Paroxetine alleviates dendritic cell and T lymphocyte activation via GRK2-mediated PI3K-AKT signaling in rheumatoid arthritis.

BACKGROUND: G protein-coupled receptor kinase 2 (GRK2) could participate in the regulation of diverse cells via interacting with non-G-protein-coupled receptors. In the present work, we explored how paroxetine, a GRK2 inhibitor, modulates the differentiation and activation of immune cells in rheumatoid arthritis (RA). METHODS: The blood samples of healthy individuals and RA patients were collected between July 2021 and March 2022 from the First Affiliated Hospital of Anhui Medical University. C57BL/6 mice were used to induce the collagen-induced arthritis (CIA) model. Flow cytometry analysis was used to characterize the differentiation and function of dendritic cells (DCs)/T cells. Co-immunoprecipitation was used to explore the specific molecular mechanism. RESULTS: In patients with RA, high expression of GRK2 in peripheral blood lymphocytes, accompanied by the increases of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In animal model, a decrease in regulatory T cells (Tregs), an increase in the cluster of differentiation 8 positive (CD8+) T cells, and maturation of DCs were observed. Paroxetine, when used in vitro and in CIA mice, restrained the maturation of DCs and the differentiation of CD8+ T cells, and induced the proportion of Tregs. Paroxetine inhibited the secretion of pro-inflammatory cytokines, the expression of C-C motif chemokine receptor 7 in DCs and T cells. Simultaneously, paroxetine upregulated the expression of programmed death ligand 1, and anti-inflammatory cytokines. Additionally, paroxetine inhibited the PI3K-AKT-mTOR metabolic pathway in both DCs and T cells. This was associated with a reduction in mitochondrial membrane potential and changes in the utilization of glucose and lipids, particularly in DCs. Paroxetine reversed PI3K-AKT pathway activation induced by 740 Y-P (a PI3K agonist) through inhibiting the interaction between GRK2 and PI3K in DCs and T cells. CONCLUSION: Paroxetine exerts an immunosuppressive effect by targeting GRK2, which subsequently inhibits the metabolism-related PI3K-AKT-mTOR pathway of DCs and T cell in RA.

Recent advances in stimuli-responsive controlled release systems for neuromodulation.

Neuromodulation aims to modulate the signaling activity of neurons or neural networks by the precise delivery of electrical stimuli or chemical agents and is crucial for understanding brain function and treating brain disorders. Conventional approaches, such as direct physical stimulation through electrical or acoustic methods, confront challenges stemming from their invasive nature, dependency on wired power sources, and unstable therapeutic outcomes. The emergence of stimulus-responsive delivery systems harbors the potential to revolutionize neuromodulation strategies through the precise and controlled release of neurochemicals in a specific brain region. This review comprehensively examines the biological barriers controlled release systems may encounter in vivo and the recent advances and applications of these systems in neuromodulation. We elucidate the intricate interplay between the molecular structure of delivery systems and response mechanisms to furnish insights for material selection and design. Additionally, the review contemplates the prospects and challenges associated with these systems in neuromodulation. The overarching objective is to propel the application of neuromodulation technology in analyzing brain functions, treating brain disorders, and providing insightful perspectives for exploiting new systems for biomedical applications.

