PSMC2 promotes glioma progression by regulating immune microenvironment and PI3K/AKT/mTOR pathway.

BACKGROUND: Glioma, the most frequent and malignant central nervous system (CNS) cancer, has a bad outcome. Proteasome 26S subunit ATPase 2 (PSMC2) is an essential part of the 26S proteasome and promotes the development of several tumors. However, the pathway and function of PSMC2 in glioma have not been unelucidated. METHODS: This study analyzed PSMC2 expression in glioma tissues and its predictive significance for patients. We examined the link between PSMC2 and DNA methylation, immune cell infiltration, tumor immune cycle, immune cell homeostasis, and immune checkpoints. Subsequently, immunohistochemistry and in vitro trials were employed to validate the expression, prognostic potential, and function of PSMC2 in glioma. The mechanisms of PSMC2 in glioma were further explored. RESULTS: Our study revealed that PSMC2 expression increased in glioma tissues contrasted with healthy tissues, and patients with high PSMC2 glioma exhibited poor overall survival (OS) compared to the low-PSMC2 group. Immune profile analysis revealed that PSMC2 was positively related to immunosuppressive cell infiltration and immune checkpoints and adversely related to the cancer immune cycle and immune cell homeostasis. In cell-based investigations, the inhibition of PSMC2 was found to effectively suppress the aggressiveness and proliferation of glioma cell lines while also enhancing cell cycle arrest and promoting cell death. Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and in vitro experiments showed that PSMC2 promoted glioma development through the PI3K/AKT/mTOR pathway. CONCLUSIONS: PSMC2 was upregulated in glioma and promoted cancer progression by modulating the tumor immune microenvironment, cancer cell biological behavior, immune cell homeostasis, and the PI3K/AKT/mTOR pathway, providing a new option to treat glioma.

Integrating Network Pharmacology and Experimental Verification to Explore the Pharmacological Mechanisms of Radix Paeoniae Rubra Against Glioma.

Glioma has a high mortality and can hardly be completely cured. Radix Paeoniae Rubra (RPR) is a prevalent component in traditional Chinese medicine used for tumor treatments. We explored the mechanism of RPR in treating glioma using network pharmacology and experiments. A network pharmacology approach was used to screen active ingredients, targets of RPR and glioma. We then constructed a herb-active ingredient-target-pathway network and conducted protein-protein interaction (PPI) network analysis, as well as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Molecular docking was also performed. Using CCK-8, colony formation, and xenograft experiments, we evaluated the effect of RPR on glioma. The involved pathway and proteins were identified by Western blot. From public databases, we identified nine active RPR ingredients and 40 overlapping targets among 109 RPR targets and 1360 glioma-associated targets. The PPI analysis revealed ten targets, such as AKT1, TP53, and VEGFA, which were identified as hub genes. The results from GO and KEGG analysis highlighted the involvement of the PI3K/AKT pathway. A herb-active ingredient-target-pathway network was constructed. By docking molecular structures, six suitable conformations have been identified. The RPR extract demonstrated anti-tumor properties by inhibiting glioma cell proliferation in vitro and in vivo, likely achieved by suppressing the phosphorylation of the PI3K/AKT signaling pathway. RPR concurrently downregulated the phosphorylation level of AKT1 and the protein expression level of VEGFA, while upregulating the expression of P53 in the U251 cell line. Utilizing network pharmacology and molecular docking, our study not only predicted the impact of RPR on glioma but also delineated the herb-active ingredient-target-pathway network. Experimentally, we confirmed that RPR may exert its anti-tumor properties by inhibiting the phosphorylation of the PI3K/AKT pathway, including AKT1, and by regulating the expression levels of VEGFA and P53.

STEAP3 is a prognostic biomarker that promotes glioma progression by regulating immune microenvironment and PI3K-AKT pathway.

