Tea polyphenols coating improves physiological properties, microstructure and chemical composition of cuticle to suppress quality deterioration of passion fruit during cold storage.

The plant cuticle plays a crucial role in modulating postharvest quality and extending shelf life of horticultural crops. Passion fruit often suffers from quality degradation primarily due to peel wrinkling after harvest. Tea polyphenols (TPs) hold potential for enhancing postharvest preservation. However, the specific effects of TPs coating on preservation of passion fruit, as well as the underlying mechanisms involving cuticle regulation, have not been thoroughly investigated. This study demonstrated that treating 'Qinmi no.9' passion fruit with TPs at a concentration of 0.1 g L-1 significantly mitigates weight loss, maintains firmness, and reduces cell membrane permeability during storage at 10 °C. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed that TPs treatment notably enhances cuticle thickness and structural integrity. Furthermore, gas chromatography-mass spectrometry (GC-MS) and metabolomics analyses indicated that TPs treatment obviously promotes the accumulation of palmitic acid, stearic acid, and their derivatives-primarily 12-Octadecenoic acid and 10(E)-Octadecenoic acid-as well as increases the levels of 11-Octadecenoic acid, primary alcohols such as 1-Eicosanol, and long-chain alkanes (including C31 and C32 alkanes) in the fruit peel cuticle. These biochemical changes contribute to the quality maintenance of passion fruit during cold storage. The findings suggest that TPs treatment is a promising biological strategy for extending shelf life and mitigating quality degradation by regulating cuticle metabolism in postharvest passion fruit.

Consistency of CSCO AI with Multidisciplinary Clinical Decision-Making Teams in Breast Cancer: A Retrospective Study.

Background: The Chinese Society of Clinical Oncology Artificial Intelligence System (CSCO AI) serves as a clinical decision support system developed utilizing Chinese breast cancer data. Our study delved into the congruence between breast cancer treatment recommendations provided by CSCO AI and their practical application in clinical settings. Methods: A retrospective analysis encompassed 537 breast cancer patients treated at the Second Affiliated Hospital of Anhui Medical University between January 2017 and December 2022. Proficient senior oncology researchers manually input patient data into the CSCO AI system. "Consistent" and "Inconsistent" treatment categories were defined by aligning our treatment protocols with the classification system in the CSCO AI recommendations. Cases that initially showed inconsistency underwent a second evaluation by the Multi-Disciplinary Treatment (MDT) team at the hospital. Concordance was achieved when MDTs' treatment suggestions were in the 'Consistent' categories. Results: An impressive 80.4% concurrence was observed between actual treatment protocols and CSCO AI recommendations across all breast cancer patients. Notably, the alignment was markedly higher for stage I (85.02%) and stage III (88.46%) patients in contrast to stage II patients (76.06%, P=0.023). Moreover, there was a significant concordance between invasive ductal carcinoma and lobular carcinoma (88.46%). Interestingly, triple-negative breast cancer (TNBC) exhibited a high concordance rate (87.50%) compared to other molecular subtypes. When contrasting MDT-recommended treatments with CSCO AI decisions, an overall 92.4% agreement was established. Furthermore, a logistic multivariate analysis highlighted the statistical significance of age, menstrual status, tumor type, molecular subtype, tumor size, and TNM stage in influencing consistency. Conclusion: In the realm of breast cancer treatment, the alignment between recommendations offered by CSCO AI and those from MDT is predominant. CSCO AI can be a useful tool for breast cancer treatment decisions.

Aloe vera and tea polyphenols composite coating delays passion fruit senescence by promoting phenolic and flavonoid accumulation.

