Numerical investigation on the impact of different coronary aneurysms morphologies on thrombus formation and hemodynamics: a comparative study.

Coronary artery aneurysms (CAAs) are morphologically classified as saccular and fusiform. There is still a great deal of clinical controversy as to which types of CAA are more likely to cause thrombosis. Therefore, the main objective of this study was to evaluate the trend of thrombus growth in CAAs with different morphologies and to assess the risk of possible long-term complications based on hemodynamic parameters. Utilizing computed tomography angiography (CTA) data from eight healthy coronary arteries, two distinct morphologies of coronary artery aneurysms (CAAs) were reconstructed. Distribution of four wall shear stress (WSS)-based indicators and three helicity indicators was analyzed in this study. Meanwhile, a thrombus growth model was introduced to analyze the thrombus formation in CAAs with different morphologies. The research results showed the distribution of most WSS indicators between saccular and fusiform CAAs was not statistically significant. However, due to the presence of a more pronounced helical flow pattern, irregular helical flow structure and longer time of flow stagnation in saccular CAAs during the cardiac cycle, the mean and maximum relative residence time (RRT) were significantly higher in saccular CAAs than in fusiform CAAs (P < 0.05). This may increase the risk of saccular coronary arteries leading to aneurysmal dilatation or even rupture. Although the two CAAs had similar rates of thrombosis, fusiform CAAs may more early cause obstruction of the main coronary flow channel where the aneurysm is located due to thrombosis growth. Thus, the risk of thrombosis in fusiform coronary aneurysms may warrant greater clinical concern.

Deep Learning Radiomics Model of Contrast-Enhanced CT for Differentiating the Primary Source of Liver Metastases.

RATIONALE AND OBJECTIVES: To develop and validate a deep learning radiomics (DLR) model based on contrast-enhanced computed tomography (CT) to identify the primary source of liver metastases. MATERIALS AND METHODS: In total, 657 liver metastatic lesions, including breast cancer (BC), lung cancer (LC), colorectal cancer (CRC), gastric cancer (GC), and pancreatic cancer (PC), from 428 patients were collected at three clinical centers from January 2018 to October 2023 series. The lesions were randomly assigned to the training and validation sets in a 7:3 ratio. An additional 112 lesions from 61 patients at another clinical center served as an external test set. A DLR model based on contrast-enhanced CT of the liver was developed to distinguish the five pathological types of liver metastases. Stepwise classification was performed to improve the classification efficiency of the model. Lesions were first classified as digestive tract cancer (DTC) and non-digestive tract cancer (non-DTC). DTCs were divided into CRC, GC, and PC and non-DTCs were divided into LC and BC. To verify the feasibility of the DLR model, we trained classical machine learning (ML) models as comparison models. Model performance was evaluated using accuracy (ACC) and area under the receiver operating characteristic curve (AUC). RESULTS: The classification model constructed by the DLR algorithm showed excellent performance in the classification task compared to ML models. Among the five categories task, highest ACC and average AUC were achieved at 0.563 and 0.796 in the validation set, respectively. In the DTC and non-DTC and the LC and BC classification tasks, AUC was achieved at 0.907 and 0.809 and ACC was achieved at 0.843 and 0.772, respectively. In the CRC, GC, and PC classification task, ACC and average AUC were the highest, at 0.714 and 0.811, respectively. CONCLUSION: The DLR model is an effective method for identifying the primary source of liver metastases.

Delineation of renal protein profiles in aristolochic acid I-induced nephrotoxicity in mice by label-free quantitative proteomics.

Introduction: Aristolochic acid nephropathy (AAN) is a kidney injury syndrome caused by aristolochic acids exposure. Our study used label-free quantitative proteomics to delineate renal protein profiles and identify key proteins after exposure to different doses of aristolochic acid I (AAI). Methods: Male C57BL/6 mice received AAI (1.25 mg/kg/d, 2.5 mg/kg/d, or 5 mg/kg/d) or vehicle for 5 days. Results and discussion: The results showed that AAI induced dose-dependent nephrotoxicity. Differences in renal protein profiles between the control and AAI groups increased with AAI dose. Comparing the control with the low-, medium-, and high-dose AAI groups, we found 58, 210, and 271 differentially expressed proteins, respectively. Furthermore, protein-protein interaction network analysis identified acyl-CoA synthetase medium-chain family member 3 (Acsm3), cytochrome P450 family 2 subfamily E member 1 (Cyp2e1), microsomal glutathione S-transferase 1 (Mgst1), and fetuin B (Fetub) as the key proteins. Proteomics revealed that AAI decreased Acsm3 and Cyp2e1 while increasing Mgst1 and Fetub expression in mice kidneys, which was further confirmed by Western blotting. Collectively, in AAI-induced nephrotoxicity, renal protein profiles were dysregulated and exacerbated with increasing AAI dose. Acsm3, Cyp2e1, Mgst1, and Fetub may be the potential therapeutic targets for AAN.