BACKGROUND: STEAP3 is a metal reductase located on the plasma membrane close to the nucleus and vesicles. Despite numerous studies indicating the involvement of STEAP3 in tumor advancement, the prognostic value of STEAP3 in glioma and the related mechanisms have not been fully investigated. METHODS: Initially, we examined the correlation between STEAP3 expression and the survival rate in various glioma datasets. To assess the prognostic capability of STEAP3 for one-year, three-year, and five-year survival, we created receiver operating characteristic (ROC) curves and nomograms. Additionally, an investigation was carried out to examine the mechanisms that contribute to the involvement of STEAP3 in gliomas, including immune and enrichment analysis. To confirm the expression of STEAP3 in LGG and GBM, tumor tissue samples were gathered, and cell experiments were conducted to explore the impacts of STEAP3. The function of STEAP3 in the tumor immune microenvironment was assessed using the M2 macrophage infiltration assay. RESULTS: We found that STEAP3 expressed differently in group with different age, tumor grade IDH and 1p19q status. The analysis of survival illustrated that glioma patients with high level of STEAP3 experienced shorter survival durations, especially for IDH-mutant astrocytoma. Cox analysis demonstrated that STEAP3 had potential to act as an independent prognostic factor for glioma. The predictive value of STEAP3 for glioma prognosis was demonstrated by ROC curves and nomogram. Immune analysis showed that STEAP3 may lead to a suppressive immune microenvironment through the control of immunosuppressive cell infiltration and Cancer-Immunity Cycle. Combining enrichment analysis and cell experiments, we discovered that STEAP3 can promote glioma progression through regulation of PI3K-AKT pathway and M2 macrophage infiltration. CONCLUSION: STEAP3 plays significant roles in the advancement of glioma by regulating immune microenvironment and PI3K-AKT pathway. It has the potential to serve as a therapy target for glioma.

Cardiac radiation improves ventricular function in mice and humans with cardiomyopathy.

BACKGROUND: Rapidly dividing cells are more sensitive to radiation therapy (RT) than quiescent cells. In the failing myocardium, macrophages and fibroblasts mediate collateral tissue injury, leading to progressive myocardial remodeling, fibrosis, and pump failure. Because these cells divide more rapidly than cardiomyocytes, we hypothesized that macrophages and fibroblasts would be more susceptible to lower doses of radiation and that cardiac radiation could therefore attenuate myocardial remodeling. METHODS: In three independent murine heart failure models, including models of metabolic stress, ischemia, and pressure overload, mice underwent 5 Gy cardiac radiation or sham treatment followed by echocardiography. Immunofluorescence, flow cytometry, and non-invasive PET imaging were employed to evaluate cardiac macrophages and fibroblasts. Serial cardiac magnetic resonance imaging (cMRI) from patients with cardiomyopathy treated with 25 Gy cardiac RT for ventricular tachycardia (VT) was evaluated to determine changes in cardiac function. FINDINGS: In murine heart failure models, cardiac radiation significantly increased LV ejection fraction and reduced end-diastolic volume vs. sham. Radiation resulted in reduced mRNA abundance of B-type natriuretic peptide and fibrotic genes, and histological assessment of the LV showed reduced fibrosis. PET and flow cytometry demonstrated reductions in pro-inflammatory macrophages, and immunofluorescence demonstrated reduced proliferation of macrophages and fibroblasts with RT. In patients who were treated with RT for VT, cMRI demonstrated decreases in LV end-diastolic volume and improvements in LV ejection fraction early after treatment. CONCLUSIONS: These results suggest that 5 Gy cardiac radiation attenuates cardiac remodeling in mice and humans with heart failure. FUNDING: NIH, ASTRO, AHA, Longer Life Foundation.

Arylsulfatase D is a prognostic biomarker that promotes glioma cells progression through JAK2/STAT3 pathway and M2 macrophage infiltration.

Background: Arylsulfatase D (ARSD) belongs to the sulfatase family and plays a crucial role in maintaining the proper structure of bone and cartilage matrix. Although several researches have revealed the functions of ARSD in tumor progression, the prognostic value of ARSD in glioma and the related mechanisms have not been fully investigated. Methods: We performed a pan-cancer analysis of ARSD, and investigated the relationship between expression of ARSD and overall survival (OS) in multiple glioma datasets. ROC curves and nomograms were created to investigate the predictive capacity of ARSD. Immune and analysis were conducted to investigate the mechanisms underlying the roles of ARSD in glioma. Glioma tissue samples were collected to verify the expression of ARSD in glioma, while the functions of ARSD were explored using cell experiment. M2 macrophage infiltration assay was used to determine the relation between ARSD and tumor immune microenvironment. Results: Survival analysis indicated that individuals with high ARSD expression in glioma had a shorter survival time. Cox analysis showed that ARSD had a good ability for predicting prognosis in glioma. Immune analysis suggested that ARSD could regulate immune cell infiltration and affect the Cancer-Immunity Cycle to create an immunosuppressive environment. Combined with cell experiment and bioinformatic analysis, we found that ARSD can promote glioma progression through regulation of JAK2/STAT3 pathway and M2 macrophage infiltration. Conclusion: Our study found that ARSD can promote glioma development by regulating immune microenvironment and JAK2/STAT3 signaling pathway, which provided a potential therapy target for glioma treatment.

