[Research progress of traditional Chinese medicine in regulating autophagy for intervening in diabetic cardiomyopathy].

Diabetic cardiomyopathy(DCM) is a chronic complication of diabetes mellitus that leads to cardiac damage in the later stages of the disease, and its pathogenesis is complex, involving metabolic disorders brought about by a variety of aberrant alterations such as endoplasmic reticulum stress, oxidative stress, inflammation, and apoptosis, defects in cardiomyocyte Ca~(2+) transporter, and myocardial fibrosis. Currently, there is a lack of specific diagnosis and treatment in the clinic. Autophagy is a highly conserved scavenging mechanism that removes proteins, damaged organelles or foreign contaminants and converts them into energy and amino acids to maintain the stability of the intracellular environment. Inhibition of autophagy can cause harmful metabolites to accumulate in the cell, while over-activation of autophagy can disrupt normal cellular structures and cause cell death. Prolonged high glucose levels disrupt cardiomyocyte autophagy levels and exacerbate the development of DCM. The protective or detrimental effects of autophagy on cells ring true with the traditional Chinese medicine theory of healthy Qi and pathogenic Qi. Autophagy in the physiological state of the removal of intracellular substances and the generation of substances beneficial to the survival of cells is the inhibition of pathogenic Qi to help the performance of healthy Qi, so the organism is healthy. In the early stages of the disease, when autophagy is impaired and incapable of removing waste substances, pathogenic Qi is prevalent; In the later stages of the disease, excessive activation of autophagy can destroy normal cells, leading to a weakening of healthy Qi. Traditional Chinese medicine has the advantage of targeting multiple sites and pathways. Studies in recent years have confirmed that traditional Chinese medicine monomers or formulas can target autophagy, promote the restoration of autophagy levels, maintain mitochondrial and endoplasmic reticulum homeostasis, and reduce oxidative stress, endoplasmic reticulum stress, inflammation, and apoptosis in order to prevent and control DCM. This study provides a review of the relationship between autophagy and DCM and the intervention of traditional Chinese medicine in autophagy for the treatment of DCM, with a view to providing new clinical ideas and methods for the treatment of DCM with traditional Chinese medicine.

MR Assessment of Acute Changes of Cerebral Perfusion, Metabolism, and Blood-Brain Barrier Permeability in Response to Aerobic Exercise.

BACKGROUND: It remains unclear how a single bout of exercise affects brain perfusion, oxygen metabolism, and blood-brain barrier (BBB) permeability. Addressing this unresolved issue is essential to understand the acute changes in cerebral physiology induced by aerobic exercise. PURPOSE: To dynamically monitor the acute changes in cerebral physiology subsequent to a single aerobic exercise training session using noninvasive MRI measurements. STUDY TYPE: Prospective. POPULATION: Twenty-three healthy participants (18-35 years, 10 females/13 males) were enrolled and divided into 10-minute exercising (N = 10) and 20-minute exercising (N = 13) groups. FIELD STRENGTH/SEQUENCE: 3.0 T/Phase Contrast (PC) MRI (gradient echo), T2-Relaxation-Under-Spin-Tagging (TRUST) MRI (gradient echo EPI), Water-Extraction-with-Phase-Contrast-Arterial-Spin-Tagging (WEPCAST) MRI (gradient echo EPI) and T1-weighted magnetization-prepared-rapid-acquisition-of-gradient-echo (MPRAGE) (gradient echo). ASSESSMENT: A baseline MR measurement plus four repeated MR measurements immediately after 10 or 20 minutes moderate running exercise. MR measurements included cerebral blood flow (CBF) as measured by PC MRI, venous oxygenation (Yv) and cerebral metabolic rate of oxygen (CMRO2) as assessed by TRUST MRI, water extraction fraction (E), and BBB permeability-surface-area product (PS) as determined by WEPCAST MRI. STATISTICAL TESTS: The time dependence of the physiological parameters was studied with a linear mixed-effect model. Additionally, pairwise t-tests comparison of the physiological parameters at each time point was conducted. A P-value of <0.05 was considered statistically significant. RESULTS: There was an initial drop (8.22 ± 2.60%) followed by a recovery in CBF after exercise, while Yv revealed a significant decrease (6.37 ± 0.92%), i.e., an increased oxygen extraction, and returned to baseline at later time points. CMRO2 showed a trend of increase (5.68 ± 3.04%) and a significant interaction between time and group. In addition, E increased significantly (3.86% ± 0.89) and returned to baseline level at later time points, while PS remained elevated (13.33 ± 4.79%). DATA CONCLUSION: A single bout of moderate aerobic exercise can induce acute alterations in cerebral perfusion, metabolism, and BBB permeability. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Machine learning-based prediction model for the efficacy and safety of statins.

