Transcription factor EB-mediated autophagy affects cell migration and inhibits apoptosis to promote endometriosis.

Autophagy has emerged as an important process of cell metabolism. With continuous in-depth research on autophagy, TFEB has been a key transcription factor regulating autophagy levels in recent years. Studies have established that TFEB regulates autophagy and apoptosis in various diseases. However, the relationship between TFEB and the pathogenesis of endometriosis remains unclear. This study aimed to investigate the effect of TFEB on the mechanism of endometriosis progression. The results showed that TFEB and autophagy-related protein LC3 are highly expressed in ectopic endometrium of patients with endometriosis, overexpression of TFEB in cultured human endometrial stromal cells (HESCs) by lentivirus not only promoted autophagy but also inhibited apoptosis. In addition, the migration and invasion ability of HESCs were enhanced by TFEB overexpression. Furthermore, inhibiting autophagy with specific inhibitors can attenuate migration and invasion of HESCs induced by TFEB. The rat models of endometriosis show that TFEB knockdown can suppress lesion growth in vivo. Our results suggest that autophagy may be involved in the progression mechanism of endometriosis, and the mechanism of autophagy disorder in endometriosis is probably related to TFEB. TFEB may be a key molecule in promoting endometriosis.

Clinical application of serum tumor abnormal protein in prostate cancer patients.

PURPOSE: To explore the clinical value of tumor abnormal protein (TAP) in the diagnosis and prognosis evaluation of prostate cancer. METHODS: This study enrolled a total of 265 patients who underwent prostate biopsy procedures from December 2017. TAP levels were assayed in their blood samples using a validated TAP testing kit. Comprehensive pathological assessments, including Gleason scores, TNM staging, and AJCC prognosis stages, were conducted on prostate cancer patients. Further analysis was carried out to examine the correlation between TAP expression levels and various clinical characteristics. RESULTS: A significantly elevated TAP concentration was discerned in prostate cancer patients relative to those with benign prostate hyperplasia. Moreover, a significantly elevated TAP expression was detected in prostate cancer patients with high Gleason score (≥ 8) and advanced stages (III and IV), as compared to those with Gleason scores of 6 and 7 and lower stages (I and II). When diagnosing prostate cancer in gray area of PSA, TAP demonstrated superior diagnostic capabilities over PSA alone, with higher diagnostic sensitivity, specificity and accuracy than fPSA/tPSA ratio. Additionally, post-surgical or hormonal treatment, there was a marked reduction in TAP expression level among prostate cancer patients. CONCLUSION: The assessment of TAP presents itself as a promising tool for early diagnosis and holds potential for sensitivity in monitoring treatment reponse in prostate cancer patients.

Mode of action exploration of reproductive toxicity induced by bisphenol S using human normal ovarian epithelial cells through ERß-MAPK signaling pathway.

BACKGROUND: In the plastics production sector, bisphenol S (BPS) has gained popularity as a replacement for bisphenol A (BPA). However, the mode of action (MOA) of female reproductive toxicity caused by BPS remains unclear and the safety of BPS is controversial. METHODS: Human normal ovarian epithelial cell line, IOSE80, were exposed to BPS at human-relevant levels for short-term exposure at 24 h or 48 h, or for long-term exposure at 28 days, either alone or together with five signaling pathway inhibitors: ICI 18,2780 (estrogen receptor [ER] antagonist), G15 (GPR30 specific inhibitor), U0126 (extracellular regulated protein kinase [ERK] 1/2 inhibitor), SP600125 (c-Jun N-terminal kinase [JNK] inhibitor) or SB203580 (p38 mitogen­activated protein kinase [p38MAPK] inhibitor). MOA through ERß-MAPK signaling pathway interruption was explored, and potential thresholds were estimated by the benchmark dose method. RESULTS: For short-term exposure, BPS exposure at human-relevant levels elevated the ESR2 and MAPK8 mRNA levels, along with the percentage of the G0/G1 phase. For long-term exposure, BPS raised the MAPK1 and EGFR mRNA levels, the ERß, p-ERK, and p-JNK protein levels, and the percentage of the G0/G1 phase, which was partly suppressed by U0126. The benchmark dose lower confidence limit (BMDL) of the percentage of the S phase after 24 h exposure was the lowest among all the BMDLs of a good fit, with BMDL5 of 9.55 µM. CONCLUSIONS: The MOA of female reproductive toxicity caused by BPS at human-relevant levels might involve: molecular initiating event (MIE)-BPS binding to ERß receptor, key event (KE)1-the interrupted expression of GnRH, KE2-the activation of JNK (for short-term exposure) and ERK pathway (for long-term exposure), KE3-cell cycle arrest (the increased percentage of the G0/G1 phase), and KE4-interruption of cell proliferation (only for short-term exposure). The BMDL of the percentage of the S phase after 24 h exposure was the lowest among all the BMDLs of a good fit, with BMDL5 of 9.55 µM.

