Exploring the underlying mechanisms of Danshen-Shanzha Decoction on coronary heart disease: An integrated analysis combining pharmacoinformatics and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: The Danshen-Shanzha Decoction (DSD) is a renowned herbal combination consisting of the root of Salvia miltiorrhiza Bunge (known as Danshen in Chinese) and the fruits of Crataegus pinnatifida Bunge (known as Shanzha in Chinese), which has exhibited remarkable clinical efficacy in the treatment of coronary heart disease (CHD) in traditional Chinese medicine, with its earliest recorded application dating to around 202 BCE during the Han Dynasty. Despite significant advancements in the fundamental research and clinical applications of DSD over the past few decades, the precise bioactive components as well as the underlying mechanisms responsible for its protective effect on CHD remain unelucidated. AIM OF THE STUDY: The present study was designed to elucidate the bioactive components and potential mechanism of DSD in the treatment of CHD using in silico technologies integrated with pharmacoinformatic methods and experimental validation. MATERIALS AND METHODS: The chemical components of DSD were analyzed and identified using UPLC-Q-TOF-MS. Pharmacoinformatic-based methods were employed to comprehensively investigate the principal active components and targets of DSD for treating CHD. GO and KEGG pathway analyses were utilized to elucidate the underlying mechanism responsible for DSD's efficacy against CHD. Molecular docking and molecular dynamics simulation were performed to assess the binding affinity between active components and putative targets. Furthermore, surface plasmon resonance (SPR) was carried out to verify the affinity and kinetic characteristics of major components to STAT3 protein. Subsequently, a series of in vitro experiments, including cell viability test, flow cytometric analysis, ELISA and western blotting, were conducted to validate the predicted results in an oxygen-glucose deprivation (OGD)-stimulated H9c2 model. RESULTS: A total of 96 compounds were characterized by UPLC-Q-TOF-MS, and 281 overlapping targets were identified through pharmacoinformatic-based methods. Among these, ten critical compounds were determined as the core active components of DSD. The core targets associated with the development of CHD included STAT3, SRC, TP53, JUN, and AKT1. Notably, Dihydrotanshinone I and (+)-Epicatechin exhibited strong binding affinity towards STAT3. The potential mechanisms by which DSD modulates the pathological progression of CHD were predicted to involve inflammation, oxidative stress, and apoptosis. Importantly, the cytoprotective effect of DSD against apoptosis was confirmed in OGD-stimulated H9c2 cells, as evidenced by the upregulation of Bcl-2 expression and downregulation of both Bax and cleaved caspase-3 expressions upon DSD treatment. Furthermore, DSD significantly enhanced the phosphorylated protein expressions of JAK2 and STAT3 compared to the OGD group, suggesting its potential role in modulating related signaling pathways. CONCLUSIONS: The current study successfully fills the gap in the understanding of the chemical profiles of DSD, predicting its active components, potential targets, and molecular mechanisms in the treatment of CHD. These findings not only provide a valuable strategy but also robust data support for future investigations into DSD, thereby facilitating the identification of novel therapeutic targets for traditional Chinese medicines in the battle against CHD.

Turning to immunosuppressive tumors: Deciphering the immunosenescence-related microenvironment and prognostic characteristics in pancreatic cancer, in which GLUT1 contributes to gemcitabine resistance.

Increasing evidence indicates that the remodeling of immune microenvironment heterogeneity influences pancreatic cancer development, as well as sensitivity to chemotherapy and immunotherapy. However, a gap remains in the exploration of the immunosenescence microenvironment in pancreatic cancer. In this study, we identified two immunosenescence-associated isoforms (IMSP1 and IMSP2), with consequential differences in prognosis and immune cell infiltration. We constructed the MLIRS score, a hazard score system with robust prognostic performance (area under the curve, AUC = 0.91), based on multiple machine learning algorithms (101 cross-validation methods). Patients in the high MLIRS score group had worse prognosis (P < 0.0001) and lower abundance of immune cell infiltration. Conversely, the low MLIRS score group showed better sensitivity to chemotherapy and immunotherapy. Additionally, our MLIRS system outperformed 68 other published signatures. We identified the immunosenescence microenvironmental windsock GLUT1 with certain co-expression properties with immunosenescence markers. We further demonstrated its positive modulation ability of proliferation, migration, and gemcitabine resistance in pancreatic cancer cells. To conclude, our study focused on training of composite machine learning algorithms in multiple datasets to develop a robust machine learning modeling system based on immunosenescence and to identify an immunosenescence-related microenvironment windsock, providing direction and guidance for clinical prediction and application.

