A novel LVPA-UNet network for target volume automatic delineation: An MRI case study of nasopharyngeal carcinoma.

Accurate delineation of Gross Tumor Volume (GTV) is crucial for radiotherapy. Deep learning-driven GTV segmentation technologies excel in rapidly and accurately delineating GTV, providing a basis for radiologists in formulating radiation plans. The existing 2D and 3D segmentation models of GTV based on deep learning are limited by the loss of spatial features and anisotropy respectively, and are both affected by the variability of tumor characteristics, blurred boundaries, and background interference. All these factors seriously affect the segmentation performance. To address the above issues, a Layer-Volume Parallel Attention (LVPA)-UNet model based on 2D-3D architecture has been proposed in this study, in which three strategies are introduced. Firstly, 2D and 3D workflows are introduced in the LVPA-UNet. They work in parallel and can guide each other. Both the fine features of each slice of 2D MRI and the 3D anatomical structure and spatial features of the tumor can be extracted by them. Secondly, parallel multi-branch depth-wise strip convolutions adapt the model to tumors of varying shapes and sizes within slices and volumetric spaces, and achieve refined processing of blurred boundaries. Lastly, a Layer-Channel Attention mechanism is proposed to adaptively adjust the weights of slices and channels according to their different tumor information, and then to highlight slices and channels with tumor. The experiments by LVPA-UNet on 1010 nasopharyngeal carcinoma (NPC) MRI datasets from three centers show a DSC of 0.7907, precision of 0.7929, recall of 0.8025, and HD95 of 1.8702 mm, outperforming eight typical models. Compared to the baseline model, it improves DSC by 2.14 %, precision by 2.96 %, and recall by 1.01 %, while reducing HD95 by 0.5434 mm. Consequently, while ensuring the efficiency of segmentation through deep learning, LVPA-UNet is able to provide superior GTV delineation results for radiotherapy and offer technical support for precision medicine.

Increased miR-3074-5p expression promotes M1 polarization and pyroptosis of macrophages via ERα/NLRP3 pathway and induces adverse pregnancy outcomes in mice.

Decidual macrophages (dMϕs) play critical roles in regulation of immune-microhomeostasis at maternal-fetal interface during pregnancy, but the underlying molecular mechanisms are still unclear. In this study, it was found that litter size and fetal weight were significantly reduced, whereas the rate of embryo resorption was increased in miR-3074-5p knock-in (3074-KI) pregnant mice, compared to that of wild-type (WT) pregnant mice. Plasma levels of pro-inflammatory cytokines in 3074-KI pregnant mice were also significantly elevated compared to WT pregnant mice at GD7.5. The quantity of M1-Mϕs in uterine tissues of 3074-KI pregnant mice was significantly increased compared to WT pregnant mice at GD13.5. Estrogen receptor-α (ERα) was validated to be a target of miR-3074-5p. Either miR-3074-5p overexpression or ERα knockdown promoted transcriptional activity of NF-κB/p65, induced M1-polarization and pyroptosis of THP1-derived Mϕs, accompanied with increased intracellular levels of cleaved Caspase-1, cleaved IL-1ß, NLRP3, cleaved GSDMD and ASC aggregation. Furthermore, ERα could not only bind to NLRP3 or ASC directly, but also inhibit the interaction between NLRP3 and ASC. The endometrial miR-3074-5p expression level at the middle secretory stage of repeated implantation failure (RIF) patients was significantly decreased compared to that of control fertile women. These data indicated that miR-3074-5p could promote M1 polarization and pyroptosis of Mϕs via activation of NLRP3 inflammasome by targeting ERα, and the dysregulation of miR-3074-5p expression in dMϕs might damage the embryo implantation and placentation by interfering with inflammatory microenvironment at the maternal-fetal interface during early pregnancy.

Primary goose kidney tubular epithelial cells for goose astrovirus genotype 2 infection: establishment and RNA sequencing analysis.