Engineering sulfur defective Bi2S3@C with remarkably enhanced electrochemical kinetics of lithium-ion batteries.

Introducing the appropriate vacancies to augment the active sites and improve the electrochemical kinetics while maintaining high cyclability is a major challenge for its widespread application in electrochemical energy storage. Here, core-shell structured Bi2S3@C with sulfur vacancies was prepared by hydrothermal method and one-step carbonization/sulfuration process, which significantly improves the intrinsic electrical conductivity and ion transport efficiency of Bi2S3. Additionally, the uniform protective carbon layer around surface of composite maintains structural stability and effectively alleviates volume expansion during alloying/dealloying. As a result, the BSC-500 anode exhibits a brilliant reversible capacity of 636 mAh/g at 0.2 A/g and a long-term stable capacity of 524 mAh/g for 500 cycles at a high current density of 3 A/g in lithium-ion batteries. In addition, the assembled Bi2S3@C//LiCoO2 full cell delivered a capacity of 184 mAh/g at 1 A/g and excellent cyclability (125 mAh/g after 1000 cycles). The proposed strategy of combining sulfur vacancies with a core-shell structure to improve the electrochemical kinetics of Bi2S3 in lithium-ion batteries off the prospect for practical applications of transition metal sulfide anodes.

Reniformin A suppresses non-small cell lung cancer progression by inducing TLR4/NLRP3/caspase-1/GSDMD-dependent pyroptosis.

Pyroptosis is an inflammatory form of programmed cell death that plays an important role in regulating tumor progression. Reniformin A (RA) is a natural compound isolated from the medicinal herb Isodon excisoides that has been applied as folk medicine in the treatment of esophageal cancer. However, whether RA has an individual function in cancer and the molecular mechanisms remain unclear. Here, we show that in non-small-cell lung cancer (NSCLC), RA inhibits tumor growth by functioning as a pyroptosis inducer to promote TLR4/NLRP3/caspase-1/GSDMD axis. Specially, RA treatment increased Toll-like receptor 4 (TLR4) protein expression level by enhancing the TLR4 stability. Based on the molecular docking, we identified that RA directly bound to TLR4 to activate the NLRP3 inflammasome and promote pyroptosis in A549 cells. Moreover, TLR4 is essential for RA-induced pyroptosis, and loss of TLR4 abolished RA-induced pyroptosis and further reduced the inhibitory effect of RA on NSCLC. In vivo experiments confirmed that RA inhibited the growth of lung tumors in mice by affecting pyroptosis in a dose-dependent manner. Furthermore, TLR4 knockdown abolished RA-induced pyroptosis and inhibited the effect of RA chemotherapy in vivo. In conclusion, we propose that RA has a significant anticancer effect in NSCLC by inducing TLR4/NLRP3/caspase-1/GSDMD-mediated pyroptosis, which may provide a potential strategy for the treatment of NSCLC.

A global meta-analysis on the drivers of salt marsh planting success and implications for ecosystem services.

Planting has been widely adopted to battle the loss of salt marshes and to establish living shorelines. However, the drivers of success in salt marsh planting and their ecological effects are poorly understood at the global scale. Here, we assemble a global database, encompassing 22,074 observations reported in 210 studies, to examine the drivers and impacts of salt marsh planting. We show that, on average, 53% of plantings survived globally, and plant survival and growth can be enhanced by careful design of sites, species selection, and novel planted technologies. Planting enhances shoreline protection, primary productivity, soil carbon storage, biodiversity conservation and fishery production (effect sizes = 0.61, 1.55, 0.21, 0.10 and 1.01, respectively), compared with degraded wetlands. However, the ecosystem services of planted marshes, except for shoreline protection, have not yet fully recovered compared with natural wetlands (effect size = -0.25, 95% CI -0.29, -0.22). Fortunately, the levels of most ecological functions related to climate change mitigation and biodiversity increase with plantation age when compared with natural wetlands, and achieve equivalence to natural wetlands after 5-25 years. Overall, our results suggest that salt marsh planting could be used as a strategy to enhance shoreline protection, biodiversity conservation and carbon sequestration.

New insights into the concentration-dependent regulation of membrane biofouling formation via continuous nanoplastics stimulation.