Passion fruits are highly perishable during postharvest storage and transportation, prompting the exploration of natural preservatives. This study investigates the synergistic effects of Aloe vera (ALV) and tea polyphenols (TP) coatings on quality retention, ripening modulation, and associated regulatory mechanisms in stored "golden" passion fruit (Passiflora spp.) at 10 °C. The application of a composite coating comprising 40 % ALV and 0.1 g/L TP led to notable improvements in fruit preservation over a 28-day storage period. At the day of 28, quantitatively, the ALV + TP treatment reduced weight loss by 41.60 %, shrinkage index by 28.13 %, and decay index by 50 %, significantly outperforming the control and individual treatments; the treated fruits exhibited enhanced firmness, reduced ethylene production, and the respiration peak was delayed about 6 days. Metabolomic analysis revealed pronounced alterations in key metabolic pathways, notably phenylpropanoid and flavonoid biosynthesis. Specifically, significant increases in metabolites such as phenolic acids (Feruloylmalic acid and Acropyrone) and flavonoids (Okanin-4'-O-glucoside, Apigenin-8-C-Arabinoside, Quercetin-3-O- (2'-O-galloyl) galactoside, and Catechin callate) were observed. Concurrently, transcript levels of key biosynthetic genes including cinnamate 4-hydroxylase (PeC4H), 4-coumarate-coenzyme a ligase (PeC4L), hydroxycinnamoyl transferase (PeHCT) and flavonol synthase (PeFLS) were significantly up-regulated by ALV + TP coating, indicating a robust activation of these pathways. The findings underscore the effectiveness of the ALV + TP composite coating as an environmentally friendly strategy for enhancing postharvest quality by promoting the accumulation of beneficial phenolic acids and flavonoids in passion fruits.

Exploring CCL11 in breast cancer: unraveling its anticancer potential and immune modulatory effects involving the Akt-S6 signaling.

BACKGROUND: CCL11, a chemokine known for recruiting immune cells to the tumor microenvironment (TME), has an unclear role in the context of its expression, patient prognosis, and the presence of tumor-infiltrating immune cells (TILs) in breast cancer. METHODS: The expression of CCL11 in invasive breast cancer (BRCA) was analyzed using TCGA database. Survival curve and Cox regression analysis determined the potential of CCL11 as an independent prognostic indicator. GSEA performed functional analysis on genes related to CCL11. CIBERSORT algorithm quantified the infiltration level of immune cells with varying CCL11 expression. Lastly, the correlation between CCL11 expression and anticancer drug sensitivity was examined. Immunohistochemistry (IHC) and qRT-PCR confirmed CCL11 expression in clinical tissue samples. The anti-tumor efficacy of CCL11 was investigated using CCK-8, plate formation, transwell assay, and Western blot. RESULTS: CCL11 expression was elevated in BRCA tumor tissues compared to adjacent normal tissues. Recurrence-free survival (RFS) was longer in patients with high expression of CCL11. Enrichment and co-expression analyses revealed CCL11's association with numerous immune-related signaling pathways and genes. Validation studies confirmed high CCL11 expression in breast cancer tissues. In vitro experiments substantiated CCL11's anticancer effects in BRCA. CONCLUSION: CCL11 expression correlates with immune cell infiltration in breast cancer, indicating its potential as a prognostic biomarker for BRCA.

Brown Adipose Tissue Promotes Autologous Fat Grafts Retention Possibly Through Inhibiting Wnt/ß-Catenin Pathway.

BACKGROUND: In plastic surgery, autologous fat grafts (AFG) play an important role because of their abundant supply, biocompatibility, and low rejection rate. However, the lower retention rate of fat grafts limits their widespread use. Brown adipose tissue (BAT) can promote angiogenesis and regulate the level of associated inflammation. This study explored whether BAT has a facilitative effect on fat graft retention. METHODS: We obtained white adipose tissue (WAT) from c57 mice and combined it with either BAT from c57 mice or phosphate-buffered saline (PBS) as a control. These mixtures were injected subcutaneously into the back of thymus-free nude mice. After 12 weeks, fat grafts were harvested, weighed, and analyzed. RESULTS: We found that the BAT-grafted group had higher mass retention, more mature adipocytes, and higher vascularity than the other group. Further analysis revealed that BAT inhibited M1 macrophages; down-regulated IL-6, IL-1ß, and TNF-ß; upregulated M2 macrophages and Vascular endothelial growth factor-A (VEGFA); and promoted adipocyte regeneration by inhibiting the Wnt/ß-catenin pathway, which together promoted adipose graft retention. CONCLUSION: The study demonstrated that BAT improved adipose graft retention by promoting angiogenesis, inhibiting tissue inflammation levels and the Wnt/ß-catenin pathway. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Pt and black phosphorus co-modified flower-like WS2 composites for fast NO2 gas detection at low temperature.

