The agreement of low lean mass with obesity using different definitions and its correlation with hyperuricemia.

Background: The agreement on the identification of sarcopenic obesity remains elusive, and its association with hyperuricemia remains unestablished. This study sought to evaluate the agreement of low lean mass (LLM) with obesity and its correlation with hyperuricemia. Methods: A total of 25,252 study participants, comprising 4,597 individuals with hyperuricemia, were obtained from the National Health and Nutrition Examination Survey spanning the years 1999-2006 and 2011-2018. LLM with obesity was characterized by the coexistence of LLM, determined by the ratio of appendicular lean mass to body mass index (BMI), and three categories of obesity including BMI, body fat percentage (BF%), and waist circumference (WC). We employed Cohen's kappa to evaluate the agreement among the different diagnostic criteria and implemented survey multiple logistic regression and stratified analyses to explicate the connection between LLM with obesity and the risk of hyperuricemia. Results: When defining obesity using BF%, BMI, and WC, the prevalence of LLM with obesity varied from 6.6 to 10.1%, with moderate-to-strong agreement. In the fully adjusted model, individuals with LLM or any of the three types of obesity exhibited notably elevated odds of developing hyperuricemia. Likewise, participants with LLM and obesity had 2.70 (LLM + BMI), 2.44 (LLM + BF%), and 3.12 (LLM + WC) times the risk of hyperuricemia, respectively, compared with healthy individuals. The association between LLM with obesity and hyperuricemia remained stable and significant across different age and sex subgroups. Conclusion: When employing the three definitions of obesity, the incidence of LLM with obesity was not high, and the diagnostic agreement was relatively good. The participants with LLM and obesity exhibited an increased risk of hyperuricemia.

Long-term exposure to air pollutants and new-onset migraine: A large prospective cohort study.

BACKGROUNDS: Short-term exposure to air pollutants increases the risk of migraine, but the long-term impacts of exposure to multiple pollutants on migraine have not been established. The aim of this large prospective cohort study was to explore these links. METHODS: A total of 458,664 participants who were free of migraine at baseline from the UK Biobank were studied. Cox proportional hazards models were used to estimate the risk of new-onset migraine from combined long-term exposure to four pollutants, quantified as an air pollution score using principal component analysis. RESULTS: During a median (IQR) follow-up of 12.5 (11.8, 13.2) years, a total of 5417 new-onset migraine cases were documented. Long-term exposure to multiple air pollutants was associated with an increased risk of new-onset migraine, as indicated by an increased in the SDs of PM2.5 (hazard ratio (HR): 1.04, 95% CI: 1.01-1.06, P = 0.009), PM10 (HR: 1.07, 95% CI: 1.04-1.10, P < 0.001), NO2 (HR: 1.10, 95% CI: 1.07-1.13, P < 0.001) and NOx (HR: 1.04, 95% CI: 1.01-1.07, P = 0.005) in the main model. The air pollution score showed a doseresponse association with an increased risk of new-onset migraine. Similarly, compared with those of the lowest tertile, the HRs (95% CI) of new-onset migraine were 1.11 (95% CI: 1.04-1.19, P = 0.002) and 1.17 (95% CI: 1.09-1.26, P < 0.001) in tertiles 2 and 3, respectively, according to the main model (P trend < 0.001). CONCLUSION: Long-term individual and joint exposure to multiple air pollutants is associated with an increased risk of new-onset migraine.

Structural and functional basis of bacteriophage K64-ORF41 depolymerase for capsular polysaccharide degradation of Klebsiella pneumoniae K64.