Methylation-regulated tumor suppressor gene PDE7B promotes HCC invasion and metastasis through the PI3K/AKT signaling pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) has a high mortality rate, and the mechanisms underlying tumor development and progression remain unclear. However, inactivated tumor suppressor genes might play key roles. DNA methylation is a critical regulatory mechanism for inactivating tumor suppressor genes in HCC. Therefore, this study investigated methylation-related tumor suppressors in HCC to identify potential biomarkers and therapeutic targets. METHODS: We assessed genome-wide DNA methylation in HCC using whole genome bisulfite sequencing (WGBS) and RNA sequencing, respectively, and identified the differential expression of methylation-related genes, and finally screened phosphodiesterase 7B (PDE7B) for the study. The correlation between PDE7B expression and clinical features was then assessed. We then analyzed the changes of PDE7B expression in HCC cells before and after DNA methyltransferase inhibitor treatment by MassArray nucleic acid mass spectrometry. Furthermore, HCC cell lines overexpressing PDE7B were constructed to investigate its effect on HCC cell function. Finally, GO and KEGG were applied for the enrichment analysis of PDE7B-related pathways, and their effects on the expression of pathway proteins and EMT-related factors in HCC cells were preliminarily explored. RESULTS: HCC exhibited a genome-wide hypomethylation pattern. We screened 713 hypomethylated and 362 hypermethylated mCG regions in HCC and adjacent normal tissues. GO analysis showed that the main molecular functions of hypermethylation and hypomethylation were "DNA-binding transcriptional activator activity" and "structural component of ribosomes", respectively, whereas KEGG analysis showed that they were enriched in "bile secretion" and "Ras-associated protein-1 (Rap1) signaling pathway", respectively. PDE7B expression was significantly down-regulated in HCC tissues, and this low expression was negatively correlated with recurrence and prognosis of HCC. In addition, DNA methylation regulates PDE7B expression in HCC. On the contrary, overexpression of PDE7B inhibited tumor proliferation and metastasis in vitro. In addition, PDE7B-related genes were mainly enriched in the PI3K/ATK signaling pathway, and PDE7B overexpression inhibited the progression of PI3K/ATK signaling pathway-related proteins and EMT. CONCLUSION: PDE7B expression in HCC may be regulated by promoter methylation. PDE7B can regulate the EMT process in HCC cells through the PI3K/AKT pathway, which in turn affects HCC metastasis and invasion.

Non-linear association and benchmark dose of blood pressure on carotid artery intima-media thickening in a general population of southern China.

Background and aims: This study aimed to evaluate whether there is a J-curve association between blood pressure (BP) and carotid artery intima-media thickening (CAIT) and estimate the effect of the turning point of BP on CAIT. Methods and results: Data from 111,494 regular physical examinations conducted on workers and retirees (aged 18 years or older) between January 2011 and December 2016, exported from the hospital information system, were analyzed. Restricted cubic splines (RCS) logistic regression was employed to access the association of BP with CAIT, and Bayesian benchmark dose methods were used to estimate the benchmark dose as the departure point of BP measurements. All the pnon-linear values of BP measurements were less than 0.05 in the RCS logistic regression models. Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) had J-curve associations with the risk of CAIT at a turning point around 120/70 mmHg in the RCS. The benchmark dose for a 1% change in CAIT risk was estimated to be 120.64 mmHg for SBP and 72.46 mmHg for DBP. Conclusion: The J-curve associations between SBP and DBP and the risk of CAIT were observed in the general population in southern China, and the turning point of blood pressure for significantly reducing the risk of CAIT was estimated to be 120.64/72.46 mmHg for SBP/DBP.

Applying virtual sample generation and ensemble modeling for improving the spectral diagnosis of cancer.

Cancer diagnosis plays a key role in facilitating treatment and improving survival rates of patients. The combination of near-infrared (NIR) spectroscopy with data-driven algorithms offers a rapid and cost-effective approach for such a task. Due to the limitations of objective cases, the number of tumor samples is usually smaller, and the resulting dataset exhibit the issues of class imbalance, which has a more serious impact on the performance of diagnostic models. To deal with class imbalance and improve the sensitivity, this work investigates the feasibility of NIR spectroscopy combined with virtual sample generation (VSG) as well as ensemble strategy for developing diagnostic models. Based on preliminary experiment, several learning algorithms such as discriminant analysis (DA) and partial least square-discriminant analysis (PLS-DA) are screened out as algorithms for constructing prediction models. Three algorithms of VSG including synthetic minority oversampling technique (SMOTE), Borderline-SMOTE and adaptive synthetic sampling (ADASYN) are used for experiment. A fixed sample subset composed of 27 cancer samples and 54 normal samples are hold out as the test set. Three training sets containing 5, 10, 25 minority class samples and 54 majority class samples are used for model development. The experimental result indicates that overall, with PLS-DA algorithm, all VSG approaches can significantly improve the sensitivity of cancer diagnosis for all cases of training sets with different minority samples, but ADASYN performs the best. It reveals that the integration of NIR, PLS-DA, and ADASYN is a promising tool package for developing diagnosis methods.