Genotoxic mode of action and threshold exploration of 2-methyl furan under 120-day sub-chronic exposure in male Sprague-Dawley rats.

2-Methylfuran (2-MF) is an important member of the furan family generated during food thermal processing. An in-vivo multiple endpoint genotoxicity assessment system was applied to explore the genotoxic mode of action and threshold of 2-MF. Male Sprague-Dawley rats received 2-MF by oral gavage at doses of 0.16, 0.625, 2.5, and 10 mg/kg.bw/day for 120 days. An additional 15 days were granted for recovery. The Pig-a gene mutation frequency of RET and RBC showed significant increases among the 2-MF groups on day 120. After a 15-day recovery period, the Pig-a gene mutation frequency returned to levels similar to those in the vehicle control. The tail intensity (TI) values of peripheral blood cells at a dose of 10 mg/kg.bw/day significantly increased from day 4 and remained at a high level after the recovery period. No statistical difference was found in the micronucleus frequency of peripheral blood between any 2-MF dose group and the corn oil group at any timepoint. 2-MF may not induce the production of micronuclei, but it could cause DNA breakage. It could not be ruled out that 2-MF may accumulate in vivo and cause gene mutations. Hence, DNA, other than the spindle, may be directly targeted. The mode of action of 2-MF may be that it was metabolized by EPHX1 to more DNA-active metabolites, thus leading to oxidative and direct DNA damage. The point of departure (PoD) of 2-MF-induced genotoxicity was derived as 0.506 mg/kg bw/day.

Milk proteomic analysis reveals differentially expressed proteins in high-yielding and low-yielding Guanzhong dairy goats at peak lactation.

The aim of this experiment was to investigate the differential proteomic characteristics of milk from high- and low-yielding Guanzhong dairy goats during the peak lactation period under the same feeding conditions. Nine Guanzhong dairy goats with high yield (H: 3.5 ± 0.17 kg/d) and nine with low yield (L:1.2 ± 0.25 kg/d) were selected for milk proteomic analysis using tandem mass tag technology. A total of 78 differentially expressed proteins were identified. Compared with L, 50 proteins including HK3, HSPB1 and ANXA2 were significantly upregulated in H milk, while 28 proteins including LALBA and XDH were significantly downregulated. Bioinformatics analysis of the differentially expressed proteins showed that galactose metabolism, purine metabolism, glycolysis/gluconeogenesis, MAPK signaling pathway, regulation of actin cytoskeleton and other pathways were closely related to milk yield. HK3, HSPB1, ANXA2, LALBA and XDH were important candidate proteins associated with the milk production characteristics of Guanzhong dairy goats. Our data provide relevant biomarkers and a theoretical basis for improving milk production in Guanzhong dairy goats.

[Toxicity of bisphenol S on human normal ovarian epithelial cells mediated by ERß-MAPK signaling pathway].