Capsule polysaccharide is an important virulence factor of Klebsiella pneumoniae (K. pneumoniae), which protects bacteria against the host immune response. A promising therapeutic approach is using phage-derived depolymerases to degrade the capsular polysaccharide and expose and sensitize the bacteria to the host immune system. Here we determined the cryo-electron microscopy (cryo-EM) structures of a bacteriophage tail-spike protein against K. pneumoniae K64, ORF41 (K64-ORF41) and ORF41 in EDTA condition (K64-ORF41EDTA), at 2.37 Å and 2.50 Å resolution, respectively, for the first time. K64-ORF41 exists as a trimer and each protomer contains a ß-helix domain including a right-handed parallel ß-sheet helix fold capped at both ends, an insertion domain, and one ß-sheet jellyroll domain. Moreover, our structural comparison with other depolymerases of K. pneumoniae suggests that the catalytic residues (Tyr528, His574 and Arg628) are highly conserved although the substrate of capsule polysaccharide is variable. Besides that, we figured out the important residues involved in the substrate binding pocket including Arg405, Tyr526, Trp550 and Phe669. This study establishes the structural and functional basis for the promising phage-derived broad-spectrum activity depolymerase therapeutics and effective CPS-degrading agents for the treatment of carbapenem-resistant K. pneumoniae K64 infections.

Long-term air pollutants exposure and respiratory mortality: A large prospective cohort study.

Ambient air pollution is a major global health concern. Yet, no study has thoroughly assessed its link to respiratory mortality. Our research evaluated the combined and individual effects of air pollutants on respiratory mortality risks based on the UK Biobank. A total of 366,478 participants were studied. A Cox proportional hazards model was used to estimate the respiratory mortality risk from combined long-term exposure to five pollutants, summarized as a weighted air pollution score. During a median of 13.6 years of follow-up, 6113 deaths due to respiratory diseases were recorded. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) of respiratory diseases were 2.64 (2.05-3.39), 1.62 (1.23-2.12), 2.06 (1.73-2.45), 1.20 (1.16-1.25), and 1.07 (1.05-1.08) per 10 µg/m3 increase in PM2.5, PM2.5-10, PM10, NO2, and NOx, respectively. The air pollution score showed a dose-response association with an elevated respiratory mortality risk. The highest versus lowest quartile air pollution score was linked to a 44% increase in respiratory mortality risk (HR 1.44, 95% CI: 1.33-1.57), with consistent findings in subgroup and sensitivity analyses. Long-term individual and joint air-pollutant exposure showed a dose-response association with an increased respiratory mortality risk, highlighting the importance of a comprehensive air-pollutant assessment to protect public health.

A single cell atlas of circulating immune cells involved in diabetic retinopathy.

This study focused on examining the exact role of circulating immune cells in the development of diabetic retinopathy (DR). In vitro co-culture experiments showed that peripheral blood mononuclear cells (PBMCs) from patients with type 1 DR crucially modulated the biological functions of human retinal microvascular endothelial cells (HRMECs), consequently disrupting their normal functionality. Single-cell RNA sequencing (scRNA-seq) study revealed unique differentially expressed genes and pathways in circulating immune cells among healthy controls, non-diabetic retinopathy (NDR) patients, and DR patients. Of significance was the observed upregulation of JUND in each subset of PBMCs in patients with type 1 DR. Further studies showed that downregulating JUND in DR patient-derived PBMCs led to the amelioration of HRMEC dysfunction. These findings highlighted the notable alterations in the transcriptomic patterns of circulating immune cells in type 1 DR patients and underscored the significance of JUND as a key factor for PBMCs in participating in the pathogenesis of DR.

Association between Whole Grain Intake and Chronic Kidney Disease.

BACKGROUND: The relationship between whole grain intake and chronic kidney disease (CKD) remains uncertain. OBJECTIVE: This study aimed to evaluate the association between whole grain intake and risk of CKD in Chinese adults. METHODS: The present cross-sectional study used data from the China Health and Nutrition Survey conducted in 2009. Whole grain intake was measured using 3 consecutive 24-h dietary recalls and a household food inventory. A multivariable logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of CKD. In addition, a restricted cubic spline was used to investigate the dose‒response relationship between whole grain and risk of CKD. RESULTS: A total of 6747 participants were included, 728 of whom had CKD. Compared with those in the lowest whole grain intake group, those in the higher grain intake group had an inverse association with risk of CKD (Q2: adjusted OR 0.70, 95% CI: 0.54, 0.89; Q3: adjusted OR 0.54, 95% CI: 0.42, 0.69; and Q4: adjusted OR 0.29, 95% CI: 0.21, 0.41). The association between whole grain intake and CKD seems to be stronger for individuals who were male (P for interaction = 0.008) or smokers (P for interaction = 0.013). In addition, the restricted cubic spline suggested an obvious L-shaped correlation. CONCLUSIONS: Increased whole grain intake was associated with a decreased risk of CKD in Chinese adults.