Platelet-Derived Growth Factor C Facilitates Malignant Behavior of Pancreatic Ductal Adenocarcinoma by Regulating SREBP1 Mediated Lipid Metabolism.

Lipid metabolism reprogramming stands as a fundamental hallmark of cancer cells. Unraveling the core regulators of lipid biosynthesis holds the potential to find promising therapeutic targets in pancreatic ductal adenocarcinoma (PDAC). Here, it is demonstrated that platelet-derived growth factor C (PDGFC) orchestrated lipid metabolism, thereby facilitated the malignant progression of PDAC. Expression of PDGFC is upregulated in PDAC cohorts and is corelated with a poor prognosis. Aberrantly high expression of PDGFC promoted proliferation and metastasis of PDAC both in vitro and in vivo. Mechanistically, PDGFC accelerated the malignant progression of PDAC by upregulating fatty acid accumulation through sterol regulatory element-binding protein 1 (SREBP1), a key transcription factor in lipid metabolism. Remarkably, Betulin, an inhibitor of SREBP1, demonstrated the capability to inhibit proliferation and metastasis of PDAC cell lines, along with attenuating the process of liver metastasis in vivo. Overall, the study underscores the pivotal role of PDGFC-mediated lipid metabolism in PDAC progression, suggesting PDGFC as a potential biomarker for PDAC metastasis. Targeting PDGFC-induced lipid metabolism emerges as a promising therapeutic strategy for metastatic PDAC, with the potential to improve clinical outcomes.

Targeting Skp2 degradation with troxerutin decreases neointima formation.

The proliferative and migratory abilities of vascular smooth muscle cells (VSMCs) play a crucial role in neointima formation following vascular injury. Skp2 facilitates proliferation and migration in cells through cell cycle regulation, presenting an important therapeutic target for atherosclerosis, pulmonary hypertension, and vascular restenosis. This study aimed to identify a natural product capable of inhibiting neointima formation post vascular injury. Here, we demonstrate that troxerutin, a flavonoid, significantly reduced viability and downregulated Skp2 in VSMCs. Moreover, troxerutin exhibited anti-proliferative effects on VSMCs and mitigated neointima formation. These findings collectively elucidate the intrinsic mechanism of troxerutin in treating atherosclerosis, pulmonary hypertension, and vascular restenosis by targeting the E3-linked enzyme Skp2.

Straw return enhances grain yield and quality of three main crops: evidence from a meta-analysis.

Straw return is regarded as a widely used field management strategy for improving soil health, but its comprehensive effect on crop grain yield and quality remains elusive. Herein, a meta-analysis containing 1822 pairs of observations from 78 studies was conducted to quantify the effect of straw return on grain yield and quality of three main crops (maize, rice, and wheat). On average, compared with no straw return, straw return significantly (p< 0.05) increased grain yield (+4.3%), protein content (+2.5%), total amino acids concentration (+1.2%), and grain phosphorus content (+3.6%), respectively. Meanwhile, straw return significantly (p< 0.05) decreased rice chalky grain rate (-14.4%), overall grain hardness (-1.9%), and water absorption of maize and wheat (-0.5%), respectively. Moreover, straw return effects on grain yield and quality traits were infected by cultivated crop types, straw return amounts, straw return methods, and straw return duration. Our findings illustrated that direct straw return increased three main crop grain yields and improved various quality traits among different agricultural production areas. Although improper straw return may increase plant disease risk and affect seed germination, our results suggest that full straw return with covered or plough mode is a more suitable way to enhance grain yield and quality. Our study also highlights that compared with direct straw return, straw burning or composting before application may also be beneficial to farmland productivity and sustainability, but comparative studies in this area are still lacking.