A Novel lncRNA lncRNA-4045 Promotes the Progression of Hepatocellular Carcinoma by Affecting the Expression of AKR1B10.

BACKGROUND: Long noncoding RNAs (lncRNAs) have been shown to be related to the occurrence and development of a variety of cancers including hepatocellular carcinoma (HCC). However, a large number of potential HCC-related lncRNAs remain undiscovered and are yet to be fully understood. METHODS: Differentially expressed lncRNAs were first obtained from the tumor tissues and adjacent normal tissues of five HCC patients using high-throughput microarray chips. Then the expression levels of 10 differentially expressed lncRNAs were verified in 50 pairs of tissue samples from patients with HCC by quantitative real-time PCR (qRT-PCR). The oncogenic effects of lncRNA-4045 (ENST00000524045.6) in HCC cell lines were verified through a series of in vitro experiments including CCK-8 assay, plate clone formation assay, transwell assay, scratch assay, and flow cytometry. Subsequently, the potential target genes of lncRNA-4045 were predicted by bioinformatics analysis, fluorescence in situ hybridization assay, and RNA sequencing. The mechanism of lncRNA-4045 in HCC was explored by WB assay as well as rescue and enhancement experiments. RESULTS: The results from microarray chips showed 1,708 lncRNAs to have been significantly upregulated and 2725 lncRNAs to have been significantly downregulated in HCC tissues. Via validation in 50 HCC patients, a novel lncRNA lncRNA-4045 was found significantly upregulated in HCC tissues. Additionally, a series of in vitro experiments showed that lncRNA-4045 promoted the proliferation, invasion, and migration of HCC cell lines, and inhibited the apoptosis of HCC cell lines. The results of qRT-PCR in HCC tissues showed that the expression levels of AKR1B10 were significantly positively correlated with lncRNA-4045. LncRNA-4045 knockdown significantly down-regulated AKR1B10 protein expression, and overexpression of lncRNA-4045 led to significant up-regulation of AKR1B10 protein in HCC cell lines. Lastly, down-regulation of AKR1B10 could partially eliminate the enhancement of cell proliferation induced by lncRNA-4045 overexpression, while up-regulation of AKR1B10 was shown to enhance those effects. CONCLUSION: LncRNA-4045 may promote HCC via enhancement of the expression of AKR1B10 protein.

Exploring the Implementation of Shared Decision-Making Involving Health Coaches for Diabetes and Hypertension Self-Management: Qualitative Study.

BACKGROUND: An emerging focus on person-centered care has prompted the need to understand how shared decision-making (SDM) and health coaching could support self-management of diabetes and hypertension. OBJECTIVE: This study aims to explore preferences for the scope of involvement of health coaches and health care professionals (HCPs) in SDM and the factors that may influence optimal implementation of SDM from the perspectives of patients and HCPs. METHODS: We conducted focus group discussions with 39 patients with diabetes and hypertension and 45 HCPs involved in their care. The main topics discussed included the roles of health coaches and HCPs in self-management, views toward health coaching and SDM, and factors that should be considered for optimal implementation of SDM that involves health coaches. All focus group discussions were audio recorded, transcribed verbatim, and analyzed using thematic analysis. RESULTS: Participants agreed that the main responsibility of HCPs should be identifying the patient's stage of change and medication education, while health coaches should focus on lifestyle education, monitoring, and motivational conversation. The health coach was seen to be more effective in engaging patients in lifestyle education and designing goal management plans as health coaches have more time available to spend with patients. The importance of a health coach's personal attributes (eg, sufficient knowledge of both medical and psychosocial management of disease conditions) and credentials (eg, openness, patience, and empathy) was commonly emphasized. Participants viewed that addressing the following five elements would be necessary for the optimal implementation of SDM: (1) target population (newly diagnosed and less stable patients), (2) commitment of all stakeholders (discrepancy on targeted times and modality), (3) continuity of care (familiar faces), (4) philosophy of care (person-centered communication), and (5) faces of legitimacy (physician as the ultimate authority). CONCLUSIONS: The findings shed light on the appropriate roles of health coaches vis-à-vis HCPs in SDM as perceived by patients and HCPs. Findings from this study also contribute to the understanding of SDM on self-management strategies for patients with diabetes and hypertension and highlight potential opportunities for integrating health coaches into the routine care process.