Up-regulation of RAN by MYBL2 maintains osteosarcoma cancer stem-like cells population during heterogeneous tumor generation.

Intratumor heterogeneity is one of the major features of cancers, leading to aggressive disease and treatment failure. Cancer stem-like cells (CSCs) are believed to give rise to the heterogeneous cell types within tumors. Hence, understanding the regulatory mechanism underlying the recurrence process of heterogeneous tumor by CSCs could facilitate the development of CSC-targeted therapies. Here, utilizing single-cell transcriptomics, we present the molecular profile of osteosarcoma CSCs-derived heterogeneous tumors consisting of CSC clusters, osteoprogenitor and differentiated cell types, such as pre-osteoblasts, osteoblasts and chondroblasts. Furthermore, by constructing the comprehensive map of modulated genes during CSCs self-renewal and differentiation, we identify RAN exhibiting specific peak expression in osteosarcoma CSCs clusters which is transcriptionally up-regulated by MYBL2. Functionality, MYBL2-RAN pathway promotes the CSCs self-renewal by enhancing the nuclear accumulation of MYC protein, which in turn boosts the overexpression of RAN as a positive feedback. Importantly, blockage of MYBL2-RAN pathway sensitizes CSCs to cisplatin treatment and synergistically enhanced the cisplatin-induced cytotoxicity. Both MYBL2 and RAN are highly expressed in clinical osteosarcoma tissues which indicate poor prognosis. Collectively, our study provides advanced insights into the regeneration process of heterogeneous tumor originating from CSCs and highlights the MYBL2-RAN pathway as a promising target for CSC-based therapy in osteosarcoma.

Clinical effectiveness of krill oil supplementation on cardiovascular health in humans: An updated systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The potential role of krill oil (KO) supplementation on cardiovascular health are inconsistent in several clinical trials. Therefore, our present meta-analysis aimed to systematically evaluate the impacts of supplementation of KO on cardiovascular disease risk factors (CVDRFs). METHODS: Intervention trials assessing KO supplementation on cardiovascular disease (CVD) outcomes were systematically retrieved for pooling. The primary outcome was lipid profile. Secondary outcomes were consisted by blood pressure, glycemic indices, body composition together with inflammatory markers. We synthesized the effect sizes with 95% confidence intervals and weighted mean difference. To explore the heterogeneity source, we employed meta-regression and subgroup analysis. Quality assessment, publication bias, sensitivity-analysis and the certainty of evidence were also carried out. RESULTS: We included 14 trials (18 treatment arms) with 1458 participants. KO supplementation had beneficial effects on total cholesterol (P = 0.01), low-density lipoprotein cholesterol (P = 0.006), and triglycerides (P = 0.0005). However, no effects were found for other CVDRFs, such as blood pressure, glycemic control, body composition as well as inflammatory markers. Subgroup analyses indicated that these notably favorable effects were observed in trials with a parallel design, treatment duration <8 weeks and subjects with baseline body mass index <28 kg/m2. The above findings remained consistent in the sensitivity analysis, without obvious publication bias detected. CONCLUSIONS: The current evidence demonstrated that daily KO supplementation may as a candidate for lipid management strategies. In future, studies should pay attention to the relationships of KO intake with the incidence of CVD events or all-cause mortality.

Tertiary lymphoid structures in gynecological cancers: prognostic role, methods for evaluating, antitumor immunity, and induction for therapy.