Unmasking of molecular players: proteomic profiling of vitreous humor in pathologic myopia.

BACKGROUND: This study aimed to identify the differentially expressed proteins in the vitreous humor (VH) of eyes with and without pathologic myopia (PM), providing insights into the molecular pathogenesis. METHODS: A cross-sectional, observational study was conducted. VH samples were collected from patients undergoing vitrectomy for idiopathic epiretinal membrane (ERM), macular hole (MH), or myopic retinoschisis (MRS). Label-free quantitative proteomic analysis identified differential protein expression, with validation using ELISA. RESULTS: The proteomic profiling revealed significantly higher expressions of tubulin alpha 1a (TUBA1A) and eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) in PM groups (MH-PM, MRS-PM) compared to controls (MH, ERM). Conversely, xylosyltransferase 1 (XYLT1), versican core protein (VCAN), and testican-2 (SPOCK2) expressions were lower in PM. ELISA validation confirmed these findings. CONCLUSIONS: Our study provides novel insights into the molecular mechanisms of PM. The differentially expressed proteins EEF1A1, TUBA1A, XYLT1, VCAN, and SPOCK2 may play crucial roles in chorioretinal cell apoptosis, scleral extracellular matrix (ECM) synthesis, and scleral remodeling in PM. These proteins represent potential new targets for therapeutic intervention in PM, highlighting the importance of further investigations to elucidate their functions and underlying mechanisms in disease pathogenesis.

One-carbon metabolism supports S-adenosylmethionine and m6A methylation to control the osteogenesis of bone marrow stem cells and bone formation.

The skeleton is a metabolically active organ undergoing continuous remodeling initiated by bone marrow stem cells (BMSCs). Recent research has demonstrated that BMSCs adapt the metabolic pathways to drive the osteogenic differentiation and bone formation, but the mechanism involved remains largely elusive. Here, using a comprehensive targeted metabolome and transcriptome profiling, we revealed that one-carbon metabolism was promoted following osteogenic induction of BMSCs. Methotrexate (MTX), an inhibitor of one-carbon metabolism that blocks S-adenosylmethionine (SAM) generation, led to decreased N6-methyladenosine (m6A) methylation level and inhibited osteogenic capacity. Increasing intracellular SAM generation through betaine addition rescued the suppressed m6A content and osteogenesis in MTX-treated cells. Using S-adenosylhomocysteine (SAH) to inhibit the m6A level, the osteogenic activity of BMSCs was consequently impeded. We also demonstrated that the pro-osteogenic effect of m6A methylation mediated by one-carbon metabolism could be attributed to HIF-1α and glycolysis pathway. This was supported by the findings that dimethyloxalyl glycine rescued the osteogenic potential in MTX-treated and SAH-treated cells by upregulating HIF-1α and key glycolytic enzymes expression. Importantly, betaine supplementation attenuated MTX-induced m6A methylation decrease and bone loss via promoting the abundance of SAM in rat. Collectively, these results revealed that one-carbon metabolite SAM was a potential promoter in BMSC osteogenesis via the augmentation of m6A methylation, and the cross talk between metabolic reprogramming, epigenetic modification, and transcriptional regulation of BMSCs might provide strategies for bone regeneration.

The bone is a self-renewing tissue that continues to reshape throughout life. Bone marrow mesenchymal stem cells (BMSCs) are essential for bone homeostasis as they are capable of osteogenic differentiation. Recent evidence suggests that BMSCs drive the osteogenic differentiation through metabolic reprogramming, but the mechanism remains unclear. In this paper, we explored the metabolic alteration following osteogenic induction of BMSCs and found that one-carbon metabolism was obviously promoted in this process. The underlining mechanisms of the osteogenic potential driven by one-carbon metabolism seem to be its contribution on N6-methyladenosine (m6A) methylation and consequent glycolysis level by providing methyl donor. We demonstrated that one-carbon metabolism-mediated m6A methylation was a potential promoter in BMSC osteogenesis, and metabolic-epigenetic coupling might provide novel therapeutic targets for bone regeneration.