RPA3 promotes the proliferation, migration, and invasion of gliomas by activating the PI3K-AKT-mTOR pathway.

Gliomas are the most common primary malignant brain tumors, with a poor prognosis and high mortality, and there is no effective treatment regimen. A number of studies have shown that replication protein A3 (RPA3) can regulate DNA replication and that the abnormal expression of RPA3 can lead to genomic instability and induce the development of a variety of tumors. However, the relationship between RPA3 and gliomas and the mechanism of action remains unclear. In this study, we investigated the role of RPA3 in the development of gliomas and the possible mechanism. The Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) databases were used to analyze the expression level of RPA3 and its correlation with clinical prognosis. A univariate Cox regression model was established to predict the prognosis of glioma patients and analyze the correlation between RPA3 and immune cell infiltration and activation. Immunohistochemistry, RT-PCR, and Western blot (WB) were used to detect the expression of RPA3 in glioma specimens. After knocking down and overexpressing RPA3 with plasmids, effects on glioma cell proliferation, migration and invasive capacity were investigated in vitro. The possible molecular mechanisms were analyzed using WB. Results showed that the expression of RPA3 in glioma tissue and cells was significantly higher than that in normal glial cells and was positively correlated with the poor prognosis of patients with gliomas. The overexpression of RPA3 expression activated the phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of the rapamycin (mTOR) pathway by promoting the phosphorylation of PI3K, AKT, and mTOR, thereby promoting the proliferation, migration and invasion of glioma cells. In conclusion, RPA3 is highly expressed in gliomas and promotes the proliferation, migration and invasion of gliomas by activating the PI3K-AKT-mTOR pathway. Therefore, RPA3 may be a prognostic biomarker and therapeutic target for gliomas.

Computational approaches for the reconstruction of optic nerve fibers along the visual pathway from medical images: a comprehensive review.

Optic never fibers in the visual pathway play significant roles in vision formation. Damages of optic nerve fibers are biomarkers for the diagnosis of various ophthalmological and neurological diseases; also, there is a need to prevent the optic nerve fibers from getting damaged in neurosurgery and radiation therapy. Reconstruction of optic nerve fibers from medical images can facilitate all these clinical applications. Although many computational methods are developed for the reconstruction of optic nerve fibers, a comprehensive review of these methods is still lacking. This paper described both the two strategies for optic nerve fiber reconstruction applied in existing studies, i.e., image segmentation and fiber tracking. In comparison to image segmentation, fiber tracking can delineate more detailed structures of optic nerve fibers. For each strategy, both conventional and AI-based approaches were introduced, and the latter usually demonstrates better performance than the former. From the review, we concluded that AI-based methods are the trend for optic nerve fiber reconstruction and some new techniques like generative AI can help address the current challenges in optic nerve fiber reconstruction.

Reduced angiogenesis and delayed endochondral ossification in CD163-/- mice highlights a role of M2 macrophages during bone fracture repair.

While recent studies showed that macrophages are critical for bone fracture healing, and lack of M2 macrophages have been implicated in models of delayed union, functional roles for specific M2 receptors have yet to be defined. Moreover, the M2 scavenger receptor CD163 has been identified as a target to inhibit sepsis following implant-associated osteomyelitis, but potential adverse effects on bone healing during blockage therapy have yet to be explored. Thus, we investigated fracture healing in C57BL/6 versus CD163-/- mice using a well-established closed, stabilized, mid-diaphyseal femur fracture model. While gross fracture healing in CD163-/- mice was similar to that of C57BL/6, plain radiographs revealed persistent fracture gaps in the mutant mice on Day 14, which resolved by Day 21. Consistently, 3D vascular micro-CT demonstrated delayed union on Day 21, with reduced bone volume (74%, 61%, and 49%) and vasculature (40%, 40%, and 18%) compared to C57BL/6 on Days 10, 14, and 21 postfracture, respectively (p < 0.01). Histology confirmed large amounts of persistent cartilage in CD163-/- versus C57BL/6 fracture callus on Days 7 and 10 that resolves over time, and immunohistochemistry demonstrated deficiencies in CD206+ M2 macrophages. Torsion testing of the fractures confirmed the delayed early union in CD163-/- femurs, which display decreased yield torque on Day 21, and a decreased rigidity with a commensurate increase in rotation at yield on Day 28 (p < 0.01). Collectively, these results demonstrate that CD163 is required for normal angiogenesis, callus formation, and bone remodeling during fracture healing, and raise potential concerns about CD163 blockade therapy.