Tertiary lymphoid structures (TLSs), referred to as tertiary lymphoid organs and lymphoid tissue neogenesis, are aggregates of immune cells that occur in nonlymphoid tissues. In recent years, it has been found that TLSs within the tumor microenvironment have been associated with local adaptive immune immunity against cancer and favorable prognosis in several human solid tumors, including gynecological cancers. The issue of the prognosis of gynecological cancers, including endometrial, cervical, and ovarian cancer, is an enormous challenge that many clinical doctors and researchers are now facing. Concerning the predictive prognostic role of TLSs, effective evaluation, and quantification of TLSs in human tissues may be used to assist gynecologists in assessing the clinical outcome of gynecological cancer patients. This review summarizes the current knowledge of TLSs in gynecological cancers, mainly focusing on the potential mechanism of TLS neogenesis, methods for evaluating TLSs, their prognostic value, and their role in antitumor immune immunity. This review also discusses the new therapeutic methods currently being explored in gynecological cancers to induce the formation of TLSs.

Augmenting L3MBTL2-induced condensates suppresses tumor growth in osteosarcoma.

Osteosarcoma is a highly aggressive cancer and lacks effective therapeutic targets. We found that L3MBTL2 acts as a tumor suppressor by transcriptionally repressing IFIT2 in osteosarcoma. L3MBTL2 recruits the components of Polycomb repressive complex 1.6 to form condensates via both Pho-binding pockets and polybasic regions within carboxyl-terminal intrinsically disordered regions; the L3MBTL2-induced condensates are required for its tumor suppression. Multi-monoubiquitination of L3MBTL2 by UBE2O results in its proteasomal degradation, and the UBE2O/L3MBTL2 axis was crucial for osteosarcoma growth. There is a reverse correlation between L3MBTL2 and UBE2O in osteosarcoma tissues, and higher UBE2O and lower L3MBTL2 are associated with poorer prognosis in osteosarcoma. Pharmacological blockage of UBE2O by arsenic trioxide can enhance L3MBTL2-induced condensates and consequently suppress osteosarcoma growth. Our findings unveil a crucial biological function of L3MBTL2-induced condensates in mediating tumor suppression, proposing the UBE2O-L3MBTL2 axis as a potential cancer therapeutic target in osteosarcoma.

Unveiling the potential role of natriuretic peptide receptor a isoforms in fine-tuning the cGMP production and tissue-specific function.

Atrial natriuretic peptide (ANP) is a peptide hormone that regulates blood pressure and volume. ANP interacts with natriuretic peptide receptor-A (NPR-A) to lower the blood pressure through vasodilation, diuresis and natriuresis. Previously, we designed two human ANP analogues, one with exclusively diuretic function (DGD-ANP) and the other with exclusively vasodilatory function (DRD-ANP). Although both ANP analogues interact with NPR-A, their ability to produce cGMP was different. Three alternatively spliced isoforms of NPR-A were previously identified in rodents. Here, we evaluated the putative human isoforms for their cGMP production independently and in combination with WT NPR-A in various percentages. All three NPR-A isoforms failed to produce cGMP in the presence of ANP, DGD-ANP, or DRD-ANP. Co-expression of isoforms with WT NPR-A were found to significantly impair cGMP production. Considering the differential tissue expression levels of all three spliced isoforms in rodents have previously been demonstrated, the existence of these non-functional receptor isoforms may act as negative regulator for ANP/NPR-A activation and fine-tune cGMP production by WT NPR-A to different degree in different tissues. Thus, NPR-A isoforms potentially contribute to tissue-specific functions of ANP.

The correlation of urinary strontium with the risk of chronic kidney disease among the general United States population.

Background: This study sought to illustrate whether urinary strontium levels were related to developing chronic kidney disease (CKD) in the United States population. Methods: A total of 5,005 subjects were identified from the National Health and Nutrition Examination Survey 2011-2016. Survey-weighted logistic regression analysis, multivariate linear regression analysis, restricted cubic spline (RCS) plots curve and stratified analyses were undertaken to explicate the correlation between urinary strontium and CKD. Results: With the increase of urinary strontium, the incidence rate of CKD and urinary albumin to creatinine ratio (UACR) levels gradually decreased, and estimated glomerular filtration rate (eGFR) levels gradually increased. After controlling all confounders, only urinary strontium in the fourth quartile was correlated to a lower CKD prevalence (OR: 0.59; 95% CI, 0.44-0.79) compared to the lowest quartile. Multivariate linear regression analysis showed that urinary strontium was positively correlated with eGFR but negatively with UACR. RCS curve suggested a nonlinear relationship between urinary strontium and CKD (P for non-linearity <0.001). Stratified analyses indicated no significant difference in the correlation between urinary strontium and CKD among different subgroups. Conclusion: Urinary strontium was strongly correlated with a low risk of CKD, and this association was non-linear among the US population.