Incomplete recovery, baseline drift, and a long response time have been impeding the practical applications of transition metal dichalcogenide (TMD)-based gas sensors. Here, we report WS2 sensors with significantly improved gas recovery, rapid response, and negligible baseline drift by the incorporation of black phosphorus (BP) as well as the decoration of Pt to detect NO2 for the first time. Compared to bare WS2, the BP-WS2 sensors show higher sensitivity, better repeatability, and more excellent selectivity towards NO2 at the optimal operating temperature of 50 °C. Furthermore, the optimized 30%BP-WS2/Pt sensors exhibit a continuous enhancement in the recovery level and sensitivity with negligible baseline drift. The 30%BP-WS2/Pt sensor also exhibits a shorter response time of 28 s than 49.5 s for its counterpart WS2 sensor towards 32 ppm NO2. The enhanced sensing properties are primarily due to the combined effects of more adsorption sites provided by BP, the spill-over effect of Pt catalysis, and the WS2/BP heterostructure. Therefore, the Pt-decorated 30%BP-WS2 sensor exhibits prominent gas-sensing properties of high gas sensitivity, a low detection limit of 100 ppb, good selectivity, and fast response. Our strategy provides a new route for designing and optimizing TMD-based gas sensors with excellent gas-sensing performance.

Enhanced Beta2-band Oscillations Denote Auditory Hallucination in Schizophrenia Patients and a Monkey Model of Psychosis.

An electroencephalographic (EEG) signature of auditory hallucinations (AHs) is important for facilitating the diagnosis and treatment of AHs in schizophrenia. We recorded EEG from 25 schizophrenia patients with recurrent AHs. During the period of AHs, EEG recordings exhibited significantly elevated beta2-band power in the temporal region, as compared to those recorded in the absence of AHs or during stimulation with verbal sounds. We further generated methamphetamine-treated rhesus monkeys exhibiting psychosis-like behaviors, including repetitive sudden searching actions in the absence of external intrusion, suggesting the occurrence of AHs. Epidural EEG beta2-band power in the temporal region of these monkeys was enhanced immediately after methamphetamine treatment and positively correlated with the frequency of sudden searching actions. Thus, the enhancement of temporal beta2-band oscillations represents a signature for AHs in both patients and a monkey model of psychosis, and this monkey model can be used for developing closed-loop neuromodulation approaches for the treatment of refractory AHs in schizophrenia.

Loosely controlled experimental EEG datasets for higher-order cognitions in design and creativity tasks.

Understanding neural mechanisms in design and creativity processes remains a challenging endeavor. To address this gap, we present two electroencephalography (EEG) datasets recorded in design and creativity experiments. We have discussed the details, similarities, differences, and corresponding cognitive tasks of the two datasets in the following sections. The design dataset (Dataset A) comprises EEG recordings of 27 participants during loosely controlled design creation experiments. Each experiment included six design problems. In each design problem, participants performed five cognitive tasks, including problem understanding, idea generation, rating idea generation, idea evaluation, and rating idea evaluation. The NASA Task Load Index was used in rating tasks. The creativity dataset (Dataset B) includes EEG signals recorded from 28 participants in creativity experiments which were based on a modified variant of the Torrance Test of Creative Thinking (TTCT-F). Participants were presented with three incomplete sketches and were asked to perform three creativity tasks for each sketch: idea generation, idea evolution, and idea evaluation. In both datasets, we structured the experiments into predefined steps, primarily to ensure participants' comfort and task clarity. This was the only control applied to the experiments. All the tasks were loosely controlled: open-ended (up to 3 min) and self-paced. 64-channel EEG signals were recorded at 500 Hz based on the international 10-10 system by the Brain Vision EEG recording system while the participants were performing their assigned tasks. EEG channels were pre-processed and finally referenced to the Cz channel to remove artifacts. EEGs were pre-processed using popular pipelines widely used in previous studies. Preprocessed EEG signals were finally segmented according to the tasks to facilitate future analyses. The EEG signals are stored in the .mat format. While the present paper mainly addresses pre-processed datasets, it also cites raw EEG recordings in the following sections. We aim to promote research and facilitate the development of experimental protocols and methodologies in design and creativity cognition by sharing these resources. There exist important points regarding the datasets which are worth mentioning. These datasets represent a novel contribution to the field, offering insights into design and creativity neurocognition. To our knowledge, publicly accessible datasets of this nature are scarce, and, to the best of our knowledge, our datasets are the first publicly available ones in design and creativity. Researchers can utilize these datasets directly or draw upon the considerations and technical insights provided to inform their studies. Furthermore, we introduce the concept of loosely controlled cognitive experiments in design and creativity cognition. These experiments strike a balance between flexibility and control, allowing participants to incubate creative ideas over extended response times while maintaining structured experimental sections. Such an approach fosters more natural data recording procedures and holds the potential to enhance the accuracy and reliability of future studies. The loosely controlled approach can be employed in future cognitive studies. This paper also conducts a comparative analysis of the two datasets, offering a holistic view of design and creativity tasks. By exploring various aspects of these cognitive processes, we provide an understanding for future researchers.