Goose astrovirus genotype 2 (GAstV-2) mainly causes gout in goslings; therefore, it is a major pathogen threatening to goose flocks. However, the mechanisms underlying host-GAstV-2 interactions remain unclear because host cells suitable for GAstV-2 replication have been unavailable. We previously noted that GAstV-2 is primarily located in goose renal epithelial cells, where it causes kidney damage. Therefore, here, we derived goose primary renal tubular epithelial (RTE) cells (GRTE cells) from the kidneys of goose embryos after collagenase I digestion. After culture in Dulbecco's modified Eagle medium/Nutrient mixture F-12 with 10% fetal bovine serum (FBS), the isolated cells had polygonal with roadstone-like morphology; they were identified to be epithelial cells based on the presence of cytokeratin 18 expression detected through immunofluorescence assay (IFA). GAstV-2 infection in GRTE cells led to no obvious cytopathic effects; the maximum amounts of infectious virions were observed 48 h post infection through IFA and quantitative PCR. Next, RNA-seq was performed to identify and map post-GAstV-2 infection differentially expressed genes. The downregulated pathways were mainly related to metabolism, including tryptophan metabolism, drug metabolism by cytochrome P450, xenobiotic metabolism by cytochrome P450, retinol metabolism, butanoate metabolism, starch and sucrose metabolism, ascorbate and aldarate metabolism, and drug metabolism by other enzymes and peroxisome. In contrast, the upregulated pathways were mostly related to the host cell defense and proliferation, including extracellular matrix-receptor interaction, complement and coagulation cascades, phagosome, PI3K-Akt signaling pathway, human T-lymphotropic virus 1 infection, lysosome, and tumor necrosis factor signaling pathway. In conclusion, we developed a GRTE cell line for GAstV-2 replication and analyzed the potential host-GAstV-2 interactions through RNA-seq; our results may aid in further investigating the pathogenic mechanisms underlying GAstV-2 infection and provide strategies for its prevention and control.

New insights into interaction between oil and solid during hydrothermal treatment of oily sludge.

Hydrothermal treatment (HT) can effectively dehydrate and reduce oily sludge (OS) volume, but the resulting hydrothermal oily sludge (HOS) presents greater challenges for washing than the initial oily sludge (IOS). This study examines the effects of HT on OS by analyzing changes in water, oil, and solid. Results indicate that HT considerably decreases the water content in OS while increasing resin and asphaltenes contents. In addition, condensation, side-chain scission, and oxidation reactions occur during the HT process, resulting in coking, agglomeration, and an increase in oxygen-containing groups. This increase, further confirmed by X-ray photoelectron spectroscopy (XPS), enhances the interaction between oil and solids. Calcite, the most prevalent solid-phase component, may form a calcium bridge with the oxygen-containing groups. Moreover, HT reduces the solid particle size, thereby increasing the oil-solid contact area. Interestingly, the process of deasphalting diminishes the interaction between oil and solids, facilitating sludge washing. After washing, the residual oil content in HOS is reduced to less than 0.34%. This study elucidates why HOS is challenging to separate from oil and solids and introduces a novel method that combines dodecylbenzene sulfonic acid (DBSA)-assisted heptane deasphalting with conventional washing techniques. This method shows promise for applications in OS affected by weathering processes.

Effects of Goose Astrovirus Type 2 Infection on Peripheral Blood Lymphocyte and Macrophage Activity In Vitro.

Goose astrovirus type 2 (GAstV-2) is a novel pathogen causing visceral gout in goslings; it not only causes necrosis of renal epithelial cells but also causes spleen damage, indicating that GAstV-2 induces immunosuppression in goslings. However, to date, the interaction between GAstV-2 and immune cells remains unclear. In this study, peripheral blood lymphocytes and macrophages were isolated from goslings without GAstV-2 infection and then inoculated in vitro with GAstV-2, and the virus localization in the lymphocytes and macrophages, proliferation and apoptosis of lymphocytes, and phagocytic activity, reactive oxygen species (ROS) and nitric oxide (NO) production, and cell polarity in macrophages were determined. The results showed that GAstV-2 was observed in the cytoplasm of CD4 and CD8 T cells and macrophages, indicating that GAstV-2 can infect both lymphocytes and macrophages. GAstV-2 infection reduced the lymphocyte proliferation induced by Concanavalin A and lipopolysaccharide stimulation and increased the lymphocyte apoptosis rate and mRNA expression of Fas, demonstrating that GAstV-2 causes damage to lymphocytes. Moreover, GAstV-2 infection enhanced phagocytic activity and production of ROS and NO and induced a proinflammatory phenotype in macrophages (M1 macrophages), indicating that macrophages play an antiviral role during GAstV-2 infection. In conclusion, these results demonstrate that GAstV-2 infection causes damages to lymphocytes, and host macrophages inhibit GAstV-2 invasion during infection.