Observer-Based Adaptive Sliding Mode Compensation Position-Tracking Control for Drilling Tool Attitude Adjustment.

This study develops an adaptive sliding mode control approach for a drilling tool attitude adjustment system, aiming at solving the problems of model uncertainties and insufficient ability of disturbance suppression during the regulation behavior. To further improve the performance of the position-tracking loop in terms of response time, tracking accuracy, and robustness, a state observer based on an improved radial basis function is designed to approximate the model uncertainties, a valve dead-zone compensate controller is used to reduce control deviation, an adaptive sliding mode controller is designed to improve the position-tracking precision and attenuate sliding mode chattering. Finally, simulation and experimental results are carried out to verify the observability of the model uncertainties and position-tracking errors of the drilling tool attitude adjustment system, which can effectively improve the position-tracking performance and robustness of the drilling tool attitude adjustment system.

Acceptability of Mobile App-Based Motivational Interviewing and Preferences for App Features to Support Self-Management in Patients With Type 2 Diabetes: Qualitative Study.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) experience multiple barriers to improving self-management. Evidence suggests that motivational interviewing (MI), a patient-centered communication method, can address patient barriers and promote healthy behavior. Despite the value of MI, existing MI studies predominantly used face-to-face or phone-based interventions. With the growing adoption of smartphones, automated MI techniques powered by artificial intelligence on mobile devices may offer effective motivational support to patients with T2DM. OBJECTIVE: This study aimed to explore the perspectives of patients with T2DM on the acceptability of app-based MI in routine health care and collect their feedback on specific MI module features to inform our future intervention. METHODS: We conducted semistructured interviews with patients with T2DM, recruited from public primary care clinics. All interviews were audio recorded and transcribed verbatim. Thematic analysis was conducted using NVivo. RESULTS: In total, 33 patients with T2DM participated in the study. Participants saw MI as a mental reminder to increase motivation and a complementary care model conducive to self-reflection and behavior change. Yet, there was a sense of reluctance, mainly stemming from potential compromise of autonomy in self-care by the introduction of MI. Some participants felt confident in their ability to manage conditions independently, while others reported already making changes and preferred self-management at their own pace. Compared with in-person MI, app-based MI was viewed as offering a more relaxed atmosphere for open sharing without being judged by health care providers. However, participants questioned the lack of human touch, which could potentially undermine a patient-provider therapeutic relationship. To sustain motivation, participants suggested more features of an ongoing supportive nature such as the visualization of milestones, gamified challenges and incremental rewards according to achievements, tailored multimedia resources based on goals, and conversational tools that are interactive and empathic. CONCLUSIONS: Our findings suggest the need for a hybrid model of intervention involving both app-based automated MI and human coaching. Patient feedback on specific app features will be incorporated into the module development and tested in a randomized controlled trial.

Sm and Gd Contacts in 2D Semiconductors for High-Performance Electronics and Spintronics.