The Ongoing Necessity of Sentinel Lymph Node Biopsy for cT1-2N0 Breast Cancer Patients.

Background: Recent clinical trials attempt to determine whether it is appropriate to omit axillary lymph node surgery in patients with cT1-2N0 breast cancer. The study aimed to investigate the true extent of axillary node disease in patients with clinically negative nodes and explore the differences between negative axillary ultrasound (AUS-cN0) and suspicious axillary ultrasound with negative fine-needle aspiration (FNA-cN0). Methods: Pathologically identified T1-2 invasive breast cancer patients with clinically negative nodes were retrospectively analyzed at our center between January 2019 and December 2022. Patients who received any systematic treatment before surgery were excluded from this study. Results: A total of 538 patients were enrolled in this study. 134 (24.9%) patients had pathologically positive nodes, and 404 (75.1%) patients had negative nodes. Univariate analysis revealed that tumor size, T stage, Ki67 level, and vascular invasion (VI) were strongly associated with pathological axillary lymph node positivity. In multivariate analysis, VI was the only independent risk factor for node positivity in patients with cT1-2N0 disease (OR: 3.723, confidence interval [CI]: 2.380-5.824, p < 0.001). Otherwise, pathological node positivity was not significantly different between AUS-cN0 and FNA-cN0 groups (23.4% vs. 28.8%, p = 0.193). However, the rate of high nodal burden (≥3 positive nodes) was significantly higher in FNA-cN0 group. Further investigation revealed that FNA-cN0 and VI were independently associated with a high nodal burden (OR: 2.650, CI: 1.081-6.496, p = 0.033; OR: 3.521, CI: 1.249-9.931, p = 0.017, respectively). Conclusions: cT1-2 breast cancer patients with clinically negative axillary lymph nodes may have pathologically positive lymph nodes and even a high nodal burden. False negatives in AUS and AUS-guided FNA should not be ignored, and sentinel lymph node biopsy remains an ongoing necessity for cT1-2N0 breast cancer patients.

CD1C is associated with breast cancer prognosis and immune infiltrates.

BACKGROUND: The tumor microenvironment (TME) in breast cancer plays a vital role in occurrence, development, and therapeutic responses. However, immune and stroma constituents in the TME are major obstacles to understanding and treating breast cancer. We evaluated the significance of TME-related genes in breast cancer. METHODS: Invasive breast cancer (BRCA) samples were retrieved from the TCGA and GEO databases. Stroma and immune scores of samples as well as the proportion of tumor infiltrating immune cells (TICs) were calculated using the ESTIMATE and CIBERSORT algorithms. TME-related differentially expressed genes (DEGs) were analyzed by a protein interaction (PPI) network and univariate Cox regression to determine CD1C as a hub gene. Subsequently, the prognostic value of CD1C, its response to immunotherapy, and its mechanism in the TME were further studied. RESULTS: In BRCA, DEGs were determined to identify CD1C as a hub gene. The expression level of CD1C in BRCA patients was verified based on the TCGA database, polymerase chain reaction (PCR) results, and western blot analysis. Immunohistochemical staining (IHC) results revealed a correlation between prognosis, clinical features, and CD1C expression in BRCA. Enrichment analysis of GSEA and GSVA showed that CD1C participates in immune-associated signaling pathways. CIBERSORT showed that CD1C levels were associated with tumor immune infiltrating cells (TILs), such as different kinds of T cells. Gene co-expression analysis showed that CD1C and the majority of immune-associated genes were co-expressed in BRCA. In renal cell carcinoma, patients with a high expression of CD1C had a better immunotherapy effect. CONCLUSION: CD1C is an important part of the TME and participates in immune activity regulation in breast tumors. CD1C is expected to become a prognostic marker and a new treatment target for breast cancer.

1-Methylcyclopropene counteracts ethylene promotion of fruit softening and roles of MiERF2/8 and MiPG in postharvest mangoes.