Multimodal Study of the Superior Mesenteric Artery Wall.

BACKGROUND: To quantitatively analyze histological and fiber structure of the superior mesenteric artery (SMA) wall and to further explore the possible relationship between the architecture and histology changes of vessel wall and the occurrence of related diseases. METHODS: Histological and fiber structure analysis were performed on SMA specimens obtained from 22 cadavers. The SMA specimens were divided into initial, curved, and distal segments, and each segment was separated into the anterior and posterior walls. RESULTS: From the initial to the curved to the distal segment, the ratio of elastin decreased (31.4% ± 6.0%, 21.1% ± 5.8%, 18.6% ± 4.7%, respectively; P < 0.001), whereas the ratio of smooth muscle actin (24.5% ± 8.7%, 30.5% ± 6.8%, 36.1% ± 7.3%, respectively; P < 0.001) increased. Elastic fiber longitudinal amplitude of angular undulation was highest in the initial segment [7° (3.25°, 15°)] and lowest in the curved segment [2° (1°, 5°)]. In SMA curved segment, the anterior wall, when compared with the posterior wall, demonstrated a lower ratio of elastin (19.0% ± 5.8% vs. 23.3% ± 5.0%; P = 0.010) and collagen (41.4% ± 12.3% vs. 49.0% ± 10.2%; P = 0.032), a lower elastic fiber longitudinal amplitude of angular undulation [1° (1°, 5°) vs. 3° (2°, 5.25°); P = 0.013], a lower average fiber diameter (8.06 ± 0.36 pixels vs. 8.45 ± 0.50 pixels; P = 0.005), and a lower average segment length (17.96 ± 1.59 pixels vs. 20.05 ± 2.33 pixels; P = 0.001). CONCLUSIONS: SMA wall structure varies along the circumferential and axial directions, the presence of dense undulated elastic fiber protects the SMA initial segment of from dissection and aneurysm, but highly cross-linked collagen fiber here increases the likelihood of plaque formation. In the anterior wall of the curved segment, lower elastin and collagen content, lower elastic fiber undulation, and higher degree of collagen fiber cross-linking leads to the occurrence of SMA dissection and aneurysm. In the distal segment, high levels of vascular smooth muscle cells and bundles of long collagen fiber offer protection against the development of SMA-related diseases.

Sakuranetin reduces inflammation and chondrocyte dysfunction in osteoarthritis by inhibiting the PI3K/AKT/NF-κB pathway.

Osteoarthritis (OA) is a prevalent degenerative disease that impairs limb function, and its pathogenesis is closely related to inflammation. Sakuranetin (SK) is a cherry flavonoid phytoalexin with potent anti-inflammatory, anti-oxidant, and ant-ifungal properties. In recent studies, flavonoid and phytoalexin-related medicines have shown promise in the treatment of OA. However, the effects of SK on chondrocyte inflammation and the chondrogenesis process have remained unexplored, as have its functions in OA treatment. This study sought to confirm the therapeutic effects of SK in the OA rat model and reveal the potential mechanisms for protecting chondrocytes. The relevant mechanisms of SK were analyzed by network pharmacology analysis. Chondrocytes were subjected to IL-1ß intervention to simulate an inflammatory environment and received SK treatment. Then, anabolism, catabolism, and inflammatory markers were detected by western blot, qPCR, elisa, and immunofluorescence. Chondrogenic ability was evaluated by micromass and 3D culture assays. The rats were treated with destabilization of the medial meniscus (DMM) surgery to establish an OA model and SK intra-articular injections subsequently. Histological staining, immunohistochemistry, and micro-CT were performed to analyze the structural and morphological changes of cartilage and subchondral bone. In chondrocytes, IL-1ß treatment reduced chondrogenic ability, promoted catabolism, and exacerbated inflammation by triggering the PI3K/AKT/NF-κB pathway, whereas SK treatment partially rescued these negative effects. In vivo, SK treatment effectively alleviated the degeneration of cartilage and subchondral bone, thereby delaying the progression of OA. In summary, SK alleviates chondrocyte inflammation and promotes chondrogenesis by inhibiting the PI3K/AKT/NF-κB pathway, thereby improving OA progression.