OBJECTIVE: To investigate the effects of long-term(7 days and 14 days) bisphenol S(BPS) exposure on the ERß-MAPK signaling pathway, hormone secretion phenotype and cell cycle in human normal ovarian epithelial cells IOSE 80 at actual human exposure level. METHODS: Physiologically based pharmacokinetic model combined with BPS levels in the serum of women along the Yangtze River in China was used to determine the dosing concentrations of BPS, and vehicle control and 17 ß-estradiol(E_2) control were used. Complete medium with corresponding concentrations(0, 6.79×10~(-6), 6.79×10~(-4), 6.79×10~(-2), 6.79 µmol/L BPS and 10 nmol/L E_2) was replaced every 2 days. mRNA expressions of estrogen receptor(ERß and GPR30), key genes in MAPK signaling pathway(P38/JNK/ERK signaling pathway) and gonadotropin-releasing hormone-related genes(GnRH-I, GnRH-II and GnRH-R) were measured by qPCR. The ERß-MAPK signaling pathway inhibitors were employed to detect the effect of long-term exposure to BPS on the cell cycle by flow cytometry. Dose-response relationship analysis was performed to calculate the benchmark does lower confidence limits. RESULTS: Compared to the vehicle control, after 7 days exposure to BPS, the ratio of G_2/M phase was significantly increased(P<0.05), and the mRNA expressions of GnRH-I, GnRH-II and GnRH-R were significantly decreased(P<0.05); after 14 days exposure to BPS, the mRNA expressions of ESR2, MAPK3, and MAPK9 were significantly increased(P<0.05), and the mRNA expressions of GnRH-II and GnRH-R were significantly decreased(P<0.05). The GnRH-II mRNA expression level of BPS treatment for 7 days; the G_0/G_1 phase ratio, MAPK3 and MAPK8 mRNA expression level of BPS exposure for 14 days; and the GnRH-I mRNA expression level after BPS treatment for 7 days and 14 days showed a good dose-response relationship but with poor fit. CONCLUSION: Long-term low-dose exposure to BPS may cause cell cycle arrest by activating the ERß-MAPK signaling pathway, and may lead to changes in the hormone secretion of IOSE 80 cells.

[Protective effects of galacto-oligosaccharide and polydextrose on Caco-2 intestinal cell barrier injury model].

OBJECTIVE: To explore the protective effect of different ratios of galactose oligosaccharide(GOS) and polydextrose(PDX) on intestinal cell barrier damage model of Caco-2. METHODS: The same batch of Caco-2 cells were cultured to form a cell barrier model and randomly divided into damaged model group without calcium, calcium-containing blank control group(1.8 mmol/L Ca~(2+)), low-ratio/low-dose group(1.8 mmol/L Ca~(2+)+2 mg/mL GOS+2 mg/mL PDX) and low-ratio/medium-dose group(1.8 mmol/L Ca~(2+)+4 mg/mL GOS+4 mg/mL PDX), low-ratio/high-dose group(1.8 mmol/L Ca~(2+)+8 mg/mL GOS+8 mg/mL PDX) and high-ratio/low-dose group(1.8 mmol/L Ca~(2+)+0.8 mg/mL GOS+3.2mg/mL PDX), high-ratio/medium-dose group(1.8 mmol/L Ca~(2+)+1.6 mg/mL GOS+6.4 mg/mL PDX), high-ratio/high-dose group(1.8 mmol/L Ca~(2+)+3.2mg/mL GOS+12.8 mg/mL PDX), a total of 8 groups, three parallel groups were performed in each group. The Trans Epithelial Electrical Resistance value and apparent permeability coefficient value of each group were determined after 4 d culture, and the morphology of tight junction proteins ZO-1, Occludin and Claudin-1 were observed by immunofluorescence method, and the expression levels of inflammatory related factors in each group were determined by protein microarray method. RESULTS: Compared with damaged model group, TEER ratio in calcium-containing blank control group was significantly increased(P<0.05), while Papp value was significantly decreased(P<0.05);Compared with calcium-containing blank control group, TEER ratio in low-ratio/medium-dose group and high-ratio/high-dose group was significantly increased(P<0.05) while Papp value was significantly decreased(P<0.05), and they could significantly down-regulate some inflammatory response related cytokines. The cell barrier was intact in all groups except for the compact junction protein structure in the model group. CONCLUSION: Compared with Ca~(2+) alone, the combination of two prebiotics can enhance the density of Caco-2 cell barrier and reduced the permeability of cell bypass. And it can significantly reduce the expression level of some inflammatory cytokines and effectively protect the intestinal cell barrier.