Ethylene burst is an important sign of the initiation of postharvest mango ripening and softening is a typical characteristic of fruit ripening. However, the intrinsic link between ethylene release and fruit softening during ripening of postharvest mangoes is still not clear. The aim of this study was to investigate the effects of ethylene and its action inhibitor 1-methylcyclopropene (1-MCP) on fruit softening and ripening and the underlying regulatory mechanisms. Results showed that ethephon (ETH) promoted ethylene release and enhanced MDA content and activities of cell wall degrading enzymes, whereas 1-MCP treatment exhibited an opposite effect. Moreover, real-time quantitative polymerase chain reaction indicated that the transcription levels of genes involved in cell wall degradation (MiPG, Miß-GAL and MiPE), ethylene biosynthesis (MiACO1 and MiACS6) and ethylene response factor (MiERF8) were remarkably induced by ETH. Correlation analysis further revealed that the production of ethylene was significantly negatively correlated with firmness, but positively correlated with MDA content, activities of cell wall degrading enzymes and expressions of MiPG and Miß-GAL. Furthermore, yeast one hybrid (Y1H) assay showed that MiERF2 and MiERF8 could directly bind to the promotor of MiPG and then regulate its transcription. These findings suggest that ethylene production is closely associated with fruit softening, and MiERF2 and MiERF8 and MiPG may play crucial roles in regulation of ripening and softening of postharvest mangoes.

Network oscillations imply the highest cognitive workload and lowest cognitive control during idea generation in open-ended creation tasks.

Design is a ubiquitous, complex, and open-ended creation behaviour that triggers creativity. The brain dynamics underlying design is unclear, since a design process consists of many basic cognitive behaviours, such as problem understanding, idea generation, idea analysis, idea evaluation, and idea evolution. In this present study, we simulated the design process in a loosely controlled setting, aiming to quantify the design-related cognitive workload and control, identify EEG-defined large-scale brain networks, and uncover their temporal dynamics. The effectiveness of this loosely controlled setting was tested through comparing the results with validated findings available in the literature. Task-related power (TRP) analysis of delta, theta, alpha and beta frequency bands revealed that idea generation was associated with the highest cognitive workload and lowest cognitive control, compared to other design activities in the experiment, including problem understanding, idea evaluation, and self-rating. EEG microstate analysis supported this finding as microstate class C, being negatively associated with the cognitive control network, was the most prevalent in idea generation. Furthermore, EEG microstate sequence analysis demonstrated that idea generation was consistently associated with the shortest temporal correlation times concerning finite entropy rate, autoinformation function, and Hurst exponent. This finding suggests that during idea generation the interplay of functional brain networks is less restricted and the brain has more degrees of freedom in choosing the next network configuration than during other design activities. Taken together, the TRP and EEG microstate results lead to the conclusion that idea generation is associated with the highest cognitive workload and lowest cognitive control during open-ended creation task.

Long non-coding RNA SNHG8 enhances triple-negative breast cancer cell proliferation and migration by regulating the miR-335-5p/PYGO2 axis.

BACKGROUND: Growing evidence has demonstrated that long non-coding RNAs (lncRNAs) can function as modulators in the development of triple-negative breast cancer (TNBC). However, the function of lncRNA small nucleolar RNA host gene 8 (SNHG8) in TNBC remains unclear. Therefore, our study aimed at investigating the role of SNHG8 in the proliferation and migration of TNBC cells. METHODS: SNHG8 expression was evaluated using RT-qPCR assay. Cell proliferation and migration were assessed by EdU, colony formation and Transwell assays. The levels of proteins related to EMT process were examined by western blot assay. The interaction among SNHG8, miR-335-5p and pygopus family PHD finger 2 (PYGO2) was detected by RIP assay, RNA pull down assay and luciferase reporter assay. RESULTS: SNHG8 expression was significantly up-regulated in TNBC cells. SNHG8 silencing obviously inhibited TNBC cell proliferation, migration and EMT process. Moreover, SNHG8 acted as a sponge to sequester miR-335-5p in TNBC cells. Besides, PYGO2 was proven as a target gene of miR-335-5p, and SNHG8 promoted TNBC cell proliferation, migration and EMT process through regulating miR-335-5p and PYGO2. CONCLUSIONS: Totally, our study indicated that SNHG8 promoted TNBC cell proliferation and migration by regulating the miR-335-5p/PYGO2 axis.

EEG signals respond differently to idea generation, idea evolution and evaluation in a loosely controlled creativity experiment.