Introducing Specific Iodine Ions in Perovskite-Based Nanocomplex to Cater for Versatile Biomedical Imaging and Tumor Radiotherapy.

Multimodal biomedical imaging and imaging-guided therapy have garnered extensive attention owing to the aid of nanoagents with the aim of further improving the therapeutic efficacy of diseases. The ability to engineer nanocomplexes (NCs) or control how they behave within an organism remains largely elusive. Here, a multifunctional nanoplatform is developed based on stabilized I-doped perovskite, CsPbBr3 -x Ix @SiO2 @Lip-c(RGD)2 (PSL-c(RGD)2 ) NCs. In particular, by regulating the amount of regular I- ions introduced, the fluorescence emission spectrum of perovskite-based NCs can be modulated well to match the requirement for biomedical optical imaging at the scale from molecule, cell to mouse; doping 125 I enables the nanoformulation to be competent for single-photon emission computed tomography (SPECT) imaging; the introduction of 131 I- imparts the NCs with the capability for radiotherapy. Through facile manipulation of specific iodine ions, this nanoplatform exhibits a remarkable ability to match multifunctional biomedical imaging and tumor therapy. In addition, their in vivo behavior can be manipulated by adjusting the thickness of the silica shell and the surface polarity for more practical applications. These experimental explorations offer a novel approach for engineering desirable multimodal NCs to simultaneously image and combat malignant tumors.

Development of a novel EphA2-targeting radioligand for SPECT imaging in different tumor models.

The erythropoietin-producing hepatoma A2 receptor (EphA2) is a tyrosine kinase, which is overexpressed in tumors while having lower expression in normal tissues, making it an excellent target for tumor diagnosis and treatment. Peptide radiotracers offer unique advantages in tumor diagnosis and therapy and have been approved for clinical use. In this study, a high-affinity EPHA2-targeted radiotracer, 99mTc-HYNIC-PEG4-EPH-3, was developed and designed based on linear peptides. 99mTc-HYNIC-PEG4-EPH-3 exhibited superior water solubility and stability. And 99mTc-HYNIC-PEG4-EPH-3 could specifically target EphA2-expressing tumors, particularly with a tumor-to-non-target (T/NT) ratio >4.7 excluding kidneys. As a result of excellent biodistribution and tumor targeting capability of 99mTc-HYNIC-PEG4-EPH-3, it might be a promising candidate drug for clinical diagnosis of EphA2-overexpressing tumors.

Melatonin Inhibits Testosterone Synthesis in Rooster Leydig Cells by Targeting CXCL14 through miR-7481-3p.

Melatonin has been proved to be involved in testosterone synthesis, but whether melatonin participates in testosterone synthesis by regulating miRNA in Leydig cells is still unclear. The purpose of this study is to clarify the mechanism of melatonin on Leydig cells testosterone synthesis from the perspective of miRNA. Our results showed that melatonin could significantly inhibit testosterone synthesis in rooster Leydig cells. miR-7481-3p and CXCL14 were selected as the target of melatonin based on RNA-seq and miRNA sequencing. The results of dual-luciferase reporter assays showed that miR-7481-3p targeted the 3'-UTR of CXCL14. The overexpression of miR-7481-3p significantly inhibited the expression of CXCL14 and restored the inhibitory role of melatonin testosterone synthesis and the expression of StAR, CYP11A1, and 3ß-HSD in rooster Leydig cells. Similarly, interference with CXCL14 could reverse the inhibitory effect of melatonin on the level of testosterone synthesis and the expression of StAR, CYP11A1, and 3ß-HSD in rooster Leydig cells. The RNA-seq results showed that melatonin could activate the PI3K/AKT signal pathway. Interference with CXCL14 significantly inhibited the phosphorylation level of PI3K and AKT, and the inhibited PI3K/AKT signal pathway could reverse the inhibitory effect of CXCL14 on testosterone synthesis and the expression of StAR, CYP11A1 and 3ß-HSD in rooster Leydig cells. Our results indicated that melatonin inhibits testosterone synthesis by targeting miR-7481-3p/CXCL14 and inhibiting the PI3K/AKT pathway.

