leading to the progression of early-stage NSCLC.

Development and Validation of Benzophenone Derivatives in Packaged Cereal-Based Foods by Solid-Liquid Extraction and Ultrahigh-Performance Liquid Chromatography-Tandem Mass Spectrometry.

We established and validated a sensitive multi-residue analytical method for identifying benzophenone (BP) and nine BP derivatives (2,4-dihydroxybenzophenone [BP-1], 2,2',4,4'-tetrahydroxydroxybenzophenone, 2-hydroxy-4-methoxy benzophenone, 2,2'-dihydroxy 4-methoxy benzophenone, 2-hydroxybenzophenone [2-OHBP], 4-hydroxybenzophenone, 4-methylbenzophenone [4-MBP], methyl-2-benzoylbenzoate, and 4-benzoylbiphenyl). Solid−liquid extraction pretreatment and ultra-high-performance liquid chromatography−tandem mass spectrometry (UHPLC−MS/MS) were employed in an analysis of 85 packaged cereal-based food samples (25 pastry, 50 rice, and 10 noodle samples). The method had satisfactory linearity (R2 ≥ 0.995), low limits of detection (pastry: 0.02−4.2 ng/g; rice and noodle: 0.02−2 ng/g), and favorable precision, with within-run and between-run coefficient of variation ranges of 1−29% and 1−28%, respectively. BP and 4-MBP were detected in 100% of the pastry samples, and BP-1 and 2-OHBP were found in 76% and 56% of the pastry samples, respectively. BP and 2-OHBP were found in 92% and 38% of the rice samples, respectively. BP was found in 50% of the noodle samples. BP contributed the most to the total level of BPs in pastries, with significantly higher mean ± standard deviation (range) levels for pastries (26.8 ± 32.6 [1.8−115.4] ng/g) than rice (1.2 ± 2.0 [0.4−13.4] ng/g) and noodles (0.7 ± 0.7 [0.4−1.9] ng/g); p < 0.0001). The trace levels of 4-MBP identified in the samples demonstrate the need for the development of analytical methods with high sensitivity and specificity; the proposed method satisfies this need.

Identification of Benzophenone Analogs in Rice Cereal through Fast Pesticide Extraction and Ultrahigh-Performance Liquid Chromatography-Tandem Mass Spectrometry.

A fast, robust, and sensitive analytical method was developed and validated for the simultaneous identification of benzophenone (BP) and nine BP analogs (BP-1, BP-2, BP-3, BP-8, 2-hydroxybenzophenone, 4-hydroxybenzophenone, 4-methylbenzophenone [4-MBP], methyl-2-benzoylbenzoate, and 4-benzoylbiphenyl) in 25 samples of rice cereal. Fast pesticide extraction (FaPEx) coupled with ultrahigh-performance liquid chromatography-tandem mass spectrometry was applied. The developed method exhibited satisfactory linearity (r > 0.997), favorable recoveries between 71% and 119%, and a limit of detection ranging from 0.001 to 0.5 ng/g. The detection frequencies of BP, 4-MBP, and BP-3 were 100%, 88%, and 52%, respectively. BP had higher geometric levels, with a mean of 39.8 (19.1-108.9) ng/g, and 4-MBP had low levels, with a mean of 1.9 (1.3-3.3) ng/g. The method can be applied to routine rice cereal analysis at the nanogram-per-gram level. For infants aged 0-3 years, the hazard quotients of BP and 4-MBP were lower than one, and the margin of exposure for BP was higher than 10,000, suggesting that rice cereal consumption poses no health concern for Taiwanese infants.

Gut microbial diversity among Yorkshire, Landrace and Duroc boars and its impact on semen quality.