Two-dimensional (2D) semiconductors have attracted great attention due to their rich electronic properties and even been considered to have the potential to extend Moore's Law. However, the Schottky barrier between the metal and 2D semiconductor is formed due to the metal-induced gap states (MIGS), which greatly hinder the development of 2D semiconductor transistors in large-scale integrated circuits. Meanwhile, most air-stable 2D semiconductors are nonmagnetic, limiting the possibility of spintronic application. Here, we report a new strategy to suppress the MIGS and reduce the Schottky barrier height on 2D semiconductors (MoS2, WS2, and WSe2) by using lanthanide metal (Sm and Gd) contacts. It was found the lanthanide contacts exhibit a good Ohmic property with a near-zero Schottky barrier. As a result, the carrier mobility of MoS2 transistors reaches 118 cm2/(V s). Furthermore, Gd-contact MoS2 transistors show the typical magnetic property where the magnetoresistance reaches 2.7% at 5 K. By studying its spin valve effect, it was demonstrated that the nonlocal magnetoresistance is 4.1% and spin polarization is 3.25%. This study provides a promising pathway for high-performance 2D electronic and spintronics, which may open a new strategy for future computing-in-memory architecture.

Electrically tunable interlayer recombination and tunneling behavior in WSe2/MoS2 heterostructure for broadband photodetector.

Electrically tunable band structure and light-matter interaction are of great importance in designing novel devices and constructing high-integrated and high-performance photodetector systems in the future. However, tunable mechanisms on the layered semiconductor, especially the heterojunction, are still unclear. Herein, the WSe2/MoS2 phototransistor with dual-gated configuration is fabricated, and its electrical and photoelectrical conversion has been studied to show large tunability. It was found that conduction and rectification characteristics can be tuned by dual gates showing four states, p-i, p-n, i-n, and n-n, as a result of the charging and depletion of WSe2 and MoS2. The rectifying ratio can be modulated across a large range from 102.5 to 10-3.2. Its photoelectronic characteristics were observed to exhibit bipolar and wavelength-dependent behaviors. The interlayer recombination of charge carriers dominates the photoresponse of the device under the illumination of visible light, while it is dominated by interlayer tunneling under the illumination of near-infrared wavelengths. This bipolar photoresponse is associated with different states of band alignment, which can be switched by dual-gating modulation. Finally, by tuning the gate voltage, responsivities reach 27 445 A W-1 and 2827 A W-1 at wavelengths of 400 and 1010 nm at room temperature, respectively, which directly extends the response region from visible light to near-infrared.

Neutrophil CD64 index as a new early predictive biomarker for infected pancreatic necrosis in acute pancreatitis.

OBJECTIVE: Infectious pancreatic necrosis (IPN) is a serious complication of acute pancreatitis, and early recognition and timely intervention are the keys to improving clinical outcomes. The purpose of this study was to investigate the predictive capacity of the neutrophil CD64 index (nCD64 index) on IPN in patients with acute pancreatitis METHODS: This study comprises two independent cohorts: the training cohort consisted of 202 patients from Hunan Provincial People's Hospital, and the validation cohort consisted of 100 patients from Changsha Central Hospital. Peripheral blood samples were collected on the day of admission and on the 3rd, 5th, 7th, and 10th days of hospitalization, and the nCD64 index was detected by flow cytometry. Additionally, relevant clinical characteristics and laboratory biomarkers were collected and analyzed. RESULTS: We observed that nCD64 index on admission was significantly higher in the IPN group than Non-IPN group (p < 0.001). In the training cohort, a higher occurrence rate of IPN was observed in the high nCD64 index group compared to the moderate and low nCD64 index group (p < 0.001). Further analysis showed that nCD64 index was significant positive correlated with the incidence rate of IPN (p < 0.001, correlation coefficient = 0.972). Furthermore, logistic regression analysis showed that high expression of the nCD64 index on admission was a risk factor for the occurrence of IPN (OR = 2.971, p = 0.038). We further found that the nCD64 index of IPN patients was significantly higher than the Non-IPN patients on the days 1, 3, and 5 after admission, and the nCD64 index of IPN patients before and after the onset (p < 0.05). At the same time, this study revealed that the nCD64 index on admission showed good predictive efficacy for IPN (AUC = 0.859, sensitivity = 80.8%, specificity = 87.5%), which was comparable to APACHE II score. And this finding was further validated in an independent cohort of 100 participants (AUC = 0.919, Sensitivity = 100.0%, Specificity = 76.6%). CONCLUSION: This study demonstrated the clinical value of nCD64 index in patients with IPN patients for the first time through two independent cohort studies. The nCD64 index can be used as an early prediction and risk assessment tool for the occurrence of IPN, contributing to the improvement of patient outcomes and efficiency of medical resource allocation.