Association between smoking and incident back pain: A prospective cohort study with 438 510 participants.

Background: Although smoking is a known potential contributor to back pain, there is still a lack of quantitative studies on the effects of different doses on back pain (BP) occurrence, including a lack of a longitudinal cohorts. To address this gap, we aimed to investigate the association between various smoking-related exposures and back pain incidence to advance global efforts toward smoking cessation and guide primary prevention of BP. Methods: In this prospective cohort study, we retrieved data on 438 510 patients from the UK Biobank who were free of back pain and who were recruited in 2006-2010, and followed them up from baseline through 1 April 2022. We extracted data on smoking-related exposures, including smoking status (SS), number of cigarettes smoked daily (CPD), and pack-years of own smoking (PY) and examined back pain incidence as an outcome. We used a Cox proportional hazard model adjusted for several covariates, multiple imputation methods, and population attribution fraction. Results: During the median follow-up of 12.98 years, 31 467 participants developed BP, with incidence rates in former and current smokers of 1.13 (95% confidence interval (CI) = 1.10-1.16, P < 0.000) and 1.50 (95% CI = 1.45-1.56, P < 0.000), respectively. The hazard ratios (HRs) of participants who smoked more than 30 CPD and those with more than 30 PY were 1.45 (95% CI = 1.36-1.55, P < 0.000) and 1.45 (95% CI = 1.40-1.50, P < 0.000), respectively. Relative to male, female smokers were at more risk of developing BP. Not smoking, quitting smoking, and reducing CPD and PY could lower the BP risk by 7.8%, 5.4%, 9.8%, and 18.0%, respectively. Conclusions: Ever smoking, higher cigarette consumption daily, and increased smoking intensity were associated with an increased BP risk. This association was stronger in female smokers. Not smoking, smoking cessation, and reducing smoking volume and intensity were effective measures to prevent BP occurrence.

A Study on the Effect of Energy on the Development of Silkworm Embryos Using an Estrogen-Related Receptor.

Energy metabolism is a fundamental process in all organisms. During silkworm (Bombyx mori) embryonic development, there is a high demand for energy due to continuous cell proliferation and differentiation. Estrogen-related receptors (ERRs) are transcriptional regulatory factors that play crucial roles in mammalian energy storage and expenditure. Although most insects have one ERR gene, it also participates in the regulation of energy metabolism, including carbohydrate metabolism in Drosophila, Aphid, and Silkworm. However, no study has reported the direct impact of energy metabolism on embryonic development in silkworms. In this study, we used transgenic technology to increase silkworm (B. mori; Bm) BmERR expression during embryonic development and explored the impact of energy on embryonic development. We found no significant change in the quality of silkworm eggs compared to that of wild-type silkworms. However, there was an increase in the consumption of vitellin, a major nutrient in embryos. This resulted in a decrease in glucose content and a significant increase in ATP content. These findings provide evidence that the acceleration of energy metabolism promotes embryonic development and enhances the motility of hatched silkworms. In addition, these results provide a novel perspective on the relationship between energy metabolism and embryonic development in other insects.

Formin protein FMNL1 is a biomarker for tumor-infiltrating immune cells and associated with well immunotherapeutic response.