Many neurocognitive studies endeavor to understand neural mechanisms of basic creative activities in strictly controlled experiments. However, little evidence is available regarding the neural mechanisms of interactions between basic activities underlying creativity in such experiments. Moreover, strictly controlled experiments might limit flexibility/freedom needed for creative exploration. Thus, this study investigated the whole-brain neuronal networks' interactions between three modes of thinking: idea generation, idea evolution, and evaluation in a loosely controlled creativity experiment. The loosely controlled creativity experiment will provide a degree of flexibility/freedom for participants to incubate creative ideas through extending response time from a few seconds to 3 min. In the experiment, participants accomplished a modified figural Torrance Test of Creative Thinking (TTCT-F) while their EEG signals were recorded. During idea generation, a participant was instructed to complete a sketch that was immediately triggered by a sketch stimulus at first sight. During idea evolution, a participant was instructed to complete a sketch that is radically distinctive from what was immediately triggered by the sketch stimulus. During the evaluation, a participant was instructed to evaluate difficulties of thinking and drawing during idea generation and evolution. It is expected that participants would use their experience to intuitively complete a sketch during idea generation while they could use more divergent and imaginative thinking to complete a possible creative sketch during idea evolution. Such an experimental design is named as a loosely controlled creativity experiment, which offers an approach to studying creativity in an ecologically valid manner. The validity of the loosely controlled creativity experiment could be verified through comparing its findings on phenomena that have been effectively studied by validated experimental research. It was found from our experiment that alpha power decreased significantly from rest to the three modes of thinking. These findings are consistent with that from visual creativity research based on event-related (de)synchronization (ERD/ERS) and task-related power changes (TRP). Specifically, in the lower alpha band (8-10 Hz), the decreases of alpha power were significantly lower over almost the entire scalp during idea evolution compared to the other modes of thinking. This finding indicated that idea evolution requires less general attention demands than the other two modes of thinking since the lower alpha ERD has been reported as being more likely to reflect general task demands such as attentional processes. In the upper alpha band (10-12 Hz), the decreases of alpha power were significantly higher over central sites during the evaluation compared to idea evolution. This finding indicated that evaluation involves more task-specific demands since the upper alpha ERD has been found as being more likely to reflect task-specific demands such as memory and intelligence, as was defined in the literature. In addition, new findings were obtained since the loosely controlled creativity experiment could activate multiple brain networks to accomplish the tasks involving the three modes of thinking. EEG microstate analysis was used to structure the unstructured EEG data to detect the activation of multiple brain networks. Combined EEG-fMRI and EEG source localization studies have indicated that EEG microstate classes are closely associated with the resting-state network as identified using fMRI. It was found that the default mode network was more active during idea evolution compared to the other two modes of thinking, while the cognitive control network was more active during the evaluation compared to the other two modes of thinking. This finding indicated that idea evolution might be more associated with unconscious and internal directed attention processes. Taken together, the loosely controlled creativity experiment with the support of EEG microstate analysis appears to offer an effective approach to investigating the real-world complex creativity activity.

Conditional loss of geranylgeranyl diphosphate synthase alleviates acute obstructive cholestatic liver injury by regulating hepatic bile acid metabolism.

Previous studies have suggested that metabolites in the mevalonate pathway are involved in hepatic bile acid metabolism, yet the details of this relationship remain unknown. In this study, we found that the hepatic farnesyl pyrophosphate (FPP) level and the ratio of FPP to geranylgeranyl pyrophosphate (GGPP) were increased in mice with acute obstructive cholestasis compared with mice that underwent a sham operation. In addition, the livers of the mice with acute obstructive cholestasis showed lower expression of geranylgeranyl diphosphate synthase (GGPPS), which synthesizes GGPP from FPP. When Ggps1 was conditionally deleted in the liver, amelioration of liver injury, as shown by downregulation of the hepatic inflammatory response and decreased hepatocellular apoptosis, was found after ligation of the common bile duct and cholecystectomy (BDLC). Subsequently, liquid chromatography/mass spectrometry analysis showed that knocking out Ggps1 decreased the levels of hepatic bile acids, including hydrophobic bile acids. Mechanistically, the disruption of Ggps1 increased the levels of hepatic FPP and its metabolite farnesol, thereby resulting in farnesoid X receptor (FXR) activation, which modulated hepatic bile acid metabolism and reduced hepatic bile acids. It was consistently indicated that digeranyl bisphosphonate, a specific inhibitor of GGPPS, and GW4064, an agonist of FXR, could also alleviate acute obstructive cholestatic liver injury in vivo. In general, GGPPS is critical for modulating acute obstructive cholestatic liver injury, and the inhibition of GGPPS ameliorates acute obstructive cholestatic liver injury by decreasing hepatic bile acids, which is possibly achieved through the activation of FXR-induced bile acid metabolism.