Design of Redispersible High-Drug-Load Amorphous Formulations: Impact of Ionic vs Nonionic Surfactants on Processing and Performance.

Amorphous solid dispersions (ASDs) are an enabling formulation approach used to enhance bioavailability of poorly water-soluble molecules in oral drug products. Drug-rich amorphous nanoparticles generated in situ during ASD dissolution maintain supersaturation that drives enhanced absorption. However, in situ formation of nanoparticles requires large quantities of polymers to release drugs rapidly, resulting in an ASD drug load <25%. Delivering directly engineered drug-rich amorphous nanoparticles can reduce the quantities of polymers significantly without sacrificing bioavailability. Preparation of 90% drug-load amorphous nanoparticles (ANPs) of <300 nm diameter using solvent/antisolvent nanoprecipitation, organic solvent removal, and spray drying was demonstrated previously on model compound ABT-530 with Copovidone and sodium dodecyl sulfate (anionic). In this work, nonionic surfactant d-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS, or TPGS) was used to prepare ANPs as a comparison. Characterization of ANPs by dynamic light scattering, filtrate potency assay, scanning electron microscopy, and differential scanning calorimetry revealed differences in surface properties of nanoparticles afforded by surfactants. This work demonstrates the importance of understanding the impact of the stabilizing agents on nanoparticle behavior when designing a high-drug-load amorphous formulation for poorly water-soluble compounds as well as the impact on redispersion.

Analysis of the circRNAs expression profile in mouse lung with H7N9 influenza A virus infection.

Influenza A virus is a single-stranded RNA virus that can cause great mortality and economic loss worldwide. Circular RNAs (circRNAs) are non-coding RNAs that have been shown to have important functions in the regulation of biological processes. However, their functions during the influenza A virus infection process remain unclear. Herein, RNA sequencing technology was used to identify circRNAs expressed in mouse lungs during infection with H7N9/PB2-627 K/701D (H7N9/Wild-type) virus and PB2 mutant viruses (H7N9/PB2-627E/701D and H7N9/PB2-627E/701 N). We identified 7126 circRNAs at different genomic locations during H7N9 influenza virus and its mutant virus infections, of which 186 were differentially expressed. Enrichment analysis revealed that the differentially expressed circRNAs were associated with the viral infection process. Our study shows that circRNA expression profiles were altered following H7N9 influenza A virus infection and the differentially expressed circRNAs may have an important immune-regulating function during viral infection.

Multiple Fingerprints and Spectrum-Effect Relationship of Polysaccharides from Saposhnikoviae Radix.

PMP-HPLC, FT-IR, and HPSEC fingerprints of 10 batches of polysaccharides from Saposhnikoviae Radix with different production areas and harvest times have been prepared, and the chemometrics analysis was performed. The anti-allergic activity of 10 batches of Saposhnikoviae Radix polysaccharide (SP) was evaluated, and the spectrum-effect relationship of the 10 batches of SP was analyzed by gray correlation degree with the chromatographic fingerprint as the independent variable. The results showed that the PMP-HPLC, HPSEC, and FT-IR fingerprints of 10 batches of SP had a high similarity. Two monosaccharides (rhamnose and galactose), the polysaccharide fragment Mn = 8.67 × 106~9.56 × 106 Da, and the FT-IR absorption peak of 892 cm-1 can be used as the quality control markers of SPs. All 10 batches of SP could significantly inhibit the release of ß-HEX in RBL-231 cells, and the polysaccharides harvested from Inner Mongolia in the winter had the best anti-allergic activity. The spectrum-effect relationship model showed that the monosaccharide composition and molecular weight were related to the anti-allergic activity of the SPs. Multiple fingerprints combined with spectrum-effect relationship analysis can evaluate and control the quality of SPs from the aspects of overall quality and efficacy, which has more application value.

