Four-year comparative analysis of return to sport and psychological recovery following ACL revision: Artificial ligament vs. anterior tibial tendon allograft.

Background: Research on return to sport and psychological recovery in anterior cruciate ligament (ACL) revision remains scarce. The clinical efficacy of artificial ligament in ACL revision requires further exploration. Our objectives were (1) to compare the midterm clinical outcomes of artificial ligament versus allogenic tendon graft in ACL revision and (2) to analyze the effects of employing artificial ligament on return to sport and psychological recovery in ACL revision. Methods: This cohort study included the cases receiving ACL revision from 2014 to 2021 in Sports Medicine Department of Huashan Hospital. The grafts used were Ligament Advanced Reinforcement System (LARS) and ATT allograft. We recorded patients' baseline data. The final follow-up assessment included subjective scales, physical examination, and return to sport status. We recorded the rates and timings of return to sport. Subjective scales included the 2000 International Knee Documentation Committee (IKDC) subjective score, Lysholm Knee Scaling Score (LKSS), Knee injury and Osteoarthritis Outcome Score (KOOS), Tegner activity score, Marx activity rating score, and Anterior Cruciate Ligament-Return to Sport after Injury (ACL-RSI). Anterior knee stability was assessed using the KT-1000 arthrometer. Results: Fifty cases (LARS group: 27; ATT group: 23) enrolled and 45 (LARS group: 23; ATT group: 22) completed evaluations with a median follow-up period of 49 months. At recent follow-up, LARS group outperformed in knee stability (1.0 ± 1.9 mm vs. 2.6 ± 3.0 mm, P = 0.039), confidence (86.7 ± 12.4 vs. 69.4 ± 18.6, P < 0.001), emotion (82.7 ± 11.3 vs. 70.7 ± 16.2, P < 0.001), KOOS knee function (78.7 ± 8.8 vs. 69.5 ± 11.0, P = 0.003), quality of life (79.1 ± 16.1 vs. 66.4 ± 19.5, P = 0.014), Tegner score (6.3 ± 1.9 vs. 5.2 ± 2.1, P < 0.001), and Marx activity score (10.7 ± 3.7 vs. 7.9 ± 4.0, P = 0.012). The LARS group had significantly higher return rates: recreational (91.3 % vs. 63.6 %, P = 0.026), knee cutting and pivoting (87.0 % vs. 59.1 %, P = 0.035), competitive (78.3 % vs. 45.5 %, P = 0.023), and pre-injury (56.5 % vs. 27.3 %, P = 0.047). For return timings, the LARS group was earlier at recreational (11.2 ± 3.9 vs. 27.8 ± 9.0 weeks, P < 0.001), knee cutting and pivoting (17.2 ± 5.8 vs. 35.6 ± 13.8 weeks, P < 0.001), competitive (24.8 ± 16.2 vs. 53.2 ± 22.0 weeks, P < 0.001), and pre-injury levels (32.8 ± 11.0 vs. 72.8 ± 16.9 weeks, P < 0.001). Conclusion: In ACL revision, using LARS demonstrated improved joint stability and functionality compared to using allogenic ATT four years postoperative. Patients accepting the LARS procedure exhibited higher rates and earlier timings of return to various levels of sport, indicating enhanced confidence and emotional resilience. The translational potential of this article: In ACL revision, the choice of artificial ligament to shorten recovery time, thereby enabling patients to return to sport more quickly and effectively, is thought-provoking. The research value extends beyond mere graft selection, guiding future clinical trials and studies. This research enhances our understanding of the application value of artificial ligament in ACL revision, emphasizing the importance of psychological recovery and updating our perceptions of return to sport levels post-revision. It stimulates exploration into personalized rehabilitation programs and treatment strategies, aiming to optimize clinical outcomes and meet the real-world needs of patients with failed ACL reconstruction.

Hydroxysafflor yellow A exerts anti-fibrotic and anti-angiogenic effects through miR-29a-3p/PDGFRB axis in liver fibrosis.