Objective: The appropriate use of statins plays a vital role in reducing the risk of atherosclerotic cardiovascular disease (ASCVD). However, due to changes in diet and lifestyle, there has been a significant increase in the number of individuals with high cholesterol levels. Therefore, it is crucial to ensure the rational use of statins. Adverse reactions associated with statins, including liver enzyme abnormalities and statin-associated muscle symptoms (SAMS), have impacted their widespread utilization. In this study, we aimed to develop a predictive model for statin efficacy and safety based on real-world clinical data using machine learning techniques. Methods: We employed various data preprocessing techniques, such as improved random forest imputation and Borderline SMOTE oversampling, to handle the dataset. Boruta method was utilized for feature selection, and the dataset was divided into training and testing sets in a 7:3 ratio. Five algorithms, including logistic regression, naive Bayes, decision tree, random forest, and gradient boosting decision tree, were used to construct the predictive models. Ten-fold cross-validation and bootstrapping sampling were performed for internal and external validation. Additionally, SHAP (SHapley Additive exPlanations) was employed for feature interpretability. Ultimately, an accessible web-based platform for predicting statin efficacy and safety was established based on the optimal predictive model. Results: The random forest algorithm exhibited the best performance among the five algorithms. The predictive models for LDL-C target attainment (AUC = 0.883, Accuracy = 0.868, Precision = 0.858, Recall = 0.863, F1 = 0.860, AUPRC = 0.906, MCC = 0.761), liver enzyme abnormalities (AUC = 0.964, Accuracy = 0.964, Precision = 0.967, Recall = 0.963, F1 = 0.965, AUPRC = 0.978, MCC = 0.938), and muscle pain/Creatine kinase (CK) abnormalities (AUC = 0.981, Accuracy = 0.980, Precision = 0.987, Recall = 0.975, F1 = 0.981, AUPRC = 0.987, MCC = 0.965) demonstrated favorable performance. The most important features of LDL-C target attainment prediction model was cerebral infarction, TG, PLT and HDL. The most important features of liver enzyme abnormalities model was CRP, CK and number of oral medications. Similarly, AST, ALT, PLT and number of oral medications were found to be important features for muscle pain/CK abnormalities. Based on the best-performing predictive model, a user-friendly web application was designed and implemented. Conclusion: This study presented a machine learning-based predictive model for statin efficacy and safety. The platform developed can assist in guiding statin therapy decisions and optimizing treatment strategies. Further research and application of the model are warranted to improve the utilization of statin therapy.

Association of Questionnaire-Based Physical Activity Analysis and Body Composition Dynamics in Type 2 Diabetes: A Cross-Sectional Study.