Effect of autogenous growth factors released from platelet concentrates on the osteogenic differentiation of periodontal ligament fibroblasts: a comparative study.

BACKGROUND: Platelet concentrates have been used in tissue regeneration. The purpose of this study was to examine effects of growth factors released from leukocyte- and platelet-rich fibrin (L-PRF) and concentrated growth factor (CGF) on the osteogenic differentiation of periodontal ligament fibroblasts (PDLFs). METHODS: Leukocyte- and platelet-rich fibrins, CGFs and PDLFs were obtained from New Zealand rabbits. The release of basic fibroblast growth factor (bFGF), bone morphogenetic protein 2 (BMP-2) and transforming growth factor ß1 (TGF-ß1) from L-PRFs and CGFs was measured at 5 h and 1, 3, 5, 7 days, using the enzyme linked immunosorbent assay. The PDLFs were treated with exudates of L-PRF or CGF. After the treatment, cell counting kit-8 assay was performed at day 1, 3, 5 and 7. Alkaline phosphatase (ALP) assay and Western blotting were applied at day 7. Three blocking antibodies were used to neutralize the proteins of bFGF, BMP-2 and TGF-ß1. RESULTS: Leukocyte- and platelet-rich fibrin and CGF showed different growth factor release pattern, but similar accumulated concentration of these growth factors. PDLFs proliferation was significantly promoted by both L-PRF and CGF at day 1, 3 and 7, and CGF group was superior to L-PRF group at day 1 and 3. Both L-PRF and CGF significantly enhanced PDLFs ALP activity and protein expression of osteogenic markers. The osteopontin level was higher in CGF group than in L-PRF group, but no significant differences were found between two groups for ALP activity. Three blocking antibodies significantly downregulated both L-PRF and CGF induced osteogenic markers expression. CONCLUSION: Both CGF and L-PRF can promote the proliferation and osteogenic differentiation of PDLFs. The bFGF, BMP-2 and TGF-ß1 are involved in both L-PRF and CGF induced osteogenic differentiation of PDLFs.

Additional Diagnostic Value of Growth Differentiation Factor-15 (GDF-15) to N-Terminal B-Type Natriuretic Peptide (NT-proBNP) in Patients with Different Stages of Heart Failure.

BACKGROUND Growth differentiation factor-15 (GDF-15) is a promising biomarker of cardiac remodeling. The purpose of this study was to explore the diagnostic value of plasma GDF-15 levels in different stages of heart failure (HF) and to assess the relationship with ventricular remodeling. MATERIAL AND METHODS We enrolled 219 HF patients from the Department of Cardiology in Tianjin Union Medical Center as the HF group and 32 healthy subjects as the control group. Circulating GDF-15, NT-proBNP, procollagen I C-terminal propeptide (PICP), and N-terminal procollagen III propeptide (PIIINP) levels were measured using ELISA. Associations between GDF-15 and clinical indicators in cardiac remodeling were assessed using receiver operating characteristic (ROC) curves and Spearman correlation. All the patients were followed up for 1 year. RESULTS The level of plasma GDF-15 in HF patients was higher than in the control group (P<0.05) and increased with higher ACCF/AHA and NYHA classification (P<0.05). Patients with HFrEF had higher GDF-15 levels compared to patients with HFmrEF (P<0.05). GDF-15 and left ventricular mass index (LVMI) were significantly increased as early as the pre-clinical HF stage. Also, GDF-15 levels were positively correlated to LVMI (r=0.433, P<0.05), PICP (r=0.378, P<0.001) and PIIINP (r=0.382, P<0.001). ROC curves were constructed and GDF-15 plus NT-proBNP (AUC=0.905, 95%CI: 0.868-0.942, P<0.001) was superior to NT-proBNP (AUC=0.869, 95%CI: 0.825-0.913, P<0.001) in identifying HF. GDF-15 levels did not predict prognosis after a 1-year follow-up period. CONCLUSIONS GDF-15 combined with NT-proBNP significantly improves the accuracy of diagnosing HF. Plasma GDF-15 levels can indirectly reflect the degree of cardiac remodeling and fibrosis.