BACKGROUND: Liver fibrosis is a prevalent pathological process in chronic liver diseases characterized by excessive extracellular matrix (ECM) deposition and abnormal angiogenesis. Notably, hepatic stellate cells (HSCs) are the primary source of ECM. Activated HSCs not only secrete numerous pro-fibrotic cytokines but also are endowed with a pro-angiogenic phenotype to promote pathological angiogenesis. Therefore, targeted modulation of HSCs has emerged as a pivotal strategy for addressing liver fibrosis. Hydroxysafflor yellow A (HSYA) is a homology of medicine and food colourant with good pharmacological activity. However, the precise mechanisms of HSYA against liver fibrosis remain unclear. PURPOSE: The objective of this study was to elucidate the impact of HSYA on liver fibrosis and pathological angiogenesis, as well as the underlying mechanisms in vitro and in vivo studies. METHODS: The efficacy and mechanisms of HSYA on TGF-ß1-induced HSCs and VEGFA-induced endothelial cells were investigated by MTT assay, EdU cell proliferation assay, cell scratch assay, Elisa assay, immunofluorescence assay, molecular docking, cell transfection assay, western blot analysis and RT-qPCR analysis. In CCl4-induced liver fibrosis mice model, H&E, Masson, and Sirius red staining were used to observe histopathology. Serum transaminase activity and liver biochemical indexes were tested by biochemical kit. Immunohistochemical, fluorescence in situ hybridization (FISH), western blot analysis and RT-qPCR analysis were implemented to determine the mechanism of HSYA in vivo. RESULTS: Herein, our findings confirmed that HSYA inhibited the proliferation, migration and activation of HSCs, as evidenced by a reduction in cell viability, relative migration rate, EdU staining intensity, and pro-fibrotic mRNAs and proteins expression in vitro. Mechanistically, HSYA played an anti-fibrotic and anti-angiogenic role by partially silencing PDGFRB in activated HSCs, thereby disrupting PDGFRB/MEK/ERK signal transduction and inhibiting the expression of HIF-1α, VEGFA and VEGFR2 proteins. Importantly, PDGFRB was a target gene of miR-29a-3p. Treatment with HSYA reversed the down-regulation of miR-29a-3p and antagonized PDGFRB signaling pathway in TGF-ß1-induced HSCs transfected with miR-29a-3p inhibitor. Consistent with our in vitro study, HSYA exhibited a good hepatoprotective effect in CCl4-induced liver fibrosis mice by reducing serum ALT and AST levels, decreasing the contents of four fibrosis indicators (HA, PIIIP, ColIV and LN) and hydroxyproline, and inhibiting the TGF-ß1/TGFBR signaling pathway. In terms of mechanisms, HSYA alleviated pathological angiogenesis in fibrotic liver by deactivating PDGFRB signaling pathway and impairing the positive expression of CD31. Subsequently, FISH results further corroborated HSYA affected the activation of HSCs and angiogenesis achieved by the concurrent upregulation of miR-29a-3p and downregulation of α-SMA and VEGFA. Additionally, treatment with HSYA also forged a link between HSCs and endothelial cells, as supported by inhibiting the aberrant proliferation of endothelial cells. CONCLUSION: Fundamentally, the current study has illustrated that HSYA ameliorates liver fibrosis by repressing HSCs-mediated pro-fibrotic and pro-angiogenic processes, which is contingent upon the regulatory effect of HSYA on the miR-29a-3p/PDGFRB axis. These findings provide compelling evidence bolstering the potential of HSYA as a therapeutic agent in liver fibrosis.

Hinesol attenuates DSS-induced ulcerative colitis through the suppression of Src-mediated NF-κB and chemokine signaling pathway.

As a common inflammatory bowel disease, ulcerative colitis (UC) is featured with inflammation, oxidative damage, and the impairment of intestinal mucosal barrier, which bring threat to patients' quality of live. Hinesol, derived from Atractylodes lancea, is a unique sesquiterpenoid. Our study proposed to survey the effects and mechanism of hinesol in UC. UC mouse model was constructed using dextran sulfate sodium (DSS). Lipopolysaccharide (LPS) was applied for RAW264.7 cells stimulation to construct cell inflammatory model. The changes of disease activity index (DAI), body weight, colon length, and intestinal pathology in mice were analyzed to estimate the severity of colitis. Enzyme-linked immunosorbent assay was applied to check the changes of interleukin (IL)-1ß, IL-18, IL-6, and tumor necrosis factor (TNF)-α. The levels of myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione peroxidase (GSH-px), catalase (CAT), and malondialdehyde (MDA) were estimated by corresponding reagent kit. The changes of phosphorylated (p)-NF-κB P65, and p-IκBα, ZO-1, Occludin, Claudin-1, Src, XCL1, CCL2, and CXCL16 protein were examined using western blot. Flow cytometry and cell counting kit-8 assay were utilized for assessment of cell apoptosis and viability. We found that DSS reduced mice body weight, increased DAI, shorten colon length, and led to severe enteric mucosal injury, while hinesol improved the above symptoms induced by DSS. In DSS mice, hinesol raised the levels of ZO-1, Occludin, Claudin-1, SOD, GSH-px, and CAT and decreased the levels of TNF-α, IL-18, IL-1ß, IL-6, MPO, and MDA. Additionally, in DSS mice and LPS-stimulated RAW264.7 cells, hinesol inhibited the high expression of Src, XCL1, CCL2, CXCL16, p-NF-κB P65, and p-IκBα. The molecular docking showed that there was a good interaction between hinesol and Src. Moreover, in LPS-stimulated RAW 264.7 cells, Src overexpression partially reversed the inhibition of hinesol on cell apoptosis, pro-inflammatory factors, and oxidative stress. In conclusion, hinesol alleviated DSS-induced colitis, which might have a bearing on the inhibition of Src-mediated NF-κB and chemokine signaling pathway.