Background: Physical activity (PA) exerts an important influence on glycemic control in type 2 diabetes (T2D) patients. Alterations in body composition in patients with T2D may be involved in the overall pathophysiologic process, but PAs and alterations in body composition have been poorly studied. Methods: A total of 615 patients with T2D were selected by convenient sampling. The patients were investigated with the International Physical Activity Questionnaire (IPAQ-S). Moreover, biochemical indices were collected, and the progression of the body composition of the subjects was determined via dual-energy X-ray absorptiometry (DXA). The variables included lumbar bone mineral density (LSBMD), femoral neck bone mineral density (FNBMD), hip bone mineral density (HBMD), whole-body bone mineral density (TBMD), limb skeletal muscle mass index (ASMI), whole-body fat percentage (B-FAT) and trunk fat percentage (T-FAT). Moreover, the levels of physical activity (high level of physical activity [H-PA], medium level of physical activity [M-PA] and low level of physical activity [L-PA]) were divided into three groups to analyze the changes in patient body composition with changes in physical activity level. Results: One-way analysis of variance showed that ß-CTX, TP1NP, HbA1c, B-FAT and T-FAT increased significantly (p<0.05), while 25(OH)D, LSBMD, FNBMD, HBMD, TBMD and ASMI decreased significantly (p<0.001) with the decrease of physical activity. However, there was no significant difference in serum lipids between lnHOMA-ir and lnHOMA-ß (p>0.05). Multiple linear regression model was established to gradually adjust for clinical confounding factors. It was found that physical activity level was independently positively correlated with LSBMD, FNBMD, HBMD, TBMD, and ASMI, and was independently negatively correlated with B-FAT and T-FAT in patients with type 2 diabetes. Conclusion: A lack of physical activity is an independent risk factor for decreased bone mineral density, decreased skeletal muscle content and increased fat content in patients with T2D.

Pembrolizumab plus chemotherapy in frontline treatment of advanced ovarian cancer: Clinical and translational results from a phase 2 trial.

BACKGROUND: The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood. METHODS: In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples. FINDINGS: Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43 months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90 months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-ß, and ß-catenin signaling. CONCLUSIONS: Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS ≥10 may benefit more from this regimen, and future studies should investigate this potential biomarker. FUNDING: This investigator-initiated trial was funded by Merck.

Simultaneous carbon, nitrogen and phosphorus removal in sequencing batch membrane aerated biofilm reactor with biofilm thickness control via air scouring aided by computational fluid dynamics.

Membrane aerated biofilm reactor (MABR) is challenged by biofilm thickness control and phosphorus removal. Air scouring aided by computational fluid dynamics (CFD) was employed to detach outer biofilm in sequencing batch MABR treating low C/N wastewater. Biofilm with 177-285 µm thickness in cycle 5-15 achieved over 85 % chemical oxygen demand (COD) and total inorganic nitrogen (TIN) removals at loading rate of 13.2 gCOD/m2/d and 2.64 gNH4+-N/m2/d. Biofilm rheology measurements in cycle 10-25 showed yield stress against detachment of 2.8-7.4 Pa, which were equal to CFD calculated shear stresses under air scouring flowrate of 3-9 L/min. Air scouring reduced effluent NH4+-N by 10 % and biofilm thickness by 78 µm. Intermittent aeration (4h off, 19.5h on) and air scouring (3 L/min, 30 s before settling) in one cycle achieved COD removal over 90 %, TIN and PO43--P removals over 80 %, showing great potential for simultaneous carbon, nitrogen and phosphorus removals.

Comparison of the diagnostic performance of contrast-enhanced ultrasound and high-resolution magnetic resonance imaging in the evaluation of histologically defined vulnerable carotid plaque: a systematic review and meta-analysis.

Background: Vulnerable carotid plaque is closely associated with ischemic stroke. Contrast-enhanced ultrasound (CEUS) and high-resolution magnetic resonance imaging (HR-MRI) are two imaging modalities capable of assessing the vulnerability of carotid plaques. This systematic review aimed to compare the diagnostic performance of CEUS and HR-MRI in the evaluation of histologically defined vulnerable carotid plaques. Methods: A systematic literature search with predefined search terms was performed on PubMed, the Cochrane library, Embase, and Web of Science from January 2001 to December 2023. Studies that evaluated the diagnostic accuracy of vulnerable carotid plaques confirmed by histology with CEUS and/or HR-MRI were included. The pooled values were calculated using a random-effects meta-analysis to determine diagnostic power. Results: This analysis included a total of 839 patients from 20 studies comprising 1,357 HR-MRI plaques and CEUS 504 plaques. With the reference to histological results, all nine CEUS studies focused on the detection of intraplaque neovascularization (IPN), and three studies also examined morphological changes or ulcerated plaques; meanwhile, among the HR-MRI studies, seven predominantly focused on identifying intraplaque hemorrhage (IPH) and three mainly examined lipid-rich necrotic cores (LRNCs). The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the area under the curve (AUC) for CEUS studies were 0.85 [95% confidence interval (CI): 0.81-0.89], 0.76 (95% CI: 0.69-0.83), 3.41 (95% CI: 1.68-6.94), 0.14 (95% CI: 0.05-0.38), 27.68 (95% CI: 5.78-132.62), and 0.89 [standard error (SE) 0.06], respectively; for HR-MRI, these values were 0.88 (95% CI: 0.85-0.90), 0.89 (95% CI: 0.86-0.92), 7.49 (95% CI: 3.28-17.09), 0.17 (95% CI: 0.12-0.24), 49.13 (95% CI: 23.87-101.11), and 0.94 (SE 0.01), respectively. The difference in AUC between the two modalities was not statistically significant (Z=0.82; P=0.68). Conclusions: CEUS and HR-MRI are valuable noninvasive diagnostic tools for identifying histologically confirmed vulnerable carotid plaques and demonstrate similar diagnostic performance. CEUS is more capable of detecting IPN and morphological changes, while HR-MRI is more suited to classifying IPH and LRNCs.