Coupling Liquid Chromatography and Tandem Mass Spectrometry to Electrophoresis for In-Depth Analysis of Glycosaminoglycan Drugs: Heparin and the Multicomponent Sulodexide.

Glycosaminoglycans (GAGs) contribute to the treatment of many human diseases, especially in the field of thrombosis, because of their anticoagulant activity. GAGs interrupt the coagulation process by interacting with multiple coagulation factors through defined sequences within their linear and negatively charged chains, which are not fully elucidated. Numerous methods have been developed to characterize the structure of pharmaceutical GAGs, including intravenously or subcutaneously administered heparin and orally administered sulodexide. However, most currently available methods only focus on the oligosaccharide portion or analyze the whole mixture because longer-chain polysaccharides are extremely difficult to resolve by chromatographic separation. We have established two novel electrophoresis-mass spectrometry methods to provide a panoramic view of the structures of pharmaceutical GAGs. In the first method, an in-gel digestion procedure was developed to recover GAGs from the polyacrylamide gels, while in the second method, a strong anion exchange ultrafiltration procedure was developed to extract multiple GAG species from the agarose gels. Both procedures are compatible with liquid chromatography-tandem mass spectrometry, and structural information, such as disaccharide composition and chain length, can be revealed for each GAG fraction. The applications of these two methods on analysis of two different GAG drugs, heparin and sulodexide, were demonstrated. The current study offers the first robust tool to directly elucidate the structure of larger GAG chains with more biological importance rather than obtaining a vague picture of all chains as a mixture, which is fundamental for better understanding the structure-activity relationship and quality control of the GAG drugs.

Integrated Liver Inflammatory Score Predicts the Therapeutic Outcome of Patients with Hepatocellular Carcinoma after Transarterial Chemoembolization.

PURPOSE: To evaluate the performance of the integrated liver inflammatory score (ILIS) in predicting survival in patients with hepatocellular carcinoma (HCC) who received transarterial chemoembolization, and to compare ILIS to other prognostic scoring systems and inflammatory indices. MATERIALS AND METHODS: This study included 192 patients with unresectable HCC who underwent transarterial chemoembolization from 3 medical centers. The potential risk factors of the patients' overall survival (OS) were determined by multivariate Cox regression analysis. The predictive performances of ILIS in 1-, 2-, 3-, 4-, and 5-year survival were evaluated using receiver operating characteristic curves. The discriminatory power in the OS of ILIS and the other known scoring systems or inflammatory indices was determined by C-statistic. RESULTS: Multivariate regression analysis showed that high ILIS (P = .047), low lymphocyte count (P = .034), beyond up-to-seven criteria (P = .021), and nonresponse to the first transarterial chemoembolization session (P = .039) were risk factors for poor prognosis after transarterial chemoembolization. The predictive performances of ILIS for 1-, 2-, 3-, 4-, and 5-year survival were good, with area under the curve values of 0.627, 0.631, 0.621, 0.577, and 0.681, respectively. ILIS outperformed other standard scoring systems and inflammatory indices in predicting OS, with a C-statistic of 0.625. CONCLUSIONS: ILIS is a powerful prognostic index for predicting the survival of patients with HCC after transarterial chemoembolization, which suggests that ILIS before treatment should be considered during the patient evaluation process.

EDSSA: An Encoder-Decoder Semantic Segmentation Networks Accelerator on OpenCL-Based FPGA Platform.