Effects of BBIBP-CorV vaccine on gut microbiota and short-chain fatty acids in mice exposed to bis (2-ethylhexyl) phthalate and dioctyl terephthalate.

As the COVID-19 pandemic has progressed, increasing evidences suggest that the gut microbiota may play a crucial role in the effectiveness of SARS-CoV-2 vaccine. Thus, this study was aimed at investigating the influence of SARS-CoV-2 vaccine on the gut microbiota and short-chain fatty acids (SCFAs) of organisms exposed to environmental contaminants, i.e., plasticizers: phthalate esters. We found that in mice, exposure to dioctyl terephthalate (DOTP) and bis -2-ethylhexyl phthalate (DEHP) decreased the blood glucose level and white fat weight, induced inflammatory responses, caused damage to liver and intestinal tissues, and disrupted the gut microbiota composition and SCFAs metabolism. Specifically, the Bacteroidetes phylum was positively correlated with BBIBP-CorV vaccine, while acetic acid was negatively associated with the vaccine. Interestingly, the BBIBP-CorV vaccine somewhat alleviated tissue inflammation and reduced the contents of acetic acid and propionic acid in mice exposed to DEHP and DOTP. These findings were confirmed by a fecal microbiota transplantation assay. Overall, this study revealed that exposure to DEHP and DOTP adversely affects the gut microbiota and SCFAs, while the BBIBP-CorV vaccine can protect mice against these effects. This work highlighted the relationship between BBIBP-CorV vaccination, gut microbiome composition, and responses to plasticizers, which may facilitate the development and risk assessment of SARS-CoV-2 vaccines and environmental contaminants on microbiota health.

Corrigendum: Effects of essential oil extracted from Artemisia argyi leaf on lipid metabolism and gut microbiota in high-fat diet-fed mice.

[This corrects the article DOI: 10.3389/fnut.2022.1024722.].

MicroRNA and Gut Microbiota Alter Intergenerational Effects of Paternal Exposure to Polyethylene Nanoplastics.

Nanoplastics (NPs), as emerging contaminants, have been shown to cause testicular disorders in mammals. However, whether paternal inheritance effects on offspring health are involved in NP-induced reproductive toxicity remains unclear. In this study, we developed a mouse model where male mice were administered 200 nm polyethylene nanoparticles (PE-NPs) at a concentration of 2 mg/L through daily gavage for 35 days to evaluate the intergenerational effects of PE-NPs in an exclusive male-lineage transmission paradigm. We observed that paternal exposure to PE-NPs significantly affected growth phenotypes and sex hormone levels and induced histological damage in the testicular tissue of both F0 and F1 generations. In addition, consistent changes in sperm count, motility, abnormalities, and gene expression related to endoplasmic reticulum stress, sex hormone synthesis, and spermatogenesis were observed across paternal generations. The upregulation of microRNA (miR)-1983 and the downregulation of miR-122-5p, miR-5100, and miR-6240 were observed in both F0 and F1 mice, which may have been influenced by reproductive signaling pathways, as indicated by the RNA sequencing of testis tissues and quantitative real-time polymerase chain reaction findings. Furthermore, alterations in the gut microbiota and subsequent Spearman correlation analysis revealed that an increased abundance of Desulfovibrio (C21_c20) and Ruminococcus (gnavus) and a decreased abundance of Allobaculum were positively associated with spermatogenic dysfunction. These findings were validated in a fecal microbiota transplantation trial. Our results demonstrate that changes in miRNAs and the gut microbiota caused by paternal exposure to PE-NPs mediated intergenerational effects, providing deeper insights into mechanisms underlying the impact of paternal inheritance.

Exploring the Anticancer Properties of Sakuranin Flavanone in Human Oropharyngeal Squamous Carcinoma Cells by Studying Its Effects on Caspase-driven Apoptosis, Mitochondrial Membrane Potential (MMP) Loss, Cell Migratory and Invasiveness and m-TOR/PI3K/AKT Signalling Pathway.