Differences in T cell-associated serum markers between ischemic cardiomyopathy and dilated cardiomyopathy.

Background: Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) have similar clinical manifestations but differ in pathogenesis. We aimed to identify T cell-associated serum markers that can be used to distinguish between ICM and DCM. Methods: We identified differentially expressed genes (DEGs) with transcriptome sequencing data in GSE116250, and then conducted enrichment analysis of DEGs in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Protein-protein interaction (PPI) networks were used to analyze the relationship between T cells-related genes and identify hub genes. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect T cell-associated proteins in serum, and receiver operating characteristic (ROC) curves were used to evaluate the diagnostic efficacy of these serum markers. Results: Using the limma package and Venn plots, we found that the non-failing donors (NFD) and DCM groups shared many of the same DEGs and DEGs-enriched functions compared to the ICM group, which were involved in T cell activation and differentiation, among other functions. Subsequently, the immune cell score showed no difference between NFD and DCM, but they were significantly different from ICM patients in CD8 T cells CD4 T cells memory resting and activated, T cells follicular helper, and M1 macrophage. After analyzing T cell-associated DEGs, it was found that 4 DEGs encoding secreted proteins were highly expressed in the ICM group compared with the NFD and DCM groups, namely chemokine (C-C motif) ligand 21 (CCL21), interleukin (IL)-1ß, lymphocyte-activation gene 3 (LAG3), and vascular cell adhesion molecule-1 (VCAM-1). Importantly, the serum levels of CCL21, IL-1ß, LAG3, and VCAM-1 in ICM patients were all significantly higher than those in DCM patients. The ROC curves showed that the area under the curve (AUC) values of serum CCL21, IL-1ß, LAG3, and VCAM-1 were 0.775, 0.868, 0.934, and 0.903, respectively. Conclusions: We have identified four T cell-associated serum markers, CCL21, IL-1ß, LAG3, and VCAM-1, as potential diagnostic serum markers that differentiate ICM from DCM.

Screening of Diagnostic Biomarkers and Immune Infiltration Characteristics Linking Rheumatoid Arthritis and Rosacea Based on Bioinformatics Analysis.

Introduction: Both rheumatoid arthritis (RA) and rosacea represent common chronic systemic autoimmune conditions. Recent research indicates a heightened RA risk among individuals with rosacea. However, the molecular mechanisms linking these diseases remain largely unknown. This study aims to uncover shared molecular regulatory networks and immune cell infiltration patterns in both rosacea and RA. Methods: The gene expression profiles of RA (GSE12021, GSE55457), and the rosacea gene expression profile (GSE6591), were downloaded from Gene Expression Omnibus (GEO) databases, and obtained to screen differentially expressed genes (DEGs) by using "limma" package in R software. Various analyses including GO, KEGG, protein-protein interaction (PPI) network, and weighted gene co-expression network analyses (WGCNA) were conducted to explore potential biological functions and signaling pathways. CIBERSORT was used to assess the abundance of immune cells. Pearson coefficients were used to calculate the correlations between overlapped genes and the leukocyte gene signature matrix. Flow cytometry (FCM) analysis confirmed the most abundant immune cells detected in rheumatoid arthritis and rosacea. Receiver operator characteristic (ROC) analysis, enzyme-linked immunosorbent assay (ELISA), and qRT-PCR were used to confirm biomarkers and functions. Results: Two hundred seventy-seven co-expressed DEGs were identified from these datasets. Functional enrichment analysis indicated that these DEGs were associated with immune processes and chemokine-mediated signaling pathways. Fourteen and 17 hub genes overlapped between cytoHubba and WGCNA were identified in RA and rosacea, respectively. Macrophages and dendritic cells were RA and rosacea's most abundant immune cells, respectively. The ROC curves demonstrated potential diagnostic values of CXCL10 and CCL27, showing higher levels in the serum of patients with RA or rosacea, and suggesting possible regulation in the densities and functions of macrophages and dendritic cells from RA and rosacea, which were validated by FCM and qRT-PCR. Conclusion: Importantly, our findings may contribute to the scientific basis for biomarkers and therapeutic targets for patients with RA and rosacea in the future.