Visual semantic segmentation, which is represented by the semantic segmentation network, has been widely used in many fields, such as intelligent robots, security, and autonomous driving. However, these Convolutional Neural Network (CNN)-based networks have high requirements for computing resources and programmability for hardware platforms. For embedded platforms and terminal devices in particular, Graphics Processing Unit (GPU)-based computing platforms cannot meet these requirements in terms of size and power consumption. In contrast, the Field Programmable Gate Array (FPGA)-based hardware system not only has flexible programmability and high embeddability, but can also meet lower power consumption requirements, which make it an appropriate solution for semantic segmentation on terminal devices. In this paper, we demonstrate EDSSA-an Encoder-Decoder semantic segmentation networks accelerator architecture which can be implemented with flexible parameter configurations and hardware resources on the FPGA platforms that support Open Computing Language (OpenCL) development. We introduce the related technologies, architecture design, algorithm optimization, and hardware implementation of the Encoder-Decoder semantic segmentation network SegNet as an example, and undertake a performance evaluation. Using an Intel Arria-10 GX1150 platform for evaluation, our work achieves a throughput higher than 432.8 GOP/s with power consumption of about 20 W, which is a 1.2× times improvement the energy-efficiency ratio compared to a high-performance GPU.

Lipidomics coupled with pathway analysis characterizes serum metabolic changes in response to potassium oxonate induced hyperuricemic rats.

BACKGROUND: Hyperuricemia as a metabolic disease is usually associated with lipid metabolic disorder. The purpose of this study is to identify potential lipid biomarkers and provide the evidence for the relationship between hyperuricemia and lipid-related diseases. METHODS: Lipidomics-a specialized study of lipid metabolites-has become a highly sensitive and powerful tool for biomarker discovery. In this work, an ultra-performance liquid chromatography-quadruole-time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS)-based on Lipidomics approach was employed to investigate serum samples from potassium oxonate-treated rats to find potential biomarkers. Principal component analysis (PCA) was used to analyze the MS data to assess the establishment of hyperuricemia model. Orthogonal partial least-squares discriminant analysis (OPLS-DA) in combination with independent samples t-test was performed for biomarker selection and identification. RESULTS: Thirteen potential biomarkers in rat serum were identified in the screen, and two abnormal metabolism pathways were found, namely glycerolphospholipid metabolism and glycosylphosphatidylinositol-anchored protein biosynthesis. CONCLUSIONS: In this work, the Lipidomics approach based on UPLC-Q-TOF/MS was employed to investigate serum metabolic changes in the rat model, 13 potential biomarkers related to hyperuricemia were identified, primarily involved in glycerolphospholipid metabolism and glycosylphosphatidylinositol-anchored protein biosynthesis. Abnormal glycerophospholipid metabolism pathway may be associated with lipid metabolism disorder caused by hyperuricemia, while the relationship between hyperuricemia and glycosylphosphatidylinositol-anchored protein biosynthesis needs further study.

Factors influencing the distribution, risk, and transport of microplastics and heavy metals for wildlife and habitats in "island" landscapes: From source to sink.

Microplastics (MPs) and heavy metals (HMs) are important pollutants in terrestrial ecosystems. In particular, the "island" landscape's weak resistance makes it vulnerable to pollution. However, there is a lack of research on MPs and HMs in island landscapes. Therefore, we used Helan Mountain as the research area. Assess the concentrations, spatial distribution, ecological risks, sources, and transport of MPs and HMs in the soil and blue sheep (Pseudois nayaur) feces. Variations in geographical distribution showed a connection between human activity and pollutants. Risk assessment indicated soil and wildlife were influenced by long-term pollutant polarization and multi-element inclusion (Igeo, Class I; PHI, Class V; RI (MPs), 33 % Class II, and 17 % Class IV; HI = 452.08). Source apportionment showed that tourism and coal combustion were the primary sources of pollutants. Meanwhile, a new coupling model of PMF/Risk was applied to quantify the source contribution of various risk types indicated transportation roads and tourism sources were the main sources of ecological and health risks, respectively. Improve the traceability of pollution source risks. Furthermore, also developed a novel tracing model for pollutant transportation, revealing a unique "source-sink-source" cycle in pollutant transportation, which provides a new methodological framework for the division of pollution risk areas in nature reserves and the evaluation of spatial transport between sources and sinks. Overall, this study establishes a foundational framework for conducting comprehensive risk assessments and formulating strategies for pollution control and management.