NiCo-LDH coupled with 2D ZIF-derived Co nitrogen doped carbon nanosheet arrays as a self-supporting electrocatalyst for detection of formaldehyde.

Formaldehyde is susceptible to illegal addition to foodstuffs to extend their shelf life due to its antimicrobial, preservative and bleaching properties. In this study, a self-supporting "nanosheet on nanosheet" arrays electrocatalyst with core-shell heterostructure was prepared in situ by coupling NiCo layer double hydroxide with 2D ZIF derived Co-nitrogen-doped porous carbon on carbon cloth (Co-N/C@NiCo-LDH NSAs/CC). Co-N/C nanosheet arrays act as a scaffold core with good electrical conductivity, providing more NiCo-LDH nucleation sites to avoid NiCo-LDH agglomeration, thus having fast mass/charge transfer performance. While the NiCo-LDH nanosheet arrays shell with high specific surface area provide more active sites for electrochemical reactions. As an electrocatalytic sensing electrode, Co-N/C@NiCo-LDH NSAs/CC has a wide linear range of 1 µM to 13 mM for formaldehyde detection, and the detection limit is 82 nM. Besides, the sensor has been applied to the detection of formaldehyde in food samples with satisfactory results.

Fourier Ptychographic Microscopy 10 Years on: A Review.

Fourier ptychographic microscopy (FPM) emerged as a prominent imaging technique in 2013, attracting significant interest due to its remarkable features such as precise phase retrieval, expansive field of view (FOV), and superior resolution. Over the past decade, FPM has become an essential tool in microscopy, with applications in metrology, scientific research, biomedicine, and inspection. This achievement arises from its ability to effectively address the persistent challenge of achieving a trade-off between FOV and resolution in imaging systems. It has a wide range of applications, including label-free imaging, drug screening, and digital pathology. In this comprehensive review, we present a concise overview of the fundamental principles of FPM and compare it with similar imaging techniques. In addition, we present a study on achieving colorization of restored photographs and enhancing the speed of FPM. Subsequently, we showcase several FPM applications utilizing the previously described technologies, with a specific focus on digital pathology, drug screening, and three-dimensional imaging. We thoroughly examine the benefits and challenges associated with integrating deep learning and FPM. To summarize, we express our own viewpoints on the technological progress of FPM and explore prospective avenues for its future developments.

Feasibility study on identifying the source of cigarette ash based on infrared spectroscopy and chemometrics.

Crime scene investigation is a key step in collecting and identifying physical evidence that may be closely related to the crime. The size of physical evidence can range from macro to micro. Cigarettes are a type of popular consumables, and their burned ashes are valuable resources of physical evidence since they contain important information such as brand preferences. This work explores the feasibility of using attenuated total reflection mid-infrared (ATR-MIR) spectroscopy and chemometrics to achieve cigarette brand recognition from burned ash. A total of 600 cigarette samples from ten brands were collected for experiments, and the samples were divided into a training set and a testing set in a 2:1 ratio. The Relief-F algorithm was used to sort variables and the forward search was used to further optimize variables to obtain the optimal subset of variables. Based on this, a partial least-squares discriminant analysis (PLS-DA) model was established, achieving a total accuracy of 97% on the test set. As a reference, the maximum correlation coefficient method was also used for classification, with an accuracy of only 73%. It seems that using the variable selection and modeling scheme proposed in this article is feasible for identifying cigarette brands from burned ash.