The m6A eraser FTO suppresses ferroptosis via mediating ACSL4 in LPS-induced macrophage inflammation.

Acute lung injury (ALI) is a serious disorder characterized by the release of pro-inflammatory cytokines and cascade activation of macrophages. Ferroptosis, a form of iron-dependent cell death triggered by intracellular phospholipid peroxidation, has been implicated as an internal mechanism underlying ALI. In this study, we investigated the effects of m6A demethylase fat mass and obesity-associated protein (FTO) on the inhibition of macrophage ferroptosis in ALI. Using a mouse model of lipopolysaccharide (LPS)-induced ALI, we observed the induction of ferroptosis and its co-localization with the macrophage marker F4/80, suggesting that ferroptosis might be induced in macrophages. Ferroptosis was promoted during LPS-induced inflammation in macrophages in vitro, and the inflammation was counteracted by the ferroptosis inhibitor ferrostatin-1 (fer-1). Given that FTO showed lower expression levels in the lung tissue of mice with ALI and inflammatory macrophages, we further dissected the regulatory capacity of FTO in ferroptosis. The results demonstrated that FTO alleviated macrophage inflammation by inhibiting ferroptosis. Mechanistically, FTO decreased the stability of ACSL4 mRNA via YTHDF1, subsequently inhibiting ferroptosis and inflammation by interrupting polyunsaturated fatty acid consumption. Moreover, FTO downregulated the synthesis and secretion of prostaglandin E2, thereby reducing ferroptosis and inflammation. In vivo, the FTO inhibitor FB23-2 aggravated lung injury, the inflammatory response, and ferroptosis in mice with ALI; however, fer-1 therapy mitigated these effects. Overall, our findings revealed that FTO may function as an inhibitor of the inflammatory response driven by ferroptosis, emphasizing its potential as a target for ALI treatment.

Potential mechanisms implied in tick infection by arboviruses and their transmission to vertebrate hosts.

Ticks can transmit many pathogens, including arboviruses, to their vertebrate hosts. Arboviruses must overcome or evade defense mechanisms during their passage from the tick gut to the hemolymph, salivary glands, and the feeding site in the host skin. This review summarizes current knowledge of defense mechanisms in specific tick tissues and at the feeding site in the host skin. We discuss the possible roles of these defense mechanisms in viral infection and transmission. The responses of tick salivary proteins to arbovirus infection are also discussed. This review provides information that may help accelerate research on virus-tick interactions.

Therapeutic effects of Lingguizhugan decoction in a rat model of high-fat diet-induced insulin resistance.

BACKGROUND: Lingguizhugan (LGZG) decoction is a widely used classic Chinese medicine formula that was recently shown to improve high-fat diet (HFD)-induced insulin resistance (IR) in animal studies. AIM: To assess the therapeutic effect of LGZG decoction on HFD-induced IR and explore the potential underlying mechanism. METHODS: To establish an IR rat model, a 12-wk HFD was administered, followed by a 4-wk treatment with LGZG. The determination of IR status was achieved through the use of biochemical tests and oral glucose tolerance tests. Using a targeted meta-bolomics platform to analyze changes in serum metabolites, quantitative real-time PCR (qRT-PCR) was used to assess the gene expression of the ribosomal protein S6 kinase beta 1 (S6K1). RESULTS: In IR rats, LGZG decreased body weight and indices of hepatic steatosis. It effectively controlled blood glucose and food intake while protecting islet cells. Metabolite analysis revealed significant differences between the HFD and HFD-LGZG groups. LGZG intervention reduced branched-chain amino acid levels. Levels of IR-related metabolites such as tryptophan, alanine, taurine, and asparagine decreased significantly. IR may be linked to amino acids due to the contemporaneous increase in S6K1 expression, as shown by qRT-PCR. CONCLUSIONS: Our study strongly suggests that LGZG decoction reduces HFD-induced IR. LGZG may activate S6K1 via metabolic pathways. These findings lay the groundwork for the potential of LGZG as an IR treatment.