Intracranial penetrating injury by clothes fork in an infant: case report and review of the literature.

Nonmissile intracranial penetrating injury (IPI) in pediatric population is rare. Here, we report the exceedingly rare case of a 5-month-old infant sustained by a metallic clothes fork penetrating into his left forehead. The little baby was identified to carry a traumatic hemorrhagic shock, and a multidisciplinary team (MDT) was immediately established response for whole-course evaluation and decision-making. Computed tomography revealed that the clothes fork had impaled into the left frontal bone and brain parenchyma with about 3.2 cm inside the cranial vault. The infant underwent emergency surgery, and the clothes fork was removed jointly by MDT members under general anesthesia in the retrograde direction. His recovery was uneventful and was followed up 2 years without growth and developmental abnormality. As an extremely rare entity with distinct age-related characteristics, a MDT approach is a best choice and effective strategy to manage infant nonmissile IPI, including preoperative management, surgical treatment, and even following rehabilitation.

Attapulgite Nanorod-Incorporated Polyimide Membrane for Enhanced Gas Separation Performance.

Polyimide (PI) membrane is an ideal gas separation material due to its advantages of high designability, good mechanical properties and easy processing; however, it has equilibrium limitations in gas selectivity and permeability. Introducing nanoparticles into polymers is an effective method to improve the gas separation performance. In this work, nano-attapulgite (ATP) functionalized with KH-550 silane coupling agent was used to prepare polyimide/ATP composite membranes by in-situ polymerization. A series of characterization and performance tests were carried out on the membranes. The obtained results suggested a significant increase in gas permeability upon increasing the ATP content. When the content of ATP was 50%, the gas permeability of H2, He, N2, O2, CH4, and CO2 reached 11.82, 12.44, 0.13, 0.84, 0.10, and 4.64 barrer, which were 126.87%, 119.40%, 160.00%, 140.00%, 150.00% and 152.17% higher than that of pure polyimide, respectively. No significant change in gas selectivity was observed. The gas permeabilities of membranes at different pressures were also investigated. The inefficient polymer chain stacking and the additional void volume at the interface between the polymer and TiO2 clusters leaded to the increase of the free volume, thus improving the permeability of the polyimide membrane. As a promising separation material, the PI/ATP composite membrane can be widely used in gas separation industry.

The effect of human papillomavirus status on prognosis and local treatment strategies of T1-2N0 oropharyngeal squamous cell cancer.

Purpose: To explore the effect of human papillomavirus (HPV) status on prognosis and further investigate whether human papillomavirus (HPV) status has an impact on the local treatment strategies for T1-2N0 oropharyngeal squamous cell cancer (OPSCC) patients. Methods: Patients diagnosed with T1-2N0 OPSCC between 2010 and 2015 were included from the Surveillance, Epidemiology, and End Results database. Data were analyzed using propensity score matching (PSM), Chi-square test, Kaplan-Meier survival analysis, and Cox multivariable analyses. Results: A total of 1,004 patients were identified, of whom 595 (59.3%) had HPV-related tumors. Of all the patients, 386 (38.4%) and 618 (61.6%) received definitive radiotherapy and radical surgery, respectively. HPV status had no significant effect on local treatment strategies for early-stage OPSCC (P = 0.817). The 3-year cancer-specific survival (CSS) and overall survival (OS) were 89.6 and 80.1%, respectively. Compared to those with HPV-negative diseases, patients with HPV-positive diseases had better CSS and OS. A total of 222 pairs of patients were completely matched after PSM. The results of multivariate Cox regression analysis showed that patients with HPV-positive disease had significantly better CSS (P = 0.001) and OS (P < 0.001) compared to those with HPV-negative tumors. However, local treatment strategy was not associated with survival outcomes after PSM (CSS, P = 0.771; OS, P = 0.440). The subgroup analysis showed comparable CSS and OS between those treated with radical surgery and definitive radiotherapy regardless of HPV status. Conclusions: HPV status is an independent prognostic factor for the survival of stage T1-2N0 OPSCC patients. Local treatment strategies had no significant effect on the survival of early-stage OPSCC regardless of HPV status. Patients with early-stage OPSCC should be informed regarding the pros and cons of definitive radiotherapy or radical surgery.