The release of nanoplastics (NPs) into the environment is growing due to the extensive use of plastic products. Numerous studies have confirmed the negative effects of NPs on microorganisms, which poses uncertainties concerning their impact on nanofiltration (NF) membrane biofouling. This study investigated the initial cell adhesion process, NF membrane biofouling kinetic processes and bacterial responses of Pseudomonas aeruginosa (P. aeruginosa) exposed to varied NPs concentrations (0-50 mg·L-1). Transcriptome analysis demonstrated that low concentration of NPs (0.1 mg·L-1) promoted bacterial quorum sensing, energy metabolism, exopolysaccharide biosynthesis and bacterial secretion systems. Correspondingly, the polysaccharide content increased remarkably to 2.77 times the unexposed control, which served as a protective barrier for bacteria to avoid the impact of NPs-induced stress. Suppressed homologous recombination, microbial metabolic potentials and flagellar assembly were detected in bacteria exposed to a high concentration (50 mg·L-1) of NPs, mainly due to the triggered reactive oxygen species (ROS) generation, genomic DNA damage, and decreased energy production. Overall, enhanced formation of the extracellular polymeric substances (EPS) and aggravated membrane flux decline were observed when NPs interacted with the membrane surface by cell secretions (low NPs levels) or cell lysis (high NPs levels). These findings shed light on understanding the microbial metabolism mechanism and membrane biofouling propensity with NPs stress at both the molecular and gene levels.

Identifying Pathological Subtypes of Brain Metastasis from Lung Cancer Using MRI-Based Deep Learning Approach: A Multicenter Study.

The aim of this study was to investigate the feasibility of deep learning (DL) based on multiparametric MRI to differentiate the pathological subtypes of brain metastasis (BM) in lung cancer patients. This retrospective analysis collected 246 patients (456 BMs) from five medical centers from July 2016 to June 2022. The BMs were from small-cell lung cancer (SCLC, n = 230) and non-small-cell lung cancer (NSCLC, n = 226; 119 adenocarcinoma and 107 squamous cell carcinoma). Patients from four medical centers were assigned to training set and internal validation set with a ratio of 4:1, and we selected another medical center as an external test set. An attention-guided residual fusion network (ARFN) model for T1WI, T2WI, T2-FLAIR, DWI, and contrast-enhanced T1WI based on the ResNet-18 basic network was developed. The area under the receiver operating characteristic curve (AUC) was used to assess the classification performance. Compared with models based on five single-sequence and other combinations, a multiparametric MRI model based on five sequences had higher specificity in distinguishing BMs from different types of lung cancer. In the internal validation and external test sets, AUCs of the model for the classification of SCLC and NSCLC brain metastasis were 0.796 and 0.751, respectively; in terms of differentiating adenocarcinoma from squamous cell carcinoma BMs, the AUC values of the prediction models combining the five sequences were 0.771 and 0.738, respectively. DL together with multiparametric MRI has discriminatory feasibility in identifying pathology type of BM from lung cancer.

Molecular basis and current insights of atypical Rho small GTPase in cancer.

Atypical Rho GTPases are a subtype of the Rho GTPase family that are involved in diverse cellular processes. The typical Rho GTPases, led by RhoA, Rac1 and Cdc42, have been well studied, while relative studies on atypical Rho GTPases are relatively still limited and have great exploration potential. With the increase in studies, current evidence suggests that atypical Rho GTPases regulate multiple biological processes and play important roles in the occurrence and development of human cancers. Therefore, this review mainly discusses the molecular basis of atypical Rho GTPases and their roles in cancer. We summarize the sequence characteristics, subcellular localization and biological functions of each atypical Rho GTPase. Moreover, we review the recent advances and potential mechanisms of atypical Rho GTPases in the development of multiple cancers. A comprehensive understanding and extensive exploration of the biological functions of atypical Rho GTPases and their molecular mechanisms in tumors will provide important insights into the pathophysiology of tumors and the development of cancer therapeutic strategies.

Effect of enzymolysis combined with Maillard reaction treatment on functional and structural properties of gluten protein.

In this work, the modified gluten was prepared by enzymolysis combined with Maillard reaction (MEG), and its functional and structural properties were investigated. The result showed that the maximum foamability of MEG was 19.58 m2/g, the foam stability was increased by 1.8 times compared with gluten, and the solubility and degree of graft were increased to 44.4 % and 28.1 % at 100 °C, whereas the content of sulfhydryl group decreased to 0.81 µmol/g. The scavenging ability on ABTS+radical and DPPH radical of MEG was positively correlated with reaction temperature, and the maximum values were 86.57 % and 71.71 % at 140 °C, respectively. Furthermore, the fluorescence quenching effect of tryptophan and tyrosine residues was enhanced, while the fluorescence intensity decreased with the temperature increase. Scanning electron microscopy revealed that the surface of enzymatically hydrolyzed-gluten became smooth and the cross section became straightened, while MEG turned smaller and irregular approaching a circular structure. FT-IR spectroscopy showed that enzymatic hydrolysis promoted the occurrence of more carbonyl ammonia reactions and the formation of precursors of advanced glycosylation end products. These results provide a feasible method for improving the structure and functional properties of gluten protein.