Differentiating tumour progression from pseudoprogression in glioblastoma patients: a monoexponential, biexponential, and stretched-exponential model-based DWI study.

BACKGROUND: To investigate the diagnostic performance of parameters derived from monoexponential, biexponential, and stretched-exponential diffusion-weighted imaging models in differentiating tumour progression from pseudoprogression in glioblastoma patients. METHODS: Forty patients with pathologically confirmed glioblastoma exhibiting enhancing lesions after completion of chemoradiation therapy were enrolled in the study, which were then classified as tumour progression and pseudoprogression. All patients underwent conventional and multi-b diffusion-weighted MRI. The apparent diffusion coefficient (ADC) from a monoexponential model, the true diffusion coefficient (D), pseudodiffusion coefficient (D*) and perfusion fraction (f) from a biexponential model, and the distributed diffusion coefficient (DDC) and intravoxel heterogeneity index (α) from a stretched-exponential model were compared between tumour progression and pseudoprogression groups. Receiver operating characteristic curves (ROC) analysis was used to investigate the diagnostic performance of different DWI parameters. Interclass correlation coefficient (ICC) was used to evaluate the consistency of measurements. RESULTS: The values of ADC, D, DDC, and α values were lower in tumour progression patients than that in pseudoprogression patients (p < 0.05). The values of D* and f were higher in tumour progression patients than that in pseudoprogression patients (p < 0.05). Diagnostic accuracy for differentiating tumour progression from pseudoprogression was highest for α(AUC = 0.94) than that for ADC (AUC = 0.91), D (AUC = 0.92), D* (AUC = 0.81), f (AUC = 0.75), and DDC (AUC = 0.88). CONCLUSIONS: Multi-b DWI is a promising method for differentiating tumour progression from pseudoprogression with high diagnostic accuracy. In addition, the α derived from stretched-exponential model is the most promising DWI parameter for the prediction of tumour progression in glioblastoma patients.

MicroRNA-194-3p impacts autophagy and represses rotavirus replication via targeting silent information regulator 1.

BACKGROUND: Rotavirus (RV) is the main cause of serious diarrhea in infants and young children worldwide. Numerous studies have demonstrated that RV use host cell mechanisms to motivate their own stabilization and multiplication by degrading, enhancing, or hijacking microRNAs (miRNAs). Therefore, exploring the molecular mechanisms by which miRNAs motivate or restrain RV replication by controlling different biological processes, including autophagy, will help to better understand the pathogenesis of RV development. This study mainly explored the effect of miR-194-3p on autophagy after RV infection and its underlying mechanism of the regulation of RV replication. METHODS: Caco-2 cells were infected with RV and used to measure the expression levels of miR-194-3p and silent information regulator 1 (SIRT1). After transfection with plasmids and RV infection, viral structural proteins, RV titer, cell viability, and autophagy-linked proteins were tested. The degree of acetylation of p53 was further investigated. A RV-infected neonatal mouse model was constructed in vivo and was evaluated for diarrhea symptoms and lipid droplet formation. RESULTS: The results showed that miR-194-3p was reduced but SIRT1 was elevated after RV infection. Elevation of miR-194-3p or repression of SIRT1 inhibited RV replication through the regulation of autophagy. The overexpression of SIRT1 reversed the effects of miR-194-3p on RV replication. The upregulation of miR-194-3p or the downregulation of SIRT1 repressed RV replication in vivo. MiR-194-3p targeted SIRT1 to decrease p53 acetylation. CONCLUSION: These results were used to determine the mechanism of miR-194-3p in RV replication, and identified a novel therapeutic small RNA molecule that can be used against RV.

Proteomic profiling analysis of human endometrium in women with unexplained recurrent spontaneous abortion.