Sakuranin is a flavanone which is a class of flavonoids found abundantly in Prunus species. Flavonoids have been long known for their anticancer properties against a range of human cancers. However, there are no previous reports on the anticancer effects of sakuranin flavanone molecule. This study was designed to study the anticancer effects of sakuranin against human oropharyngeal carcinoma cells along with investigating its effects on caspase-mediated apoptosis, mitochondrial membrane potential (MMP) loss, cell migration and invasion and m-TOR/PI3K/AKT signalling pathway. MTT assay was used to study effects on cell viability. The apoptotic studies were carried out through AO/EB staining, annexin V/FITC staining, comet assay and western blotting assay. Transwell chambers assay was used to study effects on cell migration and invasion. Flow cytometry was used to study effects of Sakuranin on mitochondrial membrane potential loss (MMP). Finally, western blotting was used to investigate m-TOR/PI3K/AKT signalling pathway. Results indicated that Sakuranin led to potent cell proliferation inhibition in a dose-dependent manner. Sakuranin also induced apoptotic cell death as indicated by fluorescence microscopy and annexin V/FITC staining assays. The apoptotic induction was mediated via activation of caspase-3, caspase-9, and Bax while as it led to downregulation of Bcl-2. Sakuranin also caused inhibition of cell migration and cell invasion along with causing significant decrease in MMP. Sakuranin also caused inhibition of expressions of proteins related with m-TOR/PI3K/AKT signalling pathway. In conclusion, the current findings clearly indicate anticancer effects of Sakuranin flavanone in human oropharyngeal cancer cells and are mediated via caspase activated apoptosis, inhibition of cell migration and invasion, loss of mitochondrial membrane potential and targeting m-TOR/PI3K/AKT signalling pathway.

Kaempferol efficacy in metabolic diseases: Molecular mechanisms of action in diabetes mellitus, obesity, non-alcoholic fatty liver disease, steatohepatitis, and atherosclerosis.

The incidence of metabolic diseases has progressively increased, which has a negative impact on human health and life safety globally. Due to the good efficacy and limited side effects, there is growing interest in developing effective drugs to treat metabolic diseases from natural compounds. Kaempferol (KMP), an important flavonoid, exists in many vegetables, fruits, and traditional medicinal plants. Recently, KMP has received widespread attention worldwide due to its good potential in the treatment of metabolic diseases. To promote the basic research and clinical application of KMP, this review provides a timely and comprehensive summary of the pharmacological advances of KMP in the treatment of four metabolic diseases and its potential molecular mechanisms of action, including diabetes mellitus, obesity, non-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), and atherosclerosis. According to the research, KMP shows remarkable therapeutic effects on metabolic diseases by regulating multiple signaling transduction pathways such as NF-κB, Nrf2, AMPK, PI3K/AKT, TLR4, and ER stress. In addition, the most recent literature on KMP's natural source, pharmacokinetics studies, as well as toxicity and safety are also discussed in this review, thus providing a foundation and evidence for further studies to develop novel and effective drugs from natural compounds. Collectively, our manuscript strongly suggested that KMP could be a promising candidate for the treatment of metabolic diseases.

A Modified Frailty Phenotype Used for Identifying Frailty in Health Care Practice: Validation Among Chinese Older Adults.

OBJECTIVES: The study aimed to evaluate a simplified and practical frailty detection tool derived from the Fried frailty phenotype (FFP). This tool was developed to facilitate the identification of frail individuals in constrained settings, addressing the challenges posed by uncertain cutoffs of FFP indicators in prompt frailty assessment. DESIGN: A longitudinal study and a cross-sectional study. SETTINGS AND PARTICIPANTS: A total of 1978 older adults aged 67.4 ± 6.16 years from the China Health and Retirement Longitudinal Study (CHARLS), and 972 older adults aged 72.8 ± 6.75 years from a pilot cross-sectional study conducted in Shanghai communities. METHODS: Frailty was assessed according to the FFP criterion. A Chinese modified frailty phenotype (CMFP) was developed, incorporating specific cutoffs for grip strength and an alternative test for walk speed. The internal consistency reliability, the criterion, and predictive validity of the CMFP were evaluated. RESULTS: The 5-time chair stand test (5t-CST) was significantly associated with the 2.5-m walk test (r = 0.373 in the CHARLS and 0.423 in the pilot study). Each element of the CMFP showed moderate to strong correlations with the total CMFP score and showed Cronbach's alpha of 0.303 and 0.358 in both populations. The Spearman's r and kappa values between the CMFP and the FFP were 0.795 and 0.663 in the CHARLS, and 0.676 and 0.537 in the pilot study. The areas under the curve (AUC) were 0.936 and 0.928 in the 2 studies, respectively. In addition, frailty assessed by the CMFP significantly predicted future incidence of outcomes, including all-cause mortality, activities of daily living (ADL)/instrumental ADL disability, hospitalization, and depression. CONCLUSIONS AND IMPLICATIONS: The study demonstrated the CMFP as a valid tool, particularly highlighting its excellent predictive ability on outcomes. The 5t-CST may act as a viable alternative test for assessing slowness. The CMFP can be systematically integrated into preclinical practice to identify frail individuals, especially within constrained spaces.