Investigation of the Metabolism of Astragaloside IV in a Puromycin-Damaged Rat Model by UPLC-Q-TOF-MS/MS Analysis.

Astragaloside IV (AS-IV) has been shown to provide renal protection in various kidney injury models. However, the metabolic profile variation of AS-IV in pathological models in vivo is not well established. This study aims to explore the metabolic pathway of AS-IV in vivo in the classical puromycin aminonucleoside (PAN)-induced kidney injury in a rat model. Twelve Wistar rats were randomly divided into the AS-IV (CA) and the PAN+AS-IV (PA) treatment groups. PAN was injected by a single tail intravenous (i. v.) injection at 5 mg/100 g body weight, and AS-IV was administered intragastrically (i. g.) at 40 mg/kg for 10 days. Fecal samples of these rats were collected, and metabolites of AS-IV were detected by ultra-performance liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) to explore the AS-IV metabolic pathway. The metabolic differences between the AS-IV and PAN+AS-IV groups were compared. A total of 25 metabolites were detected, and deglycosylation, deoxygenation, and methyl oxidation were found to be the main metabolic pathways of AS-IV in vivo. The abundance of most of these metabolites in the PAN+AS-IV group was lower than that in the AS-IV treatment group, and differences for seven of them were statistically significant. Our study indicates that AS-IV metabolism is affected in the PAN-induced kidney injury rat model.

Spleen tyrosine kinase facilitates the progression of papillary thyroid cancer regulated by the hsa_circ_0006417/miR-377-3p axis.

Papillary thyroid cancer (PTC) is a prevalent malignancy worldwide. Spleen tyrosine kinase (SYK) is a crucial enzyme that participates in various biological processes, including cancer progression. This study aims to uncover the biological function of SYK in PTC. SYK expression patterns in PTC were evaluated using quantitative real time polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), and western blot. Cell function assays were performed to assess the effects of SYK on PTC. Bioinformatics analysis was conducted to identify intriguing microRNA (miRNA) and circular RNA (circRNA). Dual-Luciferase Reporter or RNA immunoprecipitation assays were used to investigate the correlation among SYK, miR-377-3p, and hsa_circ_0006417. SYK was upregulated in PTC. Overexpression of SYK exhibited a positive correlation with tumor size, lymph node metastasis, and unfavorable disease-free survival. Functional assays revealed that SYK exerted tumorigenic effect on PTC cells through mTOR/4E-BP1 pathway. Mechanistically, hsa_circ_0006417 and miR-377-3p regulated SYK expression, offering modulating its tumor-promoting effects. Collectively, SYK acts as an oncogene in PTC through mTOR/4E-BP1 pathway, which is regulated by the hsa_circ_0006417/miR-377-3p axis, thereby providing a potential alternative for PTC treatment.

TRIM28 promotes porcine epidemic diarrhea virus replication by mitophagy-mediated inhibition of the JAK-STAT1 pathway.

Porcine epidemic diarrhea virus (PEDV) infection causes immunosuppression and clinical symptoms such as vomiting, watery diarrhea, dehydration, and even death in piglets. TRIM28, an E3 ubiquitin ligase, is involved in the regulation of autophagy. However, the role of TRIM28 in PEDV infection is unknown. This study aimed to determine whether TRIM28 acts as a host factor for PEDV immune escape. We found that depletion of TRIM28 inhibited PEDV replication, whereas overexpression of TRIM28 promoted the viral replication in host cells. Furthermore, knockdown of TRIM28 reversed PEDV-induced downregulation of the JAK/STAT1 pathway. Treatment with the mitophagic activator carbonyl cyanide 3-chlorophenylhydrazone (CCCP) attenuated the activating effect of TRIM28 depletion on the expression of the STAT1 pathway-related proteins. Treatment with CCCP also reduced the nuclear translocation of pSTAT1. Moreover, TRIM28, via its RING domain, interacted with PEDV N. Overexpression of TRIM28 induced mitophagy, which could be enhanced by co-expression with PEDV N. The results indicate that PEDV infection upregulates the expression of TRIM28, which induces mitophagy, leading to inhibition of the JAK-STAT1 pathway. This research unveils a new mechanism by which PEDV can hijack host cellular TRIM28 to promote its own replication.

NCOA5 Haploinsufficiency in Myeloid-Lineage Cells Sufficiently