Reduced triglyceride accumulation due to overactivation of farnesoid X receptor signaling contributes to impaired liver regeneration following 50% hepatectomy in extra­cholestatic liver tissue.

The aim of the present study was to investigate the role of triglyceride metabolism in the effect of obstructive cholestasis on liver regeneration following 50% partial hepatectomy (PH). Obstructive cholestatic rat models were achieved via ligation of the common bile duct (BDL). Following comparisons between hepatic pathological alterations with patients with perihilar cholangiocarcinoma, rats in the 7 day post­BDL group were selected as the BDL model for subsequent experiments. Liver weight restoration, proliferating cell nuclear antigen labeling index, cytokine and growth factor expression levels, and hepatic triglyceride content were evaluated to analyze liver regeneration post­PH within BDL and control group rats. The results of the present study revealed that obstructive cholestasis impaired liver mass restoration, which occurred via inhibition of early stage hepatocyte proliferation. In addition, reduced triglyceride content and inhibited expression of fatty acid ß­oxidation­associated genes, peroxisome proliferator activated receptor α and carnitine palmitoyltransferase, were associated with an insufficient energy supply within the BDL group post­PH. Notably, the expression levels of fatty acid synthesis­associated genes, including sterol­regulatory element­binding protein­1c, acetyl­coA carboxylase 1 and fatty acid synthase were also reduced within the BDL group, which accounted for the reduced triglyceride content and fatty acid utilization. Further investigation revealed that overactivated farnesoid X receptor (FXR) signaling may inhibit fatty acid synthesis within BDL group rats. Collectively, the role of triglycerides in liver regeneration following PH in extra­cholestatic livers was identified in the present study. Additionally, the results indicated that overactivated FXR signaling­induced triglyceride reduction is associated with insufficient energy supply and therefore contributes to the extent of impairment of liver regeneration following PH within extra­cholestatic livers.

Perioperative oral supplementation with fish oil promotes liver regeneration following partial hepatectomy in mice via AMPK activation.

The present study aimed to observe the effects of perioperative oral supplementation with fish oil (FO) on liver regeneration in mice and examine the potential mechanism. A total of 120 male ICR mice were randomly divided into 5 groups: Sham, Control, fish oil (FO), Compound C [the AMP­activated protein kinase (AMPK) inhibitor dorsomorphin], and Compound C + FO. Changes in liver function, alterations in hepatocyte proliferation and in the expression of polarization markers, and activation of AMPK signaling were examined following partial hepatectomy (PH). The results demonstrated that restoration of serum alanine aminotransferase (ALT) and total bilirubin (TBIL) levels were significantly faster in FO­treated mice compared with Control mice, and this effect was suppressed by treatment with Compound C. FO­treated mice exhibited increased numbers of Ki­67 positive hepatocytes and their postoperative liver­to­body weight ratio was significantly increased compared with the Control mice, which was also suppressed by co­treatment with the AMPK inhibitor. Furthermore, protein expression of Occludin, Claudin­3, tight junction protein 1 and bile salt export pump was gradually increased in FO­treated mice compared with Control, whereas Compound C treatment reversed this effect. Therefore, the present study revealed that perioperative oral supplementation with FO may promote liver regeneration and improved liver function in mice following PH through AMPK activation.

Zoledronic acid, an FPPS inhibitor, ameliorates liver steatosis through inhibiting hepatic de novo lipogenesis.

Currently, there is no standard therapy for non-alcoholic fatty liver disease (NAFLD), and statins have been developed as a first-line pharmaceutical therapeutic option for NAFLD-associated dyslipidemia. However, prolonged statins therapy has side effects, as statins inhibit HMG-CoA reductase, an enzyme at the very beginning of the mevalonate pathway. Here, we found that zoledronic acid (ZA), an inhibitor of farnesyl diphosphate synthase in the downstream mevalonate pathway, could attenuate hepatic lipid accumulation and improve liver injury in both high-fat diet-induced C57BL/6J mice and ob/ob mice. Moreover, the hepatic lipid metabolism was largely inhibited after ZA administration in high-fat diet-induced obese mice. Mechanically, ZA inhibited SREBP-1c-mediated de novo lipogenesis through suppressing RhoA activation via decreasing farnesyl diphosphate and geranylgeranyl diphosphate levels. In conclusion, our data provide a novel application of ZA in improving hepatic steatosis.