Reference-free calibration method for asynchronous rotation in robotic CT.

BACKGROUND: Geometry calibration for robotic CT system is necessary for obtaining acceptable images under the asynchrony of two manipulators. OBJECTIVE: We aim to evaluate the impact of different types of asynchrony on images and propose a reference-free calibration method based on a simplified geometry model. METHODS: We evaluate the impact of different types of asynchrony on images and propose a novel calibration method focused on asynchronous rotation of robotic CT. The proposed method is initialized with reconstructions under default uncalibrated geometry and uses grid sampling of estimated geometry to determine the direction of optimization. Difference between the re-projections of sampling points and the original projection is used to guide the optimization direction. Images and estimated geometry are optimized alternatively in an iteration, and it stops when the difference of residual projections is close enough, or when the maximum iteration number is reached. RESULTS: In our simulation experiments, proposed method shows better performance, with the PSNR increasing by 2%, and the SSIM increasing by 13.6% after calibration. The experiments reveal fewer artifacts and higher image quality. CONCLUSION: We find that asynchronous rotation has a more significant impact on reconstruction, and the proposed method offers a feasible solution for correcting asynchronous rotation.

Oxygen Vacancies Enrichment in Citric Acid-Assisted Synthesis of Zirconia Supported Ni Catalyst for Highly Selective Hydrogenolysis of 5-Hydroxymethylfurfural.

2, 5-Dimethylfuran (DMF), which is a promising new-generation liquid biofuel, has attracted widespread attention owing to the sustainability of biomass-derived energy sources. In this study, a highly dispersed zirconia-supported nickel catalyst (CA-Ni/ZrO2) was prepared via citric acid-assisted wetness impregnation for the selective hydrogenolysis of 5-hydroxymethylfurfural (HMF) to produce DMF. The characterization results confirmed the presence of Zr3+ species in the mesoporous CA-Ni/ZrO2 catalyst and the formation of oxygen vacancies during its preparation, which led to the formation of a large number of catalytically active sites for the adsorption and activation of the C=O/C-O groups. Under appropriate reaction parameters, an excellent DMF selectivity of 99.1 % and an HMF conversion of 98.4 % were achieved. A suitable kinetic model revealed that DMF was preferentially formed via the 2,5-dihydroxymethylfuran intermediate route, although a 5-methylfurfural route was also observed. Additionally, the interaction between Ni and ZrO2 significantly affected the stability of the catalyst. This study will provide guidelines for optimizing the catalytic conversion of furan derivatives over heterogeneous catalysts.

Sparse-view Spectral CT Reconstruction and Material Decomposition based on Multi-channel SGM.

In medical applications, the diffusion of contrast agents in tissue can reflect the physiological function of organisms, so it is valuable to quantify the distribution and content of contrast agents in the body over a period. Spectral CT has the advantages of multi-energy projection acquisition and material decomposition, which can quantify K-edge contrast agents. However, multiple repetitive spectral CT scans can cause excessive radiation doses. Sparse-view scanning is commonly used to reduce dose and scan time, but its reconstructed images are usually accompanied by streaking artifacts, which leads to inaccurate quantification of the contrast agents. To solve this problem, an unsupervised sparse-view spectral CT reconstruction and material decomposition algorithm based on the multi-channel score-based generative model (SGM) is proposed in this paper. First, multi-energy images and tissue images are used as multi-channel input data for SGM training. Secondly, the organism is multiply scanned in sparse views, and the trained SGM is utilized to generate multi-energy images and tissue images driven by sparse-view projections. After that, a material decomposition algorithm using tissue images generated by SGM as prior images for solving contrast agent images is established. Finally, the distribution and content of the contrast agents are obtained. The comparison and evaluation of this method are given in this paper, and a series of mouse scanning experiments are carried out to verify the effectiveness of the method.