Procollagen C-protease enhancer protein is a prognostic factor for glioma and promotes glioma development by regulating multiple tumor-related pathways and immune microenvironment.

OBJECTIVES: Glioma is a common type of brain tumor with high incidence and mortality rates. Procollagen C-protease enhancer protein (PCOLCE) has been shown to regulate tumor growth and metastasis in several cancers. However, the role of PCOLCE in glioma is unknown. This study aims to assess the association between PCOLCE and prognosis of glioma, and investigated the potential mechanisms. METHODS: The prognostic value of PCOLCE was determined using data from nine publicly available glioma cohorts. We also investigated the relationship between PCOLCE and glioma immune microenvironment and predicted response to immunotherapy based on the expression levels of PCOLCE. The potential roles of PCOLCE in glioma were also explored and validated in cell experiment. RESULTS: Survival analysis suggested that high-PCOLCE expression was associated with poor prognosis in glioma. Upregulation of PCOLCE enhanced an immune suppressive microenvironment in glioma by regulating immunocyte infiltration and Cancer-Immunity Cycle. Cox and ROC analysis revealed that PCOLCE was a prognostic factor for glioma and could be used to predict survival of the patients. Patients with low-PCOLCE expression were more likely to respond to Immunotherapy with ICI (immune checkpoint inhibitor) and survive longer. Enrichment analysis showed that PCOLCE was associated with multiple tumor-related pathways. Finally, we demonstrated that the knockdown of PCOLCE inhibited glioma development by regulating cell cycle and promoting apoptosis in in vitro experiments. CONCLUSION: PCOLCE promotes glioma progression by regulating multiple tumor-related pathways and immune microenvironment and can be used as a prognostic factor for glioma.

CAMK1D Inhibits Glioma Through the PI3K/AKT/mTOR Signaling Pathway.

Calcium/calmodulin-dependent protein ID (CAMK1D) is widely expressed in many tissues and involved in tumor cell growth. However, its role in gliomas has not yet been elucidated. This study aimed to investigate the roles of CAMK1D in the proliferation, migration, and invasion of glioma. Through online datasets, Western blot, and immunohistochemical analysis, glioma tissue has significantly lower CAMK1D expression levels than normal brain (NB) tissues, and CAMK1D expression was positively correlated with the WHO classification. Kaplan-Meier survival analysis shows that CAMK1D can be used as a potential prognostic indicator to predict the overall survival of glioma patients. In addition, colony formation assay, cell counting Kit-8, and xenograft experiment identified that knockdown of CAMK1D promotes the proliferation of glioma cells. Transwell and wound healing assays identified that knockdown of CAMK1D promoted the invasion and migration of glioma cells. In the above experiments, the results of overexpression of CAMK1D were all contrary to those of knockdown. In terms of mechanism, this study found that CAMK1D regulates the function of glioma cells by the PI3K/AKT/mTOR pathway. In conclusion, these findings suggest that CAMK1D serves as a prognostic predictor and a new target for developing therapeutics to treat glioma.

Associations of serum PFOA and PFOS levels with incident hypertension risk and change of blood pressure levels.

Evidence on the associations of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with hypertension or blood pressure (BP) levels was limited and inconsistent. The present prospective study aims to evaluate the longitudinal associations of serum levels of PFOA and PFOS with incident hypertension risk and change of blood pressure levels. At baseline 1080 participants (mean age 62 years, 58.9% females) free of hypertension, cardiovascular disease, diabetes, and cancer were followed up for nearly 5 years. Baseline serum levels of PFOA and PFOS were measured with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS). Hypertension was defined as any of (1) self-reported physician-diagnosed hypertension (2) use of hypotension drugs (3) measured systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg. Change of BP was evaluated as a difference between twice measurements (BP at follow-up visit－BP at baseline). After adjustment for multiple covariates, serum PFOS levels were negatively correlated with risk of hypertension [RR per lg-unit = 0.94 (95% CI: 0.88, 0.99)] and change of systolic BP [ß = -1.48 (95% CI: -2.56, -0.41)]. The highest vs lowest quartiles of PFOS concentration was negatively associated with hypertension risk. Compared with Q1, the RRs (95% CIs) for Q2, Q3, and Q4 were 0.83 (0.67-0.98), 0.81 (0.67-0.97), and 0.81(0.67-0.97), respectively (p for trend = 0.016). The negative associations remained in females but not in males (p for interaction = 0.44). No significant association of PFOA with hypertension risk was observed. Further studies are needed to validate our findings.