Background: Increased studies on the basis of bulk RNA-sequencing (RNA-seq) data of cancer identify numbers of immune-related genes which may play potential regulatory roles in the tumor microenvironment (TME) without in-depth validation. Methods: In the current study, the immunological correlation and cell subpopulation expression pattern of FMNL1 were analyzed using public data. In addition, the cell subpopulation expression pattern of FMNL1 was also deeply validated using single-cell RNA-sequencing (scRNA-seq) and multiplexed quantitative immunofluorescence (mQIF). Results: Bulk FMNL1 mRNA was related to better prognosis in hepatocellular carcinoma (HCC) and was able to identify immuno-hot tumor in not only HCC but also multiple cancer types. Bulk FMNL1 mRNA also predicted the response to immunotherapy in multiple cancers. Further validation using scRNA-seq and mQIF revealed that FMNL1 was a biomarker for immune cells. Conclusions: FMNL1 is a biomarker for immune cells in not only hepatocellular carcinoma, but also multiple cancer types. Moreover, immune infiltration analysis using the bulk RNA-seq data would be further validated using scRNA-seq and/or mQIF to describe the cell subpopulation expression pattern in tumor tissues for more in-depth and appropriate understanding.

Integrative analysis illustrates the role of PCDH7 in lung cancer development, cisplatin resistance, and immunotherapy resistance: an underlying target.

Background: Cisplatin resistance is a common clinical problem in lung cancer. However, the underlying mechanisms have not yet been fully elucidated, highlighting the importance of searching for biological targets. Methods: Bioinformatics analysis is completed through downloaded public data (GSE21656, GSE108214, and TCGA) and specific R packages. The evaluation of cell proliferation ability is completed through CCK8 assay, colony formation, and EdU assay. The evaluation of cell invasion and migration ability is completed through transwell and wound-healing assays. In addition, we evaluated cell cisplatin sensitivity by calculating IC50. Results: Here, we found that PCDH7 may be involved in cisplatin resistance in lung cancer through public database analysis (GSE21656 and GSE108214). Then, a series of in vitro experiments was performed, which verified the cancer-promoting role of PCDH7 in NSCLC. Moreover, the results of IC50 detection showed that PCDH7 might be associated with cisplatin resistance of NSCLC. Next, we investigated the single-cell pattern, biological function, and immune analysis of PCDH7. Importantly, we noticed PCDH7 may regulate epithelial-mesenchymal transition activity, and the local infiltration of CD8+ T and activated NK cells. Furthermore, we noticed that patients with high PCDH7 expression might be more sensitive to bortezomib, docetaxel, and gemcitabine, and resistant to immunotherapy. Finally, a prognosis model based on three PCDH7-derived genes (GPX8, BCAR3, and TNS4) was constructed through a machine learning algorithm, which has good prediction ability on NSCLC patients' survival. Conclusion: Our research has improved the regulatory framework for cisplatin resistance in NSCLC and can provide direction for subsequent related research, especially regarding PCDH7.

Tissue-Resident Memory T Cell: Ontogenetic Cellular Mechanism and Clinical Translation.

Mounting evidence has indicated the essential role of tissue-resident memory T (TRM) cells for frontline protection against viral infection and for cancer immune surveillance (Mueller SN, Mackay LK. Tissue-resident memory T cells: local specialists in immune defense. Nat Rev Immunol 2016, 16, 79-89. doi:10.1038/nri.2015.3.). TRM cells are transcriptionally, phenotypically, and functionally distinct from circulating memory T (Tcirm) cells. It is necessary to understand the unique ontogenetic mechanism, migratory regulation, and biological function of TRM cells. In this review, we discuss recent insights into cellular mechanisms and discrete responsiveness in different tissue microenvironments underlying TRM cell development. We also emphasize the translational potential of TRM cells by focusing on their establishment in association with improved protection in mucosal tissues against various types of diseases and effective strategies for eliciting TRM cells in both pre-clinical and clinical studies.

Moderate mechanical strain and exercise reduce inflammation and excessive autophagy in osteoarthritis by downregulating mitofusin 2.