Multiple Stimulus Response Material Based on Sr-tcbpe MOF for Mechanochromism, Visualization Labeling, and Etching Toward TNP.

The abuse and excessive discharge of organic pollutants such as nitroaromatic compounds (NACs) have become a hot topic of concern for all humanity and society, and the development of fast, effective, and targeted technical means for detecting NACs also faces many challenges. Here, we reported a strontium-based metal-organic framework (MOF) {[Sr2(tcbpe)(H2O)4]}n (Sr-tcbpe), in which tcbpe represents deprotonated 4',4‴,4″‴,4‴‴-(ethene-1,1,2,2-tetrayl)tetrakis(([1,1'biphenyl]-4-carboxylic acid)). In Sr-tcbpe, Sr-O polyhedron and deprotonated tcbpe4- ligand have a staggered connection to form a self-assembled three-dimensional network structure. In addition, it is found that Sr-tcbpe undergoes no luminescent color change when grinding under solvent protection, while mechanochromic fluorescence behavior is observed when grinding directly, leading to luminescent color changes from cyan to green (Sr-tcbpe-G). Additionally, Sr-tcbpe and Sr-tcbpe-G could selectively detect PNP, DNP, and TNP, and Sr-tcbpe achieves visual fluorescence sensing detection toward TNP at a limit of detection as low as 2.25 µM. Moreover, during the detection process, unexpectedly, TNP exhibits a selective etching effect on Sr-tcbpe, which could drill nano holes with different sizes on the surface area of MOF materials to a certain extent, achieving the conversion of chemical energy to mechanical energy. In addition, the successful preparation of a portable sensor Sr-tcbpe@gypsum block provides a platform for the perfect combination of mechanochromic fluorescence behavior and visualization detection toward TNP. It lays the foundation for the practical application of MOF materials in daily life.

Investigating the value of urinary biomarkers in relation to lupus nephritis histopathology: present insights and future prospects.

Lupus nephritis (LN), a leading cause of death in Systemic Lupus Erythematosus (SLE) patients, presents significant diagnostic and prognostic challenges. Although renal pathology offers critical insights regarding the diagnosis, classification, and therapy for LN, its clinical utility is constrained by the invasive nature and limited reproducibility of renal biopsies. Moreover, the continuous monitoring of renal pathological changes through repeated biopsies is impractical. Consequently, there is a growing interest in exploring urine as a non-invasive, easily accessible, and dynamic "liquid biopsy" alternative to guide clinical management. This paper examines novel urinary biomarkers from a renal pathology perspective, encompassing cellular components, cytokines, adhesion molecules, auto-antibodies, soluble leukocyte markers, light chain fragments, proteins, small-molecule peptides, metabolomics, urinary exosomes, and ribonucleic acids. We also discuss the application of combined models comprising multiple biomarkers in assessing lupus activity. These innovative biomarkers and models offer insights into LN disease activity, acute and chronic renal indices, fibrosis, thrombotic microangiopathy, podocyte injury, and other pathological changes, potentially improving the diagnosis, management, and prognosis of LN. These urinary biomarkers or combined models may serve as viable alternatives to traditional renal pathology, potentially revolutionizing the method for future LN diagnosis and observation.