N6-methyladenosine modified TGFB2 triggers lipid metabolism reprogramming to confer pancreatic ductal adenocarcinoma gemcitabine resistance.

Gemcitabine resistance is a major obstacle to the effectiveness of chemotherapy in pancreatic ductal adenocarcinoma (PDAC). Therefore, new strategies are needed to sensitize cancer cells to gemcitabine. Here, we constructed gemcitabine-resistant PDAC cells and analyzed them with RNA-sequence. Employing an integrated approach involving bioinformatic analyses from multiple databases, TGFB2 is identified as a crucial gene in gemcitabine-resistant PDAC and is significantly associated with poor gemcitabine therapeutic response. The patient-derived xenograft (PDX) model further substantiates the gradual upregulation of TGFB2 expression during gemcitabine-induced resistance. Silencing TGFB2 expression can enhance the chemosensitivity of gemcitabine against PDAC. Mechanistically, TGFB2, post-transcriptionally stabilized by METTL14-mediated m6A modification, can promote lipid accumulation and the enhanced triglyceride accumulation drives gemcitabine resistance by lipidomic profiling. TGFB2 upregulates the lipogenesis regulator sterol regulatory element binding factor 1 (SREBF1) and its downstream lipogenic enzymes via PI3K-AKT signaling. Moreover, SREBF1 is responsible for TGFB2-mediated lipogenesis to promote gemcitabine resistance in PDAC. Importantly, TGFB2 inhibitor imperatorin combined with gemcitabine shows synergistic effects in gemcitabine-resistant PDAC PDX model. This study sheds new light on an avenue to mitigate PDAC gemcitabine resistance by targeting TGFB2 and lipid metabolism and develops the potential of imperatorin as a promising chemosensitizer in clinical translation.

Copper Chelation Therapy Attenuates Periodontitis Inflammation through the Cuproptosis/Autophagy/Lysosome Axis.

Periodontitis development arises from the intricate interplay between bacterial biofilms and the host's immune response, where macrophages serve pivotal roles in defense and tissue homeostasis. Here, we uncover the mitigative effect of copper chelator Tetrathiomolybdate (TTM) on periodontitis through inhibiting cuproptosis, a newly identified form of cell death which is dependent on copper. Our study reveals concurrent cuproptosis and a macrophage marker within murine models. In response to lipopolysaccharide (LPS) stimulation, macrophages exhibit elevated cuproptosis-associated markers, which are mitigated by the administration of TTM. TTM treatment enhances autophagosome expression and mitophagy-related gene expression, countering the LPS-induced inhibition of autophagy flux. TTM also attenuates the LPS-induced fusion of autophagosomes and lysosomes, the degradation of lysosomal acidic environments, lysosomal membrane permeability increase, and cathepsin B secretion. In mice with periodontitis, TTM reduces cuproptosis, enhances autophagy flux, and decreases Ctsb levels. Our findings underscore the crucial role of copper-chelating agent TTM in regulating the cuproptosis/mitophagy/lysosome pathway during periodontitis inflammation, suggesting TTM as a promising approach to alleviate macrophage dysfunction. Modulating cuproptosis through TTM treatment holds potential for periodontitis intervention.

USP14 deficiency inhibits neointima formation following vascular injury via degradation of Skp2 protein.

Ubiquitin-proteasome system (UPS) is involved in vascular smooth muscle cell (VSMC) proliferation. Deubiquitinating enzymes (DUBs) have an essential role in the UPS-regulated stability of the substrate; however, the function of DUBs in intimal hyperplasia remains unclear. We screened DUBs to identify a protein responsible for regulating VSMC proliferation and identified USP14 protein that mediates cancer development, inflammation, and foam cell formation. USP14 promotes human aortic smooth muscle cell and A7r5 cell growth in vitro, and its inhibition or deficiency decreases the intimal area in the mice carotid artery ligation model. In addition, USP14 stabilizes Skp2 expression by decreasing its degradation, while Skp2 overexpression rescues USP14 loss-induced issues. The current findings suggested an essential role of USP14 in the pathology of vascular remodeling, deeming it a promising target for arterial restenosis therapy.