AIMS: The major pathological mechanisms of osteoarthritis (OA) progression include inflammation, autophagy, and apoptosis, etc. Moderate mechanical strain and exercise effectively improve chondrocyte degeneration by reducing these adverse factors. Mitofusin 2 (MFN2) is a crucial regulatory factor associated with inflammation, autophagy and apoptosis, and its expression is regulated by exercise. This study aims to elucidate the effects of moderate mechanical strain and exercise on MFN2 expression and its influence on OA progression. MAIN METHODS: Destabilization of the medial meniscus (DMM) surgery was performed on rats to induce an OA rat model. Subsequently, adeno-associated virus (overexpression/knockdown) intra-articular injection or moderate treadmill exercise was administered to evaluate the effects of these treatments on MFN2 expression and OA progression. Overexpressed plasmids and siRNA vectors were used to regulate MFN2 expression in chondrocytes. An inflammatory degeneration cell model was generated by IL-1ß stimulation. Moderate mechanical strain was applied to MFN2-overexpressing cells to explore their interactions. KEY FINDINGS: MFN2 overexpression aggravated inflammation by activating the NF-κB and P38 pathways and induced excessive autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby causing chondrocyte apoptosis and metabolic disorder. Moderate mechanical strain partially reversed these adverse effects. In the DMM rat model, MFN2 overexpression in articular cartilage exacerbated OA progression, whereas MFN2 knockdown and treadmill exercise alleviated cartilage degeneration, inflammation, and mechanical pain. SIGNIFICANCE: MFN2 is a critical factor mediating the association between inflammation and excessive autophagy in OA progression. Moderate mechanical strain and treadmill exercise may improve OA through downregulating MFN2 expression. This study may provide a theoretical basis for exercise therapy in OA treatment.

Systems biology strategy through integrating metabolomics and network pharmacology to reveal the mechanisms of Xiaopi Hewei Capsule improves functional dyspepsia.

Functional dyspepsia (FD) is one of the more common functional disorders, with a prevalence of 20-25 %. It seriously affects the quality life of patients. Xiaopi Hewei Capsule (XPHC) is a classic formula originated from the Chinese Miao minority. Clinical studies have demonstrated that XPHC can effectively alleviate the symptoms of FD, but the molecular mechanism has not been elucidated. The purpose of this work is to investigate the mechanism of XPHC on FD by integrating metabolomics and network pharmacology. The mice models of FD were established, and gastric emptying rate, small intestine propulsion rate, serum level of motilin and gastrin were evaluate to study the interventional effect of XPHC on FD. Next, a metabolomics strategy has been developed to screen differential metabolites and related metabolic pathways induced by XPHC. Then, prediction of active compounds, targets and pathways of XPHC in treating FD were carried out by commonly used network pharmacological method. Finally, two parts of the results were integrated to investigate therapeutic mechanism of XPHC on FD, which were preliminary validated based on molecular docking. Thus, twenty representative different metabolites and thirteen related pathways of XPHC in treating FD were identified. Most of these metabolites were restored using modulation after XPHC treatment. The results of the network pharmacology analysis showed ten crucial compounds and nine hub genes related to the treatment of FD with XPHC. The further integrated analysis focused on four key targets, such as albumin (ALB), epidermal growth factor receptor (EGFR), tumor necrosis factor (TNF) and roto-oncogene tyrosine-protein kinase Src (SRC), and three representative biomarkers such as citric acid, L-leucine and eicosapentaenoic acid. Furthermore, molecular docking results showed that ten bioactive compounds from XPHC have good binding interactions with the four key genes. The functional enrichment analysis indicated that the potential mechanism of XPHC in treating FD was mainly associated with energy metabolism, amino acid metabolism, lipid metabolism, inflammatory reactions and mucosal repair. Our work confirms that network pharmacology-integrated metabolomics strategyis a powerful means to reveal the therapeutic mechanisms of XPHC improves FD, which contribute its further scientific research.

PDGFRß targeted innovative imaging probe for pancreatic adenocarcinoma detection.