The cGAS-STING pathway promotes the development of preeclampsia by upregulating autophagy: Mechanisms and implications.

OBJECTIVE: To investigate the influence and significance of cGAS-STING signaling pathway and autophagy on the occurrence and development of preeclampsia. DESIGN: A case-control experimental study, in vitro cell culture study, and in vivo animal research. METHODS: Human placenta tissue was collected and the differences in HE staining were observed. Immunohistochemistry and Western blot were used to verify differences in cGAS, STING and autophagy associated proteins. The PE rat model was established, the pathological changes of placenta and kidney were observed by HE staining, and the expression levels of related proteins were detected. In the lv-STING transfected HTR-8/SVneo trophoblast cell model, the expressions of autophagy indexes such as P62 and LC3 were verified by RT-PCR, Western blot and cell fluorescence experiments, and then the invasion and migration ability of cells were detected by Transwell and scrape tests. As an effective STING antagonist, C176 was administered to PE rats to observe whether it was effective in the treatment of PE disease. RESULTS: The expression levels of cGAS, STING and autophagy related proteins were increased in human and rat placental tissues. In the HTR-8/SVneo cell model which transfected by lv-STING, the expression levels of autophagy related indicators such as P62 and LC3 were increased. The invasion and migration ability of HTR-8/SVneo cells were significantly inhibited, which was improved by the autophagy inhibitor chloroquine. Acting as an effective STING antagonist in vivo, C176 significantly reversed the outcome of PE, alleviated and prevented the occurrence and development of PE. CONCLUSION: Our study proved that the cGAS-STING signaling pathway and autophagy levels are elevated in preeclampsia disease, and the cGAS-STING signaling pathway promotes the occurrence and development of preeclampsia through up-regulation of autophagy. This finding provides new insights into the pathogenesis of preeclampsia. Targeting this pathway may provide a potential therapeutic strategy for the treatment of preeclampsia.

Proof-of-Concept in Developing a 45% Drug Loaded Amorphous Nanoparticle Formulation.

Amorphous solid dispersion (ASD) is an enabling approach utilized to deliver poorly soluble compounds. ASDs can spontaneously generate drug-rich amorphous nanoparticles upon dissolution, which can act as a reservoir for maintaining supersaturation during oral absorption. But, conventional ASDs are often limited in drug loadings to < 20 %. For indications where the dose is high, this can translate into a significant pill burden. The aim of this research was to develop a high drug loading (DL) amorphous nanoparticle (ANP) formulation that can release the drug-rich nanoparticles into solution upon contact with aqueous environment. Nanoparticles were directly engineered using solvent/anti-solvent precipitation. The obtained nanoparticle suspension was then concentrated followed by solidification to a re-dispersible amorphous dosage form using spray drying or lyophilization. The impact of process variables was studied using dynamic light scattering (DLS), scanning electron microscopy (SEM), high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSC). It was observed that spray drying led to a non-re-dispersible formulation. Sucrose and trehalose containing lyocakes resulted in re-dispersible formulations. The trehalose containing lyocakes, in a dog study, gave comparable performance to the reference tablet in the fasted state but lower area under the curve (AUC) in fed state.

Comparative analysis of different metabolites in semen of Guanzhong dairy goats with different motility rates.