De Novo Genes.

Although the majority of annotated new genes in a given genome appear to have arisen from duplication-related mechanisms, recent studies have shown that genes can also originate de novo from ancestrally nongenic sequences. Investigating de novo-originated genes offers rich opportunities to understand the origin and functions of new genes, their regulatory mechanisms, and the associated evolutionary processes. Such studies have uncovered unexpected and intriguing facets of gene origination, offering novel perspectives on the complexity of the genome and gene evolution. In this review, we provide an overview of the research progress in this field, highlight recent advancements, identify key technical and conceptual challenges, and underscore critical questions that remain to be addressed.

Aristolochic acids-hijacked p53 promotes liver cancer cell growth by inhibiting ferroptosis.

Aristolochic acids (AAs) have been identified as a significant risk factor for hepatocellular carcinoma (HCC). Ferroptosis is a type of regulated cell death involved in the tumor development. In this study, we investigated the molecular mechanisms by which AAs enhanced the growth of HCC. By conducting bioinformatics and RNA-Seq analyses, we found that AAs were closely correlated with ferroptosis. The physical interaction between p53 and AAs in HepG2 cells was validated by bioinformatics analysis and SPR assays with the binding pocket sites containing Pro92, Arg174, Asp207, Phe212, and His214 of p53. Based on the binding pocket that interacts with AAs, we designed a mutant and performed RNA-Seq profiling. Interestingly, we found that the binding pocket was responsible for ferroptosis, GADD45A, NRF2, and SLC7A11. Functionally, the interaction disturbed the binding of p53 to the promoter of GADD45A or NRF2, attenuating the role of p53 in enhancing GADD45A and suppressing NRF2; the mutant did not exhibit the same effects. Consequently, this event down-regulated GADD45A and up-regulated NRF2, ultimately inhibiting ferroptosis, suggesting that AAs hijacked p53 to down-regulate GADD45A and up-regulate NRF2 in HepG2 cells. Thus, AAs treatment resulted in the inhibition of ferroptosis via the p53/GADD45A/NRF2/SLC7A11 axis, which led to the enhancement of tumor growth. In conclusion, AAs-hijacked p53 restrains ferroptosis through the GADD45A/NRF2/SLC7A11 axis to enhance tumor growth. Our findings provide an underlying mechanism by which AAs enhance HCC and new insights into p53 in liver cancer. Therapeutically, the oncogene NRF2 is a promising target for liver cancer.

Photo-Activated Oxidative Stress Amplifier: A Strategy for Targeting Glutathione Metabolism and Enhancing ROS-Mediated Therapy in Triple-Negative Breast Cancer Treatment.

Amplifying oxidative stress within tumor cells can effectively inhibit the growth and metastasis of triple-negative breast cancer (TNBC). Therefore, the development of innovative nanomedicines that can effectively disrupt the redox balance represents a promising yet challenging therapeutic strategy for TNBC. In this study, an oxidative stress amplifier, denoted as PBCH, comprising PdAg mesoporous nanozyme and a CaP mineralized layer, loaded with GSH inhibitor L-buthionine sulfoximine (BSO), and further surface-modified with hyaluronic acid that can target CD44, is introduced. In the acidic tumor microenvironment, Ca2+ is initially released, thereby leading to mitochondrial dysfunction and eventually triggering apoptosis. Additionally, BSO suppresses the synthesis of intracellular reduced GSH and further amplifies the level of oxidative stress in cancer cells. Furthermore, PdAg nanozyme can be activated by near-infrared light to induce photothermal and photodynamic effects, causing a burst of ROS and simultaneously promoting cell apoptosis via provoking immunogenic cell death. The high-performance therapeutic effects of PBCH, based on the synergistic effect of aforementioned multiple oxidative damage and photothermal ablation, are validated in TNBC cells and animal models, declaring its potential as a safe and effective anti-tumor agent. The proposed approach offers new perspectives for precise and efficient treatment of TNBC.