A comprehensive review of miR-21 in liver disease: Big impact of little things.

microRNAs (miRNAs), a class of non-coding RNA with 20-24 nucleotides, are defined as the powerful regulators for gene expression. miR-21 is a multifunctional miRNA enriched in the circulatory system and multiple organs, which not only serves as a non-invasive biomarker in disease diagnosis, but also participates in many cellular activities. In various chronic liver diseases, the increase of miR-21 affects glycolipid metabolism, viral infection, inflammatory and immune cell activation, hepatic stellate cells activation and tissue fibrosis, and autophagy. Moreover, miR-21 is also a liaison in the deterioration of chronic liver disease to hepatocellular carcinoma (HCC), and it impacts on cell proliferation, apoptosis, migration, invasion, angiogenesis, immune escape, and epithelial-mesenchymal transformation by regulating target genes expression in different signaling pathways. In current research on miRNA therapy, some natural products can exert the hepatoprotective effects depending on the inhibition of miR-21 expression. In addition, miR-21-based therapeutic also play a role in regulating intracellular miR-21 levels and enhancing the efficacy of chemotherapy drugs. Herein, we systemically summarized the recent progress of miR-21 on biosynthesis, biomarker function, molecular mechanism and miRNA therapy in chronic liver disease and HCC, and looked forward to outputting some information to enable it from bench to bedside.

S2VQ-VAE: Semi-Supervised Vector Quantised-Variational AutoEncoder for Automatic Evaluation of Trail Making Test.

BACKGROUND: Computer-aided detection of cognitive impairment garnered increasing attention, offering older adults in the community access to more objective, ecologically valid, and convenient cognitive assessments using multimodal sensing technology on digital devices. METHODOLOGY: In this study, we aimed to develop an automated method for screening cognitive impairment, building on paper- and electronic TMTs. We proposed a novel deep representation learning approach named Semi-Supervised Vector Quantised-Variational AutoEncoder (S2VQ-VAE). Within S2VQ-VAE, we incorporated intra- and inter-class correlation losses to disentangle class-related factors. These factors were then combined with various real-time obtainable features (including demographic, time-related, pressure-related, and jerk-related features) to create a robust feature engineering block. Finally, we identified the light gradient boosting machine as the optimal classifier. The experiments were conducted on a dataset collected from older adults in the community. RESULTS: The experimental results showed that the proposed multi-type feature fusion method outperformed the conventional method used in paper-based TMTs and the existing VAE-based feature extraction in terms of screening performance. CONCLUSIONS: In conclusion, the proposed deep representation learning method significantly enhances the cognitive diagnosis capabilities of behavior-based TMTs and streamlines large-scale community-based cognitive impairment screening while reducing the workload of professional healthcare staff.

Effect of traditional Chinese medicine on metabolism disturbance in ischemic heart diseases.

ETHNOPHARMACOLOGICAL RELEVANCE: Ischemic heart diseases (IHD), characterized by metabolic dysregulation, contributes majorly to the global morbidity and mortality. Glucose, lipid and amino acid metabolism are critical energy production for cardiomyocytes, and disturbances of these metabolism lead to the cardiac injury. Traditional Chinese medicine (TCM), widely used for treating IHD, have been demonstrated to effectively and safely regulate the cardiac metabolism reprogramming. AIM OF THE REVIEW: This study discussed and analyzed the disturbed cardiac metabolism induced by IHD and development of formulas, extracts, single herb, bioactive compounds of TCM ameliorating IHD injury via metabolism regulation, with the aim of providing a basis for the development of clinical application of therapeutic strategies for TCM in IHD. MATERIALS AND METHODS: With "ischemic heart disease", "myocardial infarction", "myocardial ischemia", "metabolomics", "Chinese medicine", "herb", "extracts" "medicinal plants", "glucose", "lipid metabolism", "amino acid" as the main keywords, PubMed, Web of Science, and other online search engines were used for literature retrieval. RESULTS: IHD exhibits a close association with metabolism disorders, including but not limited to glycolysis, the TCA cycle, oxidative phosphorylation, branched-chain amino acids, fatty acid ß-oxidation, ketone body metabolism, sphingolipid and glycerol-phospholipid metabolism. The therapeutic potential of TCM lies in its ability to regulate these disturbed cardiac metabolisms. Additionally, the active ingredients of TCM have depicted wonderful effects in cardiac metabolism reprogramming in IHD. CONCLUSION: Drawing from the principles of TCM, we have pinpointed specific herbal remedies for the treatment of IHD, and leveraged advanced metabolomics technologies to uncover the effect of these TCMs on metabolomics alteration. In the future, further clinical experimental studies should be included to explore whether more TCM medicines can play a therapeutic role in IHD by reversing cardiac metabolism disorders; multi-omics would be conducted to explore more pathways and genes targeting such metabolism reprogramming by TCMs, and to seek more TCM therapies for IHD.

Precise prediction of cerebrospinal fluid amyloid beta protein for early Alzheimer's disease detection using multimodal data.