Danshen-Shanzha formula for the treatment of atherosclerosis: ethnopharmacological relevance, preparation methods, chemical constituents, pharmacokinetic properties, and pharmacological effects.

Danshen-Shanzha Formula (DSF) is a well-known herbal combination comprising Radix Salvia Miltiorrhiza (known as Danshen in Chinese) and Fructus Crataegi (known as Shanzha in Chinese), It has been documented to exhibit considerable benefits for promoting blood circulation and removing blood stasis, and was used extensively in the treatment of atherosclerotic cardiac and cerebral vascular diseases over decades. Despite several breakthroughs achieved in the basic research and clinical applications of DSF over the past decades, there is a lack of comprehensive reviews summarizing its features and research, which hinders further exploration and exploitation of this promising formula. This review aims to provide a comprehensive interpretation of DSF in terms of its ethnopharmacological relevance, preparation methods, chemical constituents, pharmacokinetic properties and pharmacological effects. The related information on Danshen, Shanzha, and DSF was obtained from internationally recognized online scientific databases, including Web of Science, PubMed, Google Scholar, China National Knowledge Infrastructure, Baidu Scholar, ScienceDirect, ACS Publications, Online Library, Wan Fang Database as well as Flora of China. Data were also gathered from documentations, printed works and classics, such as the Chinese Pharmacopoeia, Chinese herbal classics, etc. Three essential avenues for future studies were put forward as follows: a) Develop and unify the standard preparation method of DSF as to achieve optimized pharmacological properties. b) Elucidate the functional mechanisms as well as the rationality and rule for the compatibility art of DSF by focusing on the clinic syndromes together with the subsequent development of preclinic study system in vitro and in vivo with consistent pathological features, pharmacokinetical behaviour and biomarkers. c) Perform more extensive clinical studies towards the advancement of mechanism-based on evidence-based medicine on the safety application of DSF. This review will provide substantial data support and broader perspective for further research on the renowned formula.

Comparison of trial lens and computer-aided fitting in orthokeratology: A multi-center, randomized, examiner-masked, controlled study.

PURPOSE: To compare the efficacy and safety between traditional lens fitting and computer-aided fitting methods for orthokeratology (OrthoK) in the Chinese population. METHODS: A multi-center, examiner-masked, randomized controlled study was conducted with a one-year follow-up period, enrolling 280 participants with spherical equivalent (SE) ranging from -0.5D to -4.0D. Participants were assigned to either the computer-aided orthokeratology fitting group (trial group) or the traditional lens fitting group (control group) using stratified randomization based on age (8 to 13 years, 13 to 18 years, and ≥ 18 years) to ensure a minimum of 30 cases in each sub-age group. Ocular examinations included visual acuity, objective and subjective refraction, corneal endothelial cell density, corneal topography, intraocular pressure, axial length, and ocular health assessment. Successful lens-correction was defined as the residual refraction with the OK lens, which should not exceed ± 0.5D, and/or an uncorrected visual acuity of no worse than 0.1 logMAR. Statistical analysis involves t-tests, analysis of variance, and Chi-squared tests. RESULTS: 215 subjects were included in the statistical analysis (109 in the trial group and 106 in the control group). In both groups, compared to baseline data, the uncorrected visual acuity (UCVA) improved significantly, with SE reduced and central corneal curvature flattened greatly after wearing OrthoK lens (P < 0.05 for all). Compared to the control group, the trial group exhibited a higher successful rate in correcting UCVA (93.6 % vs. 84.0 %, P = 0.03) and slightly better correction in refraction (77.1 % vs. 66.0 %, P = 0.07) at 1-month follow-up. However, no significant differences were observed in the axial length elongation, corneal changes, or the incidence of adverse events between the two groups. CONCLUSION: These findings indicate the higher efficiency and slightly better performance in correcting myopia and improving UCVA of computer-aided lens fitting approach compared to the traditional one, but similar outcomes in controlling axial elongation.