Clinical outcome of cord blood transplantation for nine children with juvenile myelomonocytic leukemia receiving fludarabine-busulfan-cyclophosphamide-based conditioning.

BACKGROUND: Juvenile myelomonocytic leukemia (JMML) is a rare hematological malignancy in young children and can only be cured through the allogeneic stem cell transplantation. PROCEDURE: We have retrospectively analyzed the outcomes of nine children with JMML after unrelated cord blood transplantation (UCBT). RESULTS: Eight patients who have received a myeloablative conditioning regimen of fludarabine (FLU), busulfan (BU), and cyclophosphamide (CY) have gotten engraftment. None of the nine patients has relapsed following initial UCBT. Six patients are still alive and in complete remission after UCBT with a median observation time of 43 months (range: 10-80 months). CONCLUSIONS: This study shows that UCBT with FLU-BU-CY conditioning regimen can represent a suitable option for children with JMML.

Associations between serum PFOA and PFOS levels and incident chronic kidney disease risk in patients with type 2 diabetes.

Chronic kidney disease (CKD) is a common comorbidity among patients with type 2 diabetes. Exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) has been linked to poorer kidney function in general population, but the related studies in individuals with diabetes were very limited. We aimed to examine the longitudinal associations of PFOA and PFOS exposure and CKD incidence among diabetes patients. Baseline levels of PFOA and PFOS were measured in serum in 967 diabetes patients from the Dongfeng-Tongji cohort. Multivariable logistic regression models were used to characterize the relationship between serum PFOA and PFOS levels and incident CKD risk (defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2). During 10-years follow-up, 267 incident CKD cases were identified. Only PFOS level was significantly associated with lower risk of CKD incidence (adjusted OR: 0.67; 95%CI: 0.51, 0.88). Such inverse association was only observed among participants with lower eGFR levels (< 70 mL/min/1.73 m2), although the interaction did not achieve statistical significance. Notably, an inverted U-shaped relationship between eGFR and serum PFOS level (Pfor nonlinearity < 0.001) was observed based on the 1825 subjects with available data at baseline. PFOS exposure was negatively associated with CKD incidence in patients with diabetes, especially in those with baseline eGFR levels < 70 mL/min/1.73 m2. This may be explained by the implication of baseline kidney function on the serum PFAS concentrations which in turn affect the relationship between PFOS exposure and the incident CKD risk among diabetes.

Artesunate attenuates inflammatory injury and inhibits the NF-κB pathway in a mouse model of cerebral ischemia.

OBJECTIVE: Inflammation is an important factor in the pathological process of cerebral ischemia. Artesunate exhibits a broad range of anti-inflammatory properties in many diseases. We investigated the potential protective effect of artesunate against cerebral ischemia and the related mechanisms. METHODS: Mice were divided into distal middle cerebral artery occlusion (dMCAO), sham, low dose, and high dose groups and subjected to dMCAO, except for the sham group. The low and high dose groups were administered artesunate (15 and 30 mg/kg), and the neuroprotective effects were analyzed by evaluating infarct volumes and neurological deficits. Microglial activation and neutrophil infiltration were evaluated by immunofluorescence, immunohistochemical staining, and western blotting. Inflammatory mediators were measured by enzyme-linked immunosorbent assays. Nuclear factor (NF)-κB nuclear translocation was detected by immunofluorescence and western blotting. RESULTS: Compared with the dMCAO group, artesunate significantly improved neurological deficit scores and infarct volumes and ameliorated inflammation by reducing neutrophil infiltration, suppressing microglial activation, and downregulating tumor necrosis factor-α and interleukin-1ß expression. Furthermore, artesunate inhibited nuclear translocation of NF-κB and inhibitor protein α proteolysis. CONCLUSIONS: Artesunate protected against inflammatory injury by reducing neutrophil infiltration and microglial activation, suppressing inflammatory cytokines, and inhibiting the NF-κB pathway. Therefore, artesunate is a potential ischemic stroke treatment.

Circ-KIAA0907 inhibits the progression of oral squamous cell carcinoma by regulating the miR-96-5p/UNC13C axis.