Prediction of clear cell renal cell carcinoma ≤ 4cm: visual assessment of ultrasound characteristics versus ultrasonographic radiomics analysis.

Objective: To investigate the diagnostic efficacy of the clinical ultrasound imaging model, ultrasonographic radiomics model, and comprehensive model based on ultrasonographic radiomics for the differentiation of small clear cell Renal Cell Carcinoma (ccRCC) and Renal Angiomyolipoma (RAML). Methods: The clinical, ultrasound, and contrast-enhanced CT(CECT) imaging data of 302 small renal tumors (maximum diameter ≤ 4cm) patients in Tianjin Medical University Cancer Institute and Hospital from June 2018 to June 2022 were retrospectively analyzed, with 182 patients of ccRCC and 120 patients of RAML. The ultrasound images of the largest diameter of renal tumors were manually segmented by ITK-SNAP software, and Pyradiomics (v3.0.1) module in Python 3.8.7 was applied to extract ultrasonographic radiomics features from ROI segmented images. The patients were randomly divided into training and internal validation cohorts in the ratio of 7:3. The Random Forest algorithm of the Sklearn module was applied to construct the clinical ultrasound imaging model, ultrasonographic radiomics model, and comprehensive model. The efficacy of the prediction models was verified in an independent external validation cohort consisting of 69 patients, from 230 small renal tumor patients in two different institutions. The Delong test compared the predictive ability of three models and CECT. Calibration Curve and clinical Decision Curve Analysis were applied to evaluate the model and determine the net benefit to patients. Results: 491 ultrasonographic radiomics features were extracted from 302 small renal tumor patients, and 9 ultrasonographic radiomics features were finally retained for modeling after regression and dimensionality reduction. In the internal validation cohort, the area under the curve (AUC), sensitivity, specificity, and accuracy of the clinical ultrasound imaging model, ultrasonographic radiomics model, comprehensive model, and CECT were 0.75, 76.7%, 60.0%, 70.0%; 0.80, 85.6%, 61.7%, 76.0%; 0.88, 90.6%, 76.7%, 85.0% and 0.90, 92.6%, 88.9%, 91.1%, respectively. In the external validation cohort, AUC, sensitivity, specificity, and accuracy of the three models and CECT were 0.73, 67.5%, 69.1%, 68.3%; 0.89, 86.7%, 80.0%, 83.5%; 0.90, 85.0%, 85.5%, 85.2% and 0.91, 94.6%, 88.3%, 91.3%, respectively. The DeLong test showed no significant difference between the clinical ultrasound imaging model and the ultrasonographic radiomics model (Z=-1.287, P=0.198). The comprehensive model showed superior diagnostic performance than the ultrasonographic radiomics model (Z=4. 394, P<0.001) and the clinical ultrasound imaging model (Z=4. 732, P<0.001). Moreover, there was no significant difference in AUC between the comprehensive model and CECT (Z=-0.252, P=0.801). Both in the internal and external validation cohort, the Calibration Curve and Decision Curve Analysis showed a better performance of the comprehensive model. Conclusion: It is feasible to construct an ultrasonographic radiomics model for distinguishing small ccRCC and RAML based on ultrasound images, and the diagnostic performance of the comprehensive model is superior to the clinical ultrasound imaging model and ultrasonographic radiomics model, similar to that of CECT.

Microglia in the hypothalamic paraventricular nucleus sense hemodynamic disturbance and promote sympathetic excitation in hypertension.

Hypertension is usually accompanied by elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not clear. Recent advances revealed that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels and found that microglia in the hypothalamic paraventricular nucleus (PVN), a sympathetic center, were early responders to hypertensive challenges. Vasculature analyses revealed that the PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology relative to other brain regions. As such, the PVN was susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. Mechanistically, ATP ligation to microglial P2Y12 receptor was responsible for microglial inflammatory activation and the eventual sympathetic overflow. Together, these findings identified a distinct vasculature pattern rendering vulnerability of PVN pre-sympathetic neurons to hypertension-associated microglia-mediated inflammatory insults.

Soluble expression of hMYDGF was improved by strain engineering and optimizations of fermentation strategies in Escherichia coli.