Alzheimer's disease (AD) constitutes a neurodegenerative disorder marked by a progressive decline in cognitive function and memory capacity. The accurate diagnosis of this condition predominantly relies on cerebrospinal fluid (CSF) markers, notwithstanding the associated burdens of pain and substantial financial costs endured by patients. This study encompasses subjects exhibiting varying degrees of cognitive impairment, encompassing individuals with subjective cognitive decline, mild cognitive impairment, and dementia, constituting a total sample size of 82 participants. The primary objective of this investigation is to explore the relationships among brain atrophy measurements derived from magnetic resonance imaging, atypical electroencephalography (EEG) patterns, behavioral assessment scales, and amyloid ß-protein (Aß) indicators. The findings of this research reveal that individuals displaying reduced Aß1-42/Aß-40 levels exhibit significant atrophy in the frontotemporal lobe, alongside irregularities in various parameters related to EEG frequency characteristics, signal complexity, inter-regional information exchange, and microstates. The study additionally endeavors to estimate Aß1-42/Aß-40 content through the application of a random forest algorithm, amalgamating structural data, electrophysiological features, and clinical scales, achieving a remarkable predictive precision of 91.6%. In summary, this study proposes a cost-effective methodology for acquiring CSF markers, thereby offering a valuable tool for the early detection of AD.

Association between programmed cell death ligand-1 expression in patients with cervical cancer and apparent diffusion coefficient values: a promising tool for patient´s immunotherapy selection.

OBJECTIVE: To investigate the associations between apparent diffusion coefficient (ADC) values extracted from three different region of interest (ROI) position approaches and programmed cell death ligand-1 (PD-L1) expression, and evaluate the performance of the nomogram established based on ADC values and clinicopathological parameters in predicting PD-L1 expression in cervical cancer (CC) patients. METHODS: Through retrospective recruitment, a training cohort of 683 CC patients was created, and a validation cohort of 332 CC patients was prospectively recruited. ROIs were delineated using three different methods to measure the mean ADC (ADCmean), single-section ADC (ADCss), and the minimum ADC of tumors (ADCmin). Logistic regression was employed to identify independent factors related to PD-L1 expression. A nomogram was drawn based on ADC values combined with clinicopathological features, its discrimination and calibration performances were estimated using the area under the curve (AUC) of receiver operating characteristic and calibration curve. The clinical benefits were evaluated by decision curve analysis. RESULTS: The ADCmin independently correlated with PD-L1 expression. The nomogram constructed with ADCmin and other independent clinicopathological-related factors: FIGO staging, pathological grade, parametrial invasion, and lymph node status demonstrated excellent diagnostic performance (AUC = 0.912 and 0.903, respectively), good calibration capacities, and greater net benefits compared to the clinicopathological model in both the training and validation cohorts. CONCLUSION: ADCmin independently correlated PD-L1 expression, and the nomogram established with ADCmin and clinicopathological independent prognostic factors had a strong predictive performance for PD-L1 expression, thereby serving as a promising tool for selecting cases eligible for immunotherapy. CLINICAL RELEVANCE STATEMENT: The minimum ADC can serve as a reliable imaging biomarker related to PD-L1 expression; the established nomogram combines the minimum ADC and clinicopathological factors that can assist clinical immunotherapy decisions.

A novel spatiotemporal graph convolutional network framework for functional connectivity biomarkers identification of Alzheimer's disease.

BACKGROUND: Functional connectivity (FC) biomarkers play a crucial role in the early diagnosis and mechanistic study of Alzheimer's disease (AD). However, the identification of effective FC biomarkers remains challenging. In this study, we introduce a novel approach, the spatiotemporal graph convolutional network (ST-GCN) combined with the gradient-based class activation mapping (Grad-CAM) model (STGC-GCAM), to effectively identify FC biomarkers for AD. METHODS: This multi-center cross-racial retrospective study involved 2,272 participants, including 1,105 cognitively normal (CN) subjects, 790 mild cognitive impairment (MCI) individuals, and 377 AD patients. All participants underwent functional magnetic resonance imaging (fMRI) and T1-weighted MRI scans. In this study, firstly, we optimized the STGC-GCAM model to enhance classification accuracy. Secondly, we identified novel AD-associated biomarkers using the optimized model. Thirdly, we validated the imaging biomarkers using Kaplan-Meier analysis. Lastly, we performed correlation analysis and causal mediation analysis to confirm the physiological significance of the identified biomarkers. RESULTS: The STGC-GCAM model demonstrated great classification performance (The average area under the curve (AUC) values for different categories were: CN vs MCI = 0.98, CN vs AD = 0.95, MCI vs AD = 0.96, stable MCI vs progressive MCI = 0.79). Notably, the model identified specific brain regions, including the sensorimotor network (SMN), visual network (VN), and default mode network (DMN), as key differentiators between patients and CN individuals. These brain regions exhibited significant associations with the severity of cognitive impairment (p < 0.05). Moreover, the topological features of important brain regions demonstrated excellent predictive capability for the conversion from MCI to AD (Hazard ratio = 3.885, p < 0.001). Additionally, our findings revealed that the topological features of these brain regions mediated the impact of amyloid beta (Aß) deposition (bootstrapped average causal mediation effect: ß = -0.01 [-0.025, 0.00], p < 0.001) and brain glucose metabolism (bootstrapped average causal mediation effect: ß = -0.02 [-0.04, -0.001], p < 0.001) on cognitive status. CONCLUSIONS: This study presents the STGC-GCAM framework, which identifies FC biomarkers using a large multi-site fMRI dataset.