BACKGROUND: Circular RNA (circRNA) plays an important role in regulating cell biological function and has been shown to be involved in cancer progression, including oral squamous cell carcinoma (OSCC). Circ-KIAA0907 has been found to play an anti-cancer role in OSCC, so it is worth exploring more functions and new mechanisms of circ-KIAA0907 in OSCC progression. METHODS: Quantitative real-time PCR (qRT-PCR) was used to detect the expression of circ-KIAA0907, microRNA (miR)-96-5p, and unc-13 homolog C (UNC13C). Transwell assay, flow cytometry, and colony formation assay were employed to measure the migration, invasion, apoptosis, and radiosensitivity of cells. Besides, glucose uptake, lactate production, and extracellular acidification rate (ECAR) were determined to evaluate the glycolysis ability of cells. Dual-luciferase reporter assay and RIP assay were performed to confirm the interactions among circ-KIAA0907, miR-96-5p, and UNC13C. And RNA pull-down assay was used to verify the binding degree of miR-96-5p to its targets. Moreover, UNC13C protein level was examined using western blot (WB) analysis. OSCC xenograft models were constructed to perform in vivo experiments. RESULTS: Circ-KIAA0907 was a stability circRNA with lowly expression in OSCC. Overexpressed circ-KIAA0907 could inhibit migration, invasion, and glycolysis, while promoting apoptosis and radiosensitivity in OSCC cells. In the terms of mechanism, circ-KIAA0907 could sponge miR-96-5p to regulate UNC13C expression. MiR-96-5p overexpression could reverse the inhibitory effect of circ-KIAA0907 on OSCC progression, and UNC13C knockdown also could overturn the suppressive effect of miR-96-5p inhibitor on OSCC progression. Animal experiments revealed that circ-KIAA0907 could reduce the tumor growth of OSCC by regulating the miR-96-5p/UNC13C axis. CONCLUSION: Our study suggests that circ-KIAA0907 restrains OSCC progression via the miR-96-5p/UNC13C axis, indicating that it may be a potential target for OSCC treatment.

Associations of serum bisphenol A levels with incident chronic kidney disease risk.

Associations of bisphenol A (BPA) levels with renal disease are inconsistent. The present prospective study aims to evaluate the association of serum BPA levels with chronic kidney disease (CKD) in a Chinese middle-aged and elderly population. At baseline 1370 participants (mean age 61.7 years, 58.8% females) free of kidney disease and cancer were followed up nearly 10 years. Baseline serum BPA concentration was measured with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS). Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Multivariable logistic regression model was used to investigate relationship between serum BPA levels and incident CKD risk. During a 10-year follow-up, 246 individuals developed CKD. Baseline serum BPA concentration was 2.92 (1.00, 5.27) ng/mL. At baseline, after adjustment for multiple covariates serum BPA levels were negatively correlated with eGFR levels (ß = -0.068, P = 0.009). Compared to those with low levels of serum BPA, participants with high levels had a significant negative association with CKD [ORs (95% CI) = 0.35 (0.25, 0.50), P < 0.001], and this association was not modified by conventional risk factors. The negative associations remained in females but not in males (P for interaction = 0.016). Significant interaction between baseline eGFR and serum BPA levels on CKD risk was also found (P for interaction = 0.027), Except subjects with 60-70 mL/min/1.73 m2 eGFR at baseline, inverse association robustly existed between serum BPA levels and incident CKD risk in the other eGFR subgroups. Further studies are needed to validate our findings.

A Flow Stress Model of 300M Steel for Isothermal Tension.

To investigate the effect of hot working parameters on the flow behavior of 300M steel under tension, hot uniaxial tensile tests were implemented under different temperatures (950 °C, 1000 °C, 1050 °C, 1100 °C, 1150 °C) and strain rates (0.01 s-1, 0.1 s-1, 1 s-1, 10 s-1). Compared with uniaxial compression, the tensile flow stress was 29.1% higher because dynamic recrystallization softening was less sufficient in the tensile stress state. The ultimate elongation of 300M steel increased with the decrease of temperature and the increase of strain rate. To eliminate the influence of sample necking on stress-strain relationship, both the stress and the strain were calibrated using the cross-sectional area of the neck zone. A constitutive model for tensile deformation was established based on the modified Arrhenius model, in which the model parameters (n, α, Q, ln(A)) were described as a function of strain. The average deviation was 6.81 MPa (6.23%), showing good accuracy of the constitutive model.