The 5-year survival rate for pancreatic adenocarcinoma (PA) is less than 10%, making it one of the most lethal forms of cancer. Early-stage diagnosis and resection of the incipient lesions could increase the 4-year survival rate of PA up to 78%. Platelet-derived growth factor receptor ß (PDGFRß), an oncogenic key regulator for migration, proliferation and angiogenesis of cancer cells, has been proved to be aberrantly expressed in the majority of PA. Herein, by amino acid substitution strategy and surface plasmon resonance (SPR) analysis, we designed a novel PDGFRß-targeting peptide (YQGX-10) with high affinity (Kd = 227.7 nM) and coupled it with a near-infrared fluorescent (NIRF) dye MPA for precisely detection of PA. Great binding affinity and specificity were displayed in a series of in vitro assays. NIRF imaging experiments demonstrated that the synthesized probe could be highly accumulated in xenograft and orthotopic BxPC-3 tumors and provide favorable tumor contrast in the mice, offering a potential novel approach for the early diagnosis of PA. Moreover, YQGX-10 could visualize tumor boundaries and minor lesions in BxPC-3 xenograft mice, shedding a new light on NIRF-guided tumor resection of PA. In addition, we successfully constructed the radioactive probe 99mTc-HYNIC-YQGX-10 for the diagnosis of PA with high specificity and sensitivity. In summary, the probe warrants further exploration for clinical translation in the early diagnosis and NIRF-guided surgery of PA.

FMNL3 is Overexpressed in Tumor Tissues and Predicts an Immuno-Hot Phenotype in Pancreatic Cancer.

Background: FMNL3 (Formin-like protein 3) is involved in the tumorigenesis of multiple cancers. The critical role of FMNL3 in malignancies has been preliminarily explored, but its immunological correlation is not clear. Methods: A pan-cancer analysis was performed to investigate the expressions, prognostic values, and immunological roles of FMNL3 across cancer types in The Cancer Genome Atlas (TCGA) database. Next, the correlations between FMNL3 and immunological features in the tumor microenvironment (TME) of pancreatic cancer (PAAD) were assessed. Besides, the role of FMNL3 in predicting the clinical characteristics and the responses to various therapies in PAAD was evaluated as well. Besides, the correlations between FMNL3 and the emerging immune-related biomarkers were also evaluated. Results: The pan-cancer analysis uncovered inconsistent expression status and prognostic values in several cancers. Besides, FMNL3 exhibited positive correlations with a majority of immunomodulators and tumor-infiltrating immune cells (TIICs) in several cancer types, including PAAD. In addition, FMNL3 was associated with an inflamed phenotype in the TME and predicted significantly higher responses to multiple anti-cancer therapies. In addition, FMNL3 was notably correlated with immune-related microbiota and N6-methyladenosine (m6A) genes. Conclusion: In summary, FMNL3 predicts an immuno-hot phenotype, which could be a promising indicator for identifying high immunogenicity in PAAD.

Investigating the Active Substance and Mechanism of San-Jiu-Wei-Tai Granules via UPLC-QE-Orbitrap-MS and Network Pharmacology.

San-Jiu-Wei-Tai granules (SJWTG) are a significant Chinese patent medicine for the treatment of chronic gastritis (CG), having outstanding advantages in long-term treatment; however, the chemical composition and potential mechanism have not been investigated until now. In this study, a rapid separation and identification method based on UPLC-QE-Orbitrap-MS was established, and 95 chemical components from SJWTGs were identified, including 6 chemical components of an unknown source that are not derived from the 8 herbs included in SJWTGs. The identified chemical components were subsequently analysed by network pharmacology, suggesting that the core targets for the treatment of CG with SJWTGs were EGFR, SRC, AKT1, HSP90AA1, MAPK1, and MAPK3 and thus indicating that SJWTGs could reduce the inflammatory response of gastric epithelial cells and prevent persistent chronic inflammation that induces cancerization by regulating the MAPK signalling pathway and the C-type lectin receptor signalling pathway as well as their upstream and downstream pathways in the treatment of CG. The key bioactive components in SJWTGs were identified as 2,6-bis(4-ethylphenyl)perhydro-1,3,5,7-tetraoxanaphth-4-ylethane-1,2-diol, a chemical component of an unknown source, murrangatin, meranzin hydrate, paeoniflorin, and albiflorin. The results of molecular docking showed the strong binding interaction between the key bioactive components and the core targets, demonstrating that the key bioactive components deserve to be further studied and considered as Q-markers. By acting on multiple targets, SJWTG is less susceptible to drug resistance during the long-term treatment of CG, indicating the advantage of Chinese patent medicines. Furthermore, the preventive effect of SJWTGs on gastric cancer also demonstrates the superiority of preventive treatment of disease with traditional Chinese medicine.