Human umbilical cord mesenchymal stem cells reverse depression in rats induced by chronic unpredictable mild stress combined with lipopolysaccharide.

BACKGROUND: Inflammation and oxidative stress are considered crucial to the pathogenesis of depression. Rat models of depression can be created by combined treatments of chronic unpredictable mild stress (CUMS) and lipopolysaccharide (LPS). Behaviors associated with depression could be improved by treatment with mesenchymal stem cells (MSCs) owing to immunomodulatory functions of the cells. Therapeutic potentials of the MSCs to reverse pro-inflammatory cytokines, proteins, and metabolites were identified by transcriptomic, proteomic, and metabolomic analysis, respectively. METHODS: A depression model was established in male SD rats by 2 weeks of CUMS combined with LPS. The models were verified by behavioral tests, namely SPT, OFT, EPM, and qRT-PCR for pro-inflammatory cytokines. Such depressed rats were administered human umbilical cord MSCs (hUC-MSCs) via the tail vein once a week for 2 and 4 weeks. The homing capacity was confirmed by detection of the fluorescent dye on day 7 after the hUC-MSCs were labeled with CM-Dil and administered. The expression of GFAP in astrocytes serves as a biomarker of CNS disorders and IBA1 in microglia serves as a marker of microglia activation were detected by immunohistochemistry at 2 and 4 weeks after final administration of hUC-MSCs. At the same time, transcriptomics of rat hippocampal tissue, proteomic and metabolomic analysis of the serum from the normal, depressed, and treated rats were also compared. RESULTS: Reliable models of rat depression were successfully induced by treatments of CUMS combined with LPS. Rat depression behaviors, pro-inflammatory cytokines, and morphological disorders of the hippocampus associated with depression were reversed in 4 weeks by hUC-MSC treatment. hUC-MSCs could reach the hippocampus CA1 region through the blood circulation on day 7 after administration owing to the disruption of blood brain barrier (BBB) by microglial activation from depression. Differentiations of whole-genome expression, protein, and metabolite profiles between the normal and depression-modeled rats, which were analyzed by transcriptomic, proteomics, and metabolomics, further verified the high association with depression behaviors. CONCLUSIONS: Rat depression can be reversed or recovered by treatment with hUC-MSCs.

The trend of AIDS in China: A prediction and comparative analysis with G20 countries based on the Global Burden of Disease Study 2019.

Background: In China, AIDS has become the most severe notifiable infectious disease. The study aimed to analyse and predict the trend of AIDS in China and compared with Group of Twenty (G20) countries. Methods: We utilised incidence, mortality or disability-adjusted life years (DALY), age-standardised rates (ASR), average annual percentage changes (AAPC) to estimate the trend via GBD 2019. The Joinpoint regression analysis was applied to identify the most significant years of change. We explored the relationship between AAPC and social development index (SDI) or health care access and quality (HAQ), and predicted trends for the next 20 years. Results: The DALY in G20 increase of 340.42%, and 794.50% in China. The age-standardised DALY rate (ASDR) in G20 was 309.49 (95% uncertainty interval (UI) = 284.69, 350.58) in 2019, with an AAPC of 4.30. Among G20, the United States had the highest DALY in 1990, but it experienced a significant decline. In China, the ASDR was 98.15 (95% UI = 78.78, 119.58) with the 5th AAPC ranking. In term of gender, the incidence, mortality, DALY, and ASR of them in China and G20 were all higher in males. Furthermore, the gender gap in China had been widening. The most significant periods of ASDR increase in China were 1990-1995 and 2013-2016, and 1990-1994 in G20. The prediction for DALY indicated that high SDI countries were expected to exhibit a stable or declining trend, while low SDI countries showed an upward trend. China demonstrated a 57.66% increase in 2040 compared to 2019. Conclusions: AIDS continues to be a significant burden. In China, the ASIR exhibited a decline trend in certain age groups, while the ASMR and ASDR continued to increase, with a widening gender disparity. In addition, according to our predict results, some countries could not achieve the 2030 Agenda for Sustainable Development set by the UNAIDS. Therefore, it is necessary to establish more effective and targeted measures, as well as actively explore new treatment approaches.

Insights into drought stress response mechanism of tobacco during seed germination by integrated analysis of transcriptome and metabolome.