Unexplained recurrent spontaneous abortion (URSA) seriously affects female reproductive health, causing a great burden to patients both physically and mentally. Endometrial decidualization plays an important role in pregnancy, and impaired decidualization is an essential cause of URSA, but the cause of the damage is still poorly understood. This study aimed to reveal the pathogenesis of URSA by analyzing the differential protein expression profiles in the decidual tissue of patients with recurrent abortion compared to those with normal pregnancy. Morphological analysis revealed abnormal decidualization of endometrial tissue in patients with URSA. Quantitative proteomics analysis showed that a total of 146 differentially expressed proteins were identified between the two groups, among which 95 proteins were downregulated and 51 proteins were upregulated. Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that the protein expression profile and signaling pathways of endometrium in patients with URSA changed significantly, and cytoskeleton remodeling and morphological transformation disorders were associated with abortion induced by incomplete decidualization. Meanwhile, transcription factors analysis showed that the 3 most affected families were zf-C2H2, MYB and HMG. Therefore, our study may provide a basis for searching for potential markers of decidualization injury. SIGNIFICANCE: At present, there are still about 50% of RSA patients with unknown causes, which brings great difficulties and blindness to clinical diagnosis and treatment.The limited proteomic studies on URSA further contribute to the lack of understanding in this field. However, in this study, the focus was on proteomic profiling analysis of the human endometrium in URSA patients compared to normal women. The findings revealed that cytoskeletal remodeling disorder is a significant contributor to the failure of decidualization in URSA patients. This insight highlights the potential role of cytoskeleton-related proteins in the pathogenesis of URSA, providing valuable information for further research and potential therapeutic interventions.

CRISPR screen identifies GATAD1 as a synthetic lethal target with CDK4/6 inhibitors in estrogen receptor-positive breast cancer.

Estrogen receptor-positive (ER+) breast cancer represents approximately two-thirds of all breast cancers and has a sustained risk of late disease recurrence. Combining cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with anti-estrogen therapies significantly improves ER+ advanced breast cancer clinical outcomes. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited their success. We used CRISPR to screen MCF-7 cells to explore the targets whose inhibition is synthetic lethal with CDK4/6 inhibitors in ER+ breast cancer cells. We found that GATA zinc finger domain containing 1 (GATAD1) is a new synthetic lethal target with CDK4/6 inhibitors in ER+ breast cancer cells. Mechanistically, GATAD1 promotes cell proliferation by transcriptionally inhibiting p21 in ER+ breast cancer cells. GATAD1 depletion decreased the phosphorylation of CDK2/4 and RB transcriptional corepressor 1 (RB1), inducing cell cycle arrest. P21 overexpression abolished the enhanced proliferation induced by GATAD1 overexpression. Our results identify GATAD1 as a therapeutic target in ER+ breast cancer, which is beneficial to provide a novel treatment strategy.

Diagnostic value of programmed cell death-ligand 1 expression on circulating tumor cells in lung cancer: A systematic review and meta-analysis.

The expression of programmed cell death-ligand 1 (PD-L1) on circulating tumor cells offers a noninvasive method for the detection of PD-L1 expression in lung cancer, and could serve as a potential surrogate for cancer tissue. However, discrepant results make it difficult to apply PD-L1 on circulating tumor cells to clinical practice. Therefore, we conducted a meta-analysis to investigate the diagnostic value of PD-L1 on circulating tumor cells in lung cancer. To identify the relationship between the expression of PD-L1 on circulating tumor cells and lung cancer, the PubMed, Web of Science, Embase, China National Knowledge Infrastructure, and Wanfang databases were searched from inception to March 2023. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the corresponding 95% confidence intervals were calculated to assess the diagnostic performance of PD-L1. We also conducted subgroup and sensitivity analyses. A total of 11 studies including 472 lung cancer patients were included in our study. The overall performance in terms of pooled sensitivity and specificity was 0.72 (0.52-0.86) and 0.54 (0.25-0.81), respectively. The positive likelihood ratio, negative likelihood ratio, and area under the curve were 1.57 (0.87-2.84), 0.52 (0.30-0.90), and 0.70 (0.66-0.74), respectively. Deeks' funnel plot test indicated no publication bias. Our analysis demonstrated that positive PD-L1 expression on circulating tumor cells (CTCs) exhibited a moderate diagnostic value in lung cancer, and CTCs may serve as a feasible alternative tissue analysis for the detection of PD-L1 in lung cancer.