3,4-Dichlorophenylacetic acid acts as an auxin analog and induces beneficial effects in various crops.

Auxins and their analogs are widely used to promote root growth, flower and fruit development, and yield in crops. The action characteristics and application scope of various auxins are different. To overcome the limitations of existing auxins, expand the scope of applications, and reduce side effects, it is necessary to screen new auxin analogs. Here, we identified 3,4-dichlorophenylacetic acid (Dcaa) as having auxin-like activity and acting through the auxin signaling pathway in plants. At the physiological level, Dcaa promotes the elongation of oat coleoptile segments, the generation of adventitious roots, and the growth of crop roots. At the molecular level, Dcaa induces the expression of auxin-responsive genes and acts through auxin receptors. Molecular docking results showed that Dcaa can bind to auxin receptors, among which TIR1 has the highest binding activity. Application of Dcaa at the root tip of the DR5:GUS auxin-responsive reporter induces GUS expression in the root hair zone, which requires the PIN2 auxin efflux carrier. Dcaa also inhibits the endocytosis of PIN proteins like other auxins. These results provide a basis for the application of Dcaa in agricultural practices.

Low intake of ruminant trans fatty acids ameliorates the disordered lipid metabolism in C57BL/6J mice fed a high-fat diet.

Currently, the health benefits of ruminant trans fatty acids (R-TFA) are still controversial. Our previous investigations indicated that R-TFA at higher dosages (1.3% and 4% E) caused disordered lipid metabolism in mice; however, through collecting R-TFA intake data in 9 provinces of China, it was suggested that, in 2021, the range of R-TFA intake for Chinese residents was about 0.053-0.307 g d-1. Based on the 2022 Nutritional Dietary Guidelines for Chinese Residents, the recommended daily energy supply from R-TFA was about 0.11%-0.15% E. However, the health effects of R-TFA at a lower dosage are still unknown; therefore, our current research aims to further explore the effects of R-TFA on health. Through in vivo experiments, it was shown that R-TFA (0.15% E) decreased body weight gain and serum cholesterol levels in C57BL/6J mice fed a high-fat diet, while it had no significant effect on mice fed a low-fat diet. Besides, hepatic histopathology analysis suggested that R-TFA (0.15% E) ameliorated the degree of hepatic steatosis and reduced intrahepatocyte lipid droplet accumulation in C57BL/6J mice fed a high-fat diet. Through lipidomics analysis, we further screened 8 potential lipid metabolites that participate in regulating the dysregulation of lipid metabolism. Finally, it was suggested that R-TFA (0.15% E) down-regulated the expression of genes related to inflammation and cholesterol synthesis while up-regulated the expression of genes related to cholesterol clearance, which might partially explain the salutary effect of R-TFA (0.15% E) in ameliorating the hepatic steatosis and improving disordered lipid metabolism in mice fed a high-fat diet. Our current research will provide a reference for the intake of R-TFA and, furthermore, give some insights into understanding the health effects of R-TFA.

Development of a ferroptosis-based molecular markers for predicting RFS in prostate cancer patients.

The goal of this study was to develop a ferroptosis-based molecular signature that can predict recurrence-free survival (RFS) in patients with prostate cancer (PCa). In this study, we obtained ferroptosis-related genes (FRGs) in FerrDb database and clinical transcriptome data in TCGA database and GEO database. Consensus cluster analysis was used to identify three molecular markers of ferroptosis in PCa with differential expression of 40 FRGs, including PD-L1 expression levels. We conducted a new ferroptosis-related signature for PCa RFS using four FRGs identified through univariate and multivariate Cox regression analyses. The signature was validated in the training, testing, and validation cohorts, and it demonstrated remarkable results in the area under the time-dependent receiver operating characteristic (ROC) curve of 0.757, 0.715, and 0.732, respectively. Additionally, we observed that younger patients, those with stage T III and stage T IV, stage N0, cluster 1, and cluster 2 PCa were more accurately predicted by the signature as independent predictors of RFS. DU-145 and RWPE-1 cells were successfully analyzed by qRT-PCR and Western blot for ASNS, GPT2, RRM2, and NFE2L2. In summary, we developed a novel ferroptosis-based signature for RFS in PC, utilizing four FRGs identified through univariate and multivariate Cox regression analyses. This signature was rigorously validated across training, testing, and validation cohorts, demonstrating exceptional performance as evidenced by its ROC curves. Notably, our findings indicate that this signature is particularly effective as an independent predictor of RFS in younger patients or those with stage T III and T IV, stage N0, and in clusters 1 and 2. Finally, we confirmed the expression of these four FRGs in DU-145 and RWPE-1 cell lines.