Drought stress inhibits seed germination, plant growth and development of tobacco, and seriously affects the yield and quality of tobacco leaves. However, the molecular mechanism underlying tobacco drought stress response remains largely unknown. In this study, integrated analysis of transcriptome and metabolome was performed on the germinated seeds of a cultivated variety K326 and its EMS mutagenic mutant M28 with great drought tolerance. The result showed that drought stress inhibited seed germination of the both varieties, while the germination rate of M28 was faster than that of K326 under drought stress. Besides, the levels of phytohormone ABA, GA19, and zeatin were increased by drought stress in M28. Five vital pathways were identified through integrated transcriptomic and metabolomic analysis, including zeatin biosynthesis, aspartate and glutamate synthesis, phenylamine metabolism, glutathione metabolism, and phenylpropanoid synthesis. Furthermore, 20 key metabolites in the above pathways were selected for further analysis of gene modular-trait relationship, and then four highly correlated modules were found. Then analysis of gene expression network was carried out of Top30 hub gene of these four modules, and 9 key candidate genes were identified, including HSP70s, XTH16s, APX, PHI-1, 14-3-3, SCP, PPO. In conclusion, our study uncovered some key drought-responsive pathways and genes of tobacco during seeds germination, providing new insights into the regulatory mechanisms of tobacco drought stress response.

Integration of pharmacodynamics and metabolomics to reveal rhubarb anthraquinone protection against nonalcoholic fatty liver disease rat model.

OBJECTIVES: The objective of the present study was to investigate the effect of Rhubarb anthraquinone (RA) on a high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) rat model, and explore potential biomarker and metabolic pathways by using the metabolomics method. MATERIALS AND METHODS: We established HFD rats as the NAFLD model. Forty Sprague-Dawley rats were randomly divided into a control group, model group, RA low-dose group, RA medium-dose group, and RA high-dose group, and evaluated the protective effect of RA on NAFLD by detecting biochemical indicators of serum and pathological changes of liver tissue. Investigating potential biomarkers and metabolic pathways connected with RA's protective effects against NAFLD by UHPLC-Q-TOF-MS untargeted metabolomics. RESULTS: The results showed that RA significantly reversed the increase of TG, TC, ALT, AST, and ALP (P < .05), the decrease of HDL-C (P < .05), and alleviated pathological conditions in NAFLD rats. Based on potential biomarker analysis, RA affected metabolic pathways such as fatty acids biosynthesis, bile acids biosynthesis, and pentose phosphate pathway, delaying the progression of NAFLD. CONCLUSION: RA improved blood lipid levels, liver function, and pathological conditions of NAFLD rats. Meanwhile, affected the metabolic pathways and regulated the synthesis of fatty acids and bile acids in NAFLD rats.

Phillygenin Inhibits TGF-ß1-induced Hepatic Stellate Cell Activation and Inflammation: Regulation of the Bax/Bcl-2 and Wnt/ß-catenin Pathways.

Hepatic fibrosis (HF), a precursor to cirrhosis and hepatocellular carcinoma, is caused by abnormal proliferation of connective tissue and excessive accumulation of extracellular matrix in the liver. Notably, activation of hepatic stellate cells (HSCs) is a key link in the development of HF. Phillygenin (PHI, C21H24O6) is a lignan component extracted from the traditional Chinese medicine Forsythiae Fructus, which has various pharmacological activities such as anti-inflammatory, antioxidant and anti-tumour effects. However, whether PHI can directly inhibit HSC activation and ameliorate the mechanism of action of HF has not been fully elucidated. Therefore, the aim of the present study was to investigate the in vitro anti-HF effects of PHI and the underlying molecular mechanisms. Transforming growth factor-ß1 (TGF-ß1)-activated mouse HSCs (mHSCs) and human HSCs (LX-2 cells) were used as an in vitro model of HF and treated with different concentrations of PHI for 24 h. Subsequently, cell morphological changes were observed under the microscope, cell viability was analyzed by MTT assay, cell cycle and apoptosis were detected by flow cytometry, and the mechanism of anti-fibrotic effect of PHI was explored by immunofluorescence, ELISA, RT-qPCR and western blot. The results showed that PHI suppressed the proliferation of TGF-ß1-activated mHSCs and LX-2 cells, arrested the cell cycle at the G0/G1 phase, decreased the levels of α-SMA, Collagen I, TIMP1 and MMP2 genes and proteins, and promoted apoptosis in activated mHSCs and LX-2 cells. Besides, PHI reduced the expression of inflammatory factors in activated mHSCs and LX-2 cells, suggesting a potential anti-inflammatory effect. Mechanically, PHI inhibited TGF-ß1-induced HSC activation and inflammation, at least in part through modulation of the Bax/Bcl-2 and Wnt/ß-catenin pathways. Overall, PHI has significant anti-HF effects and may be a promising agent for the treatment of HF.