Myeloid-derived growth factor (MYDGF) is a cytokine that exhibits a variety of biological functions. This study focused on utilizing BL21(DE3) strain engineering and fermentation strategies to achieve high-level expression of soluble human MYDGF (hMYDGF) in Escherichia coli. Initially, the E. coli expressing strain BL21(DE3) was engineered by deleting the IpxM gene and inserting the GROEL/S and Trigger factor genes. The engineered E. coli strain BL21(TG)/pT-MYDGF accumulated 3557.3 ± 185.6 µg/g and 45.7 ± 6.7 mg/L of soluble hMYDGF in shake flask fermentation, representing a 15.6-fold increase compared to the control strain BL21(DE3)/pT-MYDGF. Furthermore, the yield of hMYDGF was significantly enhanced by optimizing the fermentation conditions. Under optimized conditions, the 5L bioreactor yielded up to 2665.8 ± 164.3 µg/g and 407.6 ± 42.9 mg/L of soluble hMYDGF. The results indicate that the implementation of these optimization strategies could enhance the ratio and yield of soluble proteins expressed by E.coli, thereby meeting the demands of industrial production. This study employed sophisticated strategies to lay a solid foundation for the industrial application of hMYDGF.

Inhibition of Hsp90 K284 Acetylation Aalleviates Cardiac Injury After Ischemia-Reperfusion Injury.

Our objective was to determine the role of acetyl-Hsp90 and its relationship with the NF-κB p65 signaling pathway in CVDs. We investigated the effect of acetyl-Hsp90 on cardiac inflammation and apoptosis after ischemia-reperfusion injury (I/RI). The results showed that the induction of acetyl-Hsp90 occurred in the heart during I/R and in primary cardiomyocytes during oxygen-glucose deprivation/reoxygenation (OGD/R). Moreover, the nonacetylated mutant of Hsp90 (Hsp90-K284R), through the regulation of ATPase activities within its N-terminal domain (NTD), indirectly or directly increases its interaction with NF-κB p65. This led to a reduction in the activation of the NF-κB p65 pathway, thereby attenuating inflammation, apoptosis, and fibrosis, ultimately leading to an improvement in cardiac function. Furthermore, we demonstrated that recombinant human interleukin-37 (rIL-37) exerts a similar cardioprotective effect by reducing acetylation at K284 of Hsp90 after inhibiting the expression of KAT2A.

Prion protein E219K polymorphism: from the discovery of the KANNO blood group to interventions for human prion disease.

KANNO is a new human blood group that was recently discovered. The KANNO antigen shares the PRNP gene with the prion protein and the prion protein E219K polymorphism determines the presence or absence of the KANNO antigen and the development of anti-KANNO alloantibodies. These alloantibodies specifically react with prion proteins, which serve as substrates for conversion into pathological isoforms in some prion diseases and may serve as effective targets for resisting prion infection. These findings establish a potential link between the KANNO blood group and human prion disease via the prion protein E219K polymorphism. We reviewed the interesting correlation between the human PRNP gene's E219K polymorphism and the prion proteins it expresses, as well as human red blood cell antigens. Based on the immune serological principles of human blood cells, the prion protein E219K polymorphism may serve as a foundation for earlier molecular diagnosis and future drug development for prion diseases.

Different Contributions of embB and ubiA Mutations to Variable Level of Ethambutol Resistance in Mycobacterium tuberculosis Isolates.

Objective: To explore the association between the variant mutations within embB and ubiA, and the degree of ethambutol (EMB) resistance of Mycobacterium tuberculosis (M. tuberculosis) isolates. Methods: A total of 146 M. tuberculosis isolates were used to determine the minimum inhibitory concentrations (MICs) of EMB with a 96-well microplate-based assay. The mutations within embB and ubiA among these isolates were identified with DNA sequencing. Moreover, a multivariate regression model and a computer model were established to assess the effects of mutations on EMB resistance. Results: Our data showed that overall 100 isolates exhibited 28 mutated patterns within the sequenced embB and ubiA. Statistical analysis indicated that embB mutations Met306Val, Met306Ile, Gly406Ala, and Gln497Arg, were strongly associated with EMB resistance. Of these mutations, Met306Val and Gln497Arg were significantly associated with high-level EMB resistance. Almost all multiple mutations occurred in high-level EMB-resistant isolates. Although the mutation within ubiA accompanied with embB mutation presented exclusively in EMB-resistant isolates, four single ubiA mutations (Ala39Glu, Ser173Ala, Trp175Cys, and Val283Leu) leading to protein instability were observed in EMB-susceptible isolates. Conclusion: This study highlighted the complexity of EMB resistance. Some individual mutations and multiple mutations within embB and ubiA contributed to the different levels of EMB resistance.