The gut microbiota plays an important role in pig health and performance, particularly in host growth and fecundity. In present study, the characteristics and diversity of gut microbiota in fine purebred boars from three-way crossbred "Duroc×Landrace×Yorkshire" pigs were investigated using 16 S rRNA gene sequencing. The results showed that the three breeds of boars shared similar gut microbiota, yet there remain slight differences at the family/genus level. At the family level, Ruminococcaceae, Streptococcaceae and Lactobacillaceae have the highest abundance in Landrace, while Rikenellaceae and f_p_251_o5 have the highest abundance in Duroc. The abundance of Prevotellaceae, Lachnospiraceae and Spirochaetaceae in intestinal of Yorkshire were higher than that of Landrace and Duroc. In addition, ten and six biomarkers were identified in the microbiota across breeds and months of age, respectively. Moreover, we evaluated the effect of gut microbiota on boar semen quality, revealing that Duroc had the strongest sperm vitality, significantly associated with the genus Rikenellaceae_PC9_gut_group. In addition, the spermatogenesis ability and sperm production improved gradually along with increase of age. In conclusion, this study provides a reference for understanding the gut microbiota composition of purebred boars used for three-way crosses and their impact on semen performance.

[Cell characteristics of Larix principis-rupprechtii on the edge of different stand types]. / 不同林分类型林缘华北落叶松细胞特征.

To analyze the effects of forest edge on radial growth and cell characteristics in different stand types of Larix principis-rupprechtii, we investigated the differences on radial growth, cell size and numbers between edge trees and inner trees of L. principis-rupprechtii in pure L. principis-rupprechtii forests and mixed forests of L. principis-rupprechtii and Betula platyphylla in Saihanba mechanical forest farm, China. The results showed that radial growth of the edge trees was significantly faster than that of the inner trees in pure forests, with the total ring width, earlywood width and latewood width of edge trees being 48.9%, 58.9% and 29.6% higher than those of inner trees, respectively. However, there was no difference in radial growth between edge trees and inner trees in mixed forest. The total number of earlywood cells, the number of large cells and small cells in earlywood of edge trees were increased by 63.3%, 55.6% and 70.0%, while the total number of latewood cells, the number of large cells and small cells in latewood of edge trees were increased by 35.4%, 37.5% and 28.5% compared with those of inner trees. There was no significant difference in the cell sizes between edge trees and inner trees. The cell numbers of earlywood and latewood of edge trees were not significantly different from those of inner trees in mixed forest, but the cell size in the earlywood of edge trees was 50.0% larger than those of inner trees in mixed forest. The sizes of the largest cells, the smallest cells, the large cells and the small cells in the earlywood of edge trees were increased by 28.6%, 33.3%, 16.6% and 25.0% compared with those of inner trees, respectively. The fast growth of edge trees and slow growth of inner trees in the pure forests could be effectively alleviated by cultivating mixed forests.

Fish consumption is an indicator of exposure to benzophenone derivatives: A probabilistic risk assessment in Taiwanese population.

Benzophenone (BP) derivatives (BPs) ultraviolet filters are used in industrial and commercial products and have been reported to be toxic. Studies have investigated the ecological risks but not the human exposure risks of BPs. Residues of 10 BPs (BP, BP-1, BP-2, BP-3, BP-8, 2-OHBP, 4-OHBP, 4-MBP, M2BB, and PBZ) were measured in 110 commercial samples of saltwater fish (SF) and freshwater fish (FF) from Taiwan. The estimated daily intakes (EDIs) and noncarcinogenic risks (as hazard quotients [HQs] and hazard indices [HIs]) were predicted for eight age groups by using Monte Carlo simulation, and sensitivity analysis was conducted to determine the factors influencing risks. The carcinogenic risk of exposure to BP was estimated using lifetime cancer risk (LTCR). The results revealed that seven BPs (BP, BP-3, 2-OHBP, 4-OHBP, 4-MBP, PBZ, and M2BB) were ubiquitous in the fish samples. The mean sums of the content of these seven BPs in FF and SF were 46.4 ng/g and 25.0 ng/g, respectively. Infants (age 0-3 years) exhibited the highest HI of BPs (1.6E-2) and LTCR of BP (2.8E-7) among all age groups. The HQs and HIs of all BPs were less than 1 and the LTCR for BP was lower than the acceptable range (10-4 to10-6) in all age groups, suggesting that BPs intake through fish consumption is not a health concern for Taiwanese people. The results of the sensitivity analysis demonstrated that the amount of SF consumed and 2-OHBP levels exerted the greatest effect on risk. Considering the relatively higher risk of fish consumption and concerns that ultraviolet filters are endocrine disruptors, the potential health risks of BPs intake for infants deserves further attention.