Quantitative proteomic and phosphoproteomic analyses of the hippocampus reveal the involvement of NMDAR1 signaling in repetitive mild traumatic brain injury.

The cumulative damage caused by repetitive mild traumatic brain injury can cause long-term neurodegeneration leading to cognitive impairment. This cognitive impairment is thought to result specifically from damage to the hippocampus. In this study, we detected cognitive impairment in mice 6 weeks after repetitive mild traumatic brain injury using the novel object recognition test and the Morris water maze test. Immunofluorescence staining showed that p-tau expression was increased in the hippocampus after repetitive mild traumatic brain injury. Golgi staining showed a significant decrease in the total density of neuronal dendritic spines in the hippocampus, as well as in the density of mature dendritic spines. To investigate the specific molecular mechanisms underlying cognitive impairment due to hippocampal damage, we performed proteomic and phosphoproteomic analyses of the hippocampus with and without repetitive mild traumatic brain injury. The differentially expressed proteins were mainly enriched in inflammation, immunity, and coagulation, suggesting that non-neuronal cells are involved in the pathological changes that occur in the hippocampus in the chronic stage after repetitive mild traumatic brain injury. In contrast, differentially expressed phosphorylated proteins were mainly enriched in pathways related to neuronal function and structure, which is more consistent with neurodegeneration. We identified N-methyl-D-aspartate receptor 1 as a hub molecule involved in the response to repetitive mild traumatic brain injury , and western blotting showed that, while N-methyl-D-aspartate receptor 1 expression was not altered in the hippocampus after repetitive mild traumatic brain injury, its phosphorylation level was significantly increased, which is consistent with the omics results. Administration of GRP78608, an N-methyl-D-aspartate receptor 1 antagonist, to the hippocampus markedly improved repetitive mild traumatic brain injury-induced cognitive impairment. In conclusion, our findings suggest that N-methyl-D-aspartate receptor 1 signaling in the hippocampus is involved in cognitive impairment in the chronic stage after repetitive mild traumatic brain injury and may be a potential target for intervention and treatment.

Arctigenin hinders the invasion and metastasis of cervical cancer cells via the FAK/paxillin pathway.

Context: Cervical cancer is the most common gynecological pernicious tumor with high morbidity and mortality worldwide, especially in developing countries. Arctigenin (ARG), a nature-derived component, has exhibited anti-tumor activity in various tumors. Objective: To explore the effect of ARG on cervical cancer. Materials and methods: The effect and mechanism of ARG on cervical cancer cells were explored by cell counting kit-8 (CCK-8), flow cytometry, transwell and Western blot assays. Additionally, in vivo experiment was conducted in xenografted mice by immunohistochemistry (IHC), terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) and Western blot assays. Results: ARG treatment induced both concentration-dependent and time-dependent reductions in the cell viability of SiHa and HeLa cells with a IC50 value of 9.34 µM and 14.45 µM, respectively. ARG increased the apoptosis rate and the protein levels of cleaved-caspase 3 and E-cadherin, but decreased the invaded cell numbers and the protein levels of Vimentin and N-cadherin in vitro. Mechanically, ARG inhibited the expression of focal adhesion kinase (FAK)/paxillin pathway, which was confirmed by the overexpression of FAK in SiHa cells. The inhibitory role of overexpression of FAK in proliferation and invasion, as well as its promoted role in apoptosis were reversed with ARG treatment. Meanwhile, ARG suppressed growth and metastasis, and enhanced apoptosis in vivo. Consistently, ARG administration reduced the relative protein level of p-FAK/FAK and p-paxillin/paxillin in tumor tissues of xenografted mice. Conclusion: ARG inhibited proliferation, invasion and metastasis, but enhanced apoptosis of cervical cancer via the FAK/paxillin axis.