In order to explore the different metabolites of buck semen with different motility stored at 4 °C, the semen of bucks was collected by artificial vagina. The collected semen was divided into high motility group and low motility group after treatment, with 6 replicates set for each group. The semen metabolites of high motility group and low motility group were detected by Liquid Chromatography-Mass Spectrometry (LC-MS). The results showed that 101 different metabolites were detected in the high and low motility groups of bucks, of which 48 metabolites were significantly up-regulated (P < 0.05) and 53 metabolites were significantly down regulated (P < 0.05). Most of these metabolites belonged to lipids and lipid-like molecules, organic acids and their derivatives, and organic oxygen compounds, which were mainly related to energy metabolism. According to the functional enrichment analysis of the former differential metabolites in KEGG database, the top 20 most representative metabolic pathways were detected, among which the glycerophospholipid metabolic pathways changed significantly. From the perspective of metabolomics, this study revealed the differences of metabolites and characteristic compounds of semen with different motility of bucks under low temperature preservation, which provided a scientific basis for the preservation and utilization of semen of Guanzhong dairy goats in the future.

Study on comparative analysis of differential metabolites in Guanzhong dairy goat semen before and after freezing.

In order to explore the differential metabolites between fresh and frozen-thawed semen of Guanzhong dairy goats, semen samples were collected by artificial vagina method, and divided into fresh and frozen-thawed semen groups, with six replicates in each group. Liquid Chromatography-mass spectrometry (LC-MS) technology was used to detect semen metabolites in both groups. The metabolites were analyzed and identified by the combination of multidimensional statistical analysis, namely principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), orthogonal partial least squares discriminant analysis (OPLS-DA) and univariate statistical analysis, Differential metabolites were identified according to One-step Solution for Identification of Small Molecules in Metabolomics Studies (OSI/SMMS) combined with Human Metabolome Database (HMDB), Lipidmaps and Metlin and the metabolic pathways of different metabolites were enriched and analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The results showed that a total of 53 differential metabolites were detected in fresh and frozen-thawed semen groups, of which 10 metabolites were significantly up-regulated (P < 0.05) and 43 were significantly down-regulated (P < 0.05). Most of the metabolites belonged to lipids and lipid-like molecules, organic acids and their derivatives, organic oxygen compounds, etc. According to the functional enrichment analysis of the top twenty differential metabolites in the KEGG database, significant changes occurred in linoleic acid metabolism pathway out of total eleven pathways observed. These differential metabolites can be used as metabolic markers of sperm cryo-injury in dairy goats.

The cGAS-STING pathway promotes endometriosis by up-regulating autophagy.

OBJECTIVE: To investigate the roles of the cGAS-STING signal pathway and autophagy in the disease progression of endometriosis and to explore the regulatory mechanism of the cGAS-STING signal pathway on autophagy. DESIGN: A case-control experimental study, in vitro primary cell culture study, and in vivo animal research. MAIN OUTCOME MEASURES: Immunohistochemistry, RT-PCR and Western Blot were used to detect cGAS-STING signal pathway and autophagy expression differences in human and rat models. The lentivirus was used to overexpress STING in cells. The expression level of autophagy in human endometrial stromal cells (HESCs) transfected with lv-STING was detected by Western Blot, RT-PCR, and immunofluorescence. Transwell migration and invasion assays were conducted to assess cellular motility. The STING antagonist was applicated in vivo to investigate the therapeutic effects. RESULTS: The expression levels of the cGAS-STING signal pathway and autophagy in Human and Rat ectopic endometrium were increased. STING overexpression promotes the expression of autophagy in human endometrial stromal cells (HESCs). STING overexpression enhances the migration and invasion of the human endometrial stromal cells (HESCs), but the addition of autophagy antagonists could significantly reverse this. STING antagonists inhibited the expression of autophagy in vivo and reduced the volume of ectopic lesions. CONCLUSION: The expression levels of the cGAS-STING signal pathway and autophagy were increased in endometriosis. cGAS-STING signal pathway promotes the development of endometriosis by upregulating autophagy.