[Effects of tree species interaction, stand density, and tree size on the productivity of Larix principis-rupprechtii]. / æ ‘ç§ç›¸äº’ä½œç”¨ã€æž—åˆ†å¯†åº¦å’Œæ ‘æœ¨å¤§å°å¯¹åŽåŒ—è½å¶æ¾ç”Ÿäº§åŠ›çš„å½±å“.

Pure and mixed larch (Larix pricipis-rupprechtii) and birch (Betula platyphylla) plantations in Saihanba area were selected as test objects, with two stand density (200-340 and 880-1100 trees·hm-2) of each stand type. Based on tree size-stratified sampling approach, a total of 668 tree core samples were collected. A linear mixed model was used to analyze the effects of tree species interaction, stand density, and tree size on larch productivity. Results showed that basal area increment of larch was affected by competition, diameter at breast height, tree age, and neighborhood density to different degrees. Overyielding of larch was mainly due to the positive effect of birch on larch growth in the mixed plantation with higher stand density. For mixed plantation with lower stand density, the productivity of those two species was lower than that pure plantation because of a lack of species interaction. Intraspecific competition was the main factor influencing larch productivity. Larch productivity was positively affected by tree size, with the magnitude of tree size effect varying with stand density and species composition. Suitable enhancement of stand density and selection of birch as the mixing tree species could improve productivity of larch.

[Changes of nutrient release and enzyme activity during the decomposition of mixed leaf litter of Larix principis-rupprechtii and broadleaved tree species.] / åŽåŒ—è½å¶æ¾ä¸Žé˜”å¶æ ‘ç§æ··åˆå‡‹è½å¶åˆ†è§£è¿‡ç¨‹ä¸­å »åˆ†é‡Šæ”¾å’Œé ¶æ´»æ€§å˜åŒ–.

Litter is an important contribution to forest soil. Litter decomposition plays an important role in nutrient cycling of forest ecosystem. A field litterbag experiment was conducted to examine the dynamics of decomposition rate, nutrient release and enzyme activity during litter decomposition in the pure forests of Larix principis-rupprechtii (L) and mixed forests, including L and Betula platyphylla (B), L and Quercus mongolica (Q), as well as LBQ, in Saihanba area, Hebei Pro-vince, China. The results showed that the decomposition rate of leaf litter in L forest was significantly lower than that in mixed forests during the 720 d decomposition. The LB had the highest decomposition rate of L leaf litter. All treatments had the same change trend of nutrient contents, with the contents of N and P being increased and that of C, K and C/N being decreased. Contrast to pure leaf litter of L, leaf litter in mixed forests could promote the release of C and K, and inhibit litter N and P release. During the litter decomposition, the activities of catalase, urease and acid phosphatase increased, while that of sucrase decreased in all leaf litter of forests. The decomposition rate of leaf litter was positively correlated with the activities of catalase, urease and acid phosphatase, negatively correlated with that of sucrase. Our results showed that leaf litter mixture of L. principis-rupprechtii, B. platyphylla and Q. mongolica could enhance the litter decomposition of L. principis-rupprechtii, and that enzyme activities were closely related to litter decomposition.

Rapid determination of benzophenone derivatives in cereals using FaPEx coupled with ultra-high-performance liquid chromatography-tandem mass spectrometry.