Myeloid Cell Trim59 Deficiency Worsens Experimental Ischemic Stroke and Alters Cerebral Proteomic Profile.

Background: Tripartite motif containing 59 (TRIM59) is a ubiquitin ligase and is involved in the pathogenesis of various diseases, including cancers, sepsis, and other immune-related diseases. However, it has not been defined whether TRIM59 plays a role in ischemic stroke in mice. Methods: This study determined the influence of Trim59 deficiency on experimental stroke outcomes and the cerebral proteomic profile using myeloid cell Trim59 conditional knockout (Trim59-cKO) mice and a label-free quantitative proteomic profiling technique. The possible mechanisms by which TRIM59 affected stroke onset were elucidated by in vivo and in vitro experiments. Results: Immunofluorescence staining results showed that TRIM59 expression was up-regulated after cerebral ischemia and co-localized with macrophages. Myeloid cell Trim59 deficiency exacerbated ischemic injury on day 3 after experimental stroke. In proteomic analysis, 23 differentially expressed proteins were identified in ischemic brain of Trim59-cKO mice as compared to Trim59flox/flox mice. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the differentially expressed proteins were enriched in complement and coagulation cascades. Protein-protein interaction analysis suggested the central role of clusterin in the interaction network. ELISA and Western blot assays confirmed the reduced levels of clusterin protein in the ischemic brains of Trim59-cKO mice. Further experimental results showed that clusterin was expressed in neurons. Conditional co-culture experiments of primary neurons and bone marrow-derived macrophages demonstrated that LPS stimulated macrophages to secrete complement C3. In addition, TRIM59 may affect the changes in clusterin expression in an indirect manner by influencing the secretion of complement C3 in macrophages. In vivo experiments also proved a significant increase in C3 levels in the brains of Trim59-cKO mice after ischemia. Conclusion: Myeloid cell Trim59 deficiency aggravated ischemic stroke outcomes in conjunction with a distinct cerebral proteomic profile, and the underlying mechanism may be related to the regulation of macrophage C3 expression by TRIM59.

Decadal Trends in the Prevalence of Metabolic Syndrome in Economically Developed Regions in China.

Objective: To estimate decadal trends in the prevalence of metabolic syndrome (MetS) in economically developed regions in China and its association with city economic levels. Methods: Using a comprehensive Chinese healthcare database, repeated cross-sectional studies were conducted on adults who had annual health check-ups from 2012 to 2021 in 4 economically developed cities. MetS was defined by the criteria of the Chinese Diabetes Society in 2013. The crude prevalence of MetS adjusted for sex and age was reported. The association between prevalence, calendar year, and city gross domestic product (GDP) per capita was analyzed by regression model. Results: 158 274 participants aged 18 years and older were included. The unadjusted prevalence of MetS increased from 15.5% (95% CI: 14.2%-16.8%) to 20.0% (95% CI: 19.5%-20.5%) from 2012 to 2021. The adjusted overall prevalence has increased steadily from 12.8% to 20.8% after controlling age and sex (P < .001). Male and older age groups had a higher MetS prevalence. In the regression model of the association between the MetS prevalence, calendar year, and city GDP per capita, calendar year had a positive association with the prevalence (P < .001, 95% CI: 0.648-1.954) and city GDP per capita had a negative association (P = .030, 95% CI: -0.136 to -0.007). Conclusion: The MetS prevalence increased steadily in the economically developed regions in China among the health check-up population during 2012-2021. The MetS prevalence is shown to be negatively associated with GDP per capita in the study population.