LncRNA LINC00667 gets involved in clear cell renal cell carcinoma development and chemoresistance by regulating the miR-143-3p/ZEB1 axis.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is identified as a malignant tumor in the urinary tract. The research was an attempt to probe the biological function and molecular mechanism of lncRNA LINC00667 in ccRCC development. METHODS: qRT-PCR monitored LINC00667, miR-143-3p, and ZEB1 levels. The models of LINC00667, miR-143-3p, and ZEB1 overexpression or knockdown were constructed in ccRCC cells. Cell proliferation, apoptosis, migration, and invasion of the cells were detected. The levels of apoptosis-associated proteins and epithelial-mesenchymal transition (EMT)-related proteins, and ZEB1 were detected by WB. Dual-luciferase reporter assay and RNA pull-down assay identified the binding association between LINC00667 and miR-143-3p, miR-143-3p and ZEB1. Moreover, a xenograft tumor model in nude mice was used for evaluating tumor growth in vivo. RESULTS: LINC00667 and ZEB1 displayed high expression in ccRCC tissues and cells. miR-143-3p was lowly expressed in ccRCC tissues and cells. LINC00667 targeted and repressed miR-143-3p, which inhibited ZEB1 expression in a targeted manner. Overexpression of LINC00667 facilitated ccRCC cell proliferation, migration, invasion and EMT and retarded apoptosis, whereas LINC00667 knockdown or miR-143-3p overexpression exerted reverse effects. The rescue experiments indicated that overexpressing miR-143-3p dampened LINC00667-mediated oncogenic effects. Overexpressing ZEB1 diminished miR-143-3p-mediated tumor-suppressive effects. In-vivo experiments displayed that overexpression of LINC00667 contributed to the tumor growth of ccRCC cells, in contrast to miR-143-3p overexpression, which restrained the tumor growth. CONCLUSIONS: LINC00667 is up-regulated in ccRCC and enhances the ZEB1 expression by targeting miR-143-3p, which in turn accelerates ccRCC progression and induces chemoresistance.

ZIC2 accelerates growth and stemness in gastric cancer through the Wnt/ß-catenin pathway.

In the digestive system, gastric cancer (GC) is one of the most usual pernicious tumors. Despite great improvement has been created in treatment, it is still the second major reason of cancer-relevant death. Thus, further researches are required to explicate the latent molecular mechanisms and look for novel biomarkers. ZIC2 has been confirmed to be a facilitator in diversified cancers. However, the particular regulatory of ZIC2 in GC needs further investigation. In this work, it was notarized that ZIC2 expression was up-regulated in GC, and ZIC2 knockdown weakened GC cell proliferation. Moreover, ZIC2 suppression retarded cell migration and invasion. Additionally, results from the spheroid formation assay and western blot revealed that ZIC2 silencing reduced cell stemness. Next, we discovered that ZIC2 inhibition restrain the Wnt/ß-catenin pathway through modulating ß-catenin, Axin, c-myc and MMP-7 expression. At last, it was uncovered that ZIC2 repression relieved tumor growth in vivo. In summary, ZIC2 served as a promotive regulator in GC, aggravating growth and stemness in GC progression through the Wnt/ß-catenin pathway. This discovery hinted that ZIC2 may be a valid target for anticancer treatment.