A robust and sensitive analytical method was developed and validated for the simultaneous analysis of the levels of 10 benzophenone derivatives (BPs; BP, BP-1, BP-2, BP-3, BP-8, 2-hydroxybenzophenone [2-OHBP], 4-hydroxybenzophenone [4-OHBP], 4-methylbenzophenone [4-MBP], methyl-2-benzoylbenzoate [M2BB], and 4-benzoylbiphenyl [PBZ]) in 54 breakfast cereal samples. A fast pesticide extraction (FaPEx) technique coupled with isotope-labeled internal standards ultra-high-performance liquid chromatography-tandem mass spectrometry was employed. The developed method exhibited satisfactory linearity (R2 > 0.998), high precision (intraday and interday relative standard deviations in the ranges of 1.4%-20.8% and 3.2%-23.9%, respectively), and a limit of detection ranging from 0.001 to 0.122 ng/g. BP and 4-MBP were detected in all samples, BP-3 was detected in >59% of the samples, M2BB was detected in 14% of the samples, and 4-OHBP was detected in 7% of the samples. The mean level (range) of BP was significantly higher in corn flakes [146.9 (25.3-1083.8) ng/g] than in oatmeal [22.8 (14.2-67.5) ng/g], and it contributed the most to the overall levels of the BPs, followed by 4-MBP. When the samples were stratified according to their packaging material, the mean level of BP was significantly higher in corn flake samples with plastic packaging (251.9 ng/g) than in corn flake and oatmeal samples with laminated aluminum foil packaging. Two samples of six-grain muesli contained remarkably high levels of BP (1084 and 1055 ng/g); both were nonorganic samples packaged in a polylactide bag. Future studies must examine the possible risks that these contaminants pose to human health.

Metformin protects against myocardial ischemia-reperfusion injury and cell pyroptosis via AMPK/NLRP3 inflammasome pathway.

Ischemia/reperfusion (I/R) injury is a life-threatening vascular emergency following myocardial infarction. Our previous study showed cardioprotective effects of metformin against myocardial I/R injury. In this study, we further examined the involvement of AMPK mediated activation of NLRP3 inflammasome in this cardioprotective effect of metformin. Myocardial I/R injury was simulated in a rat heart Langendorff model and neonatal rat ventricle myocytes (NRVMs) were subjected to hypoxi/reoxygenation (H/R) to establish an in vitro model. Outcome measures included myocardial infarct size, hemodynamic monitoring, myocardial tissue injury, myocardial apoptotic index and the inflammatory response. myocardial infarct size and cardiac enzyme activities. First, we found that metformin postconditioning can not only significantly alleviated myocardial infarct size, attenuated cell apoptosis, and inhibited myocardial fibrosis. Furthermore, metformin activated phosphorylated AMPK, decreased pro-inflammatory cytokines, TNF-α, IL-6 and IL-1ß, and decreased NLRP3 inflammasome activation. In isolated NRVMs metformin increased cellular viability, decreased LDH activity and inhibited cellular apoptosis and inflammation. Importantly, inhibition of AMPK phosphorylation by Compound C (CC) resulted in decreased survival of cardiomyocytes mainly by inducing the release of inflammatory cytokines and increasing NLRP3 inflammasome activation. Finally, in vitro studies revealed that the NLRP3 activator nigericin abolished the anti-inflammatory effects of metformin in NRVMs, but it had little effect on AMPK phosphorylation. Collectively, our study confirmed that metformin exerts cardioprotective effects by regulating myocardial I/R injury-induced inflammatory response, which was largely dependent on the enhancement of the AMPK pathway, thereby suppressing NLRP3 inflammasome activation.

Modulation of Lymphocyte Potassium Channel KV1.3 by Membrane-Penetrating, Joint-Targeting Immunomodulatory Plant Defensin.

We describe a cysteine-rich, membrane-penetrating, joint-targeting, and remarkably stable peptide, EgK5, that modulates voltage-gated KV1.3 potassium channels in T lymphocytes by a distinctive mechanism. EgK5 enters plasma membranes and binds to KV1.3, causing current run-down by a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. EgK5 exhibits selectivity for KV1.3 over other channels, receptors, transporters, and enzymes. EgK5 suppresses antigen-triggered proliferation of effector memory T cells, a subset enriched among pathogenic autoreactive T cells in autoimmune disease. PET-CT imaging with 18F-labeled EgK5 shows accumulation of the peptide in large and small joints of rodents. In keeping with its arthrotropism, EgK5 treats disease in a rat model of rheumatoid arthritis. It was also effective in treating disease in a rat model of atopic dermatitis. No signs of toxicity are observed at 10-100 times the in vivo dose. EgK5 shows promise for clinical development as a therapeutic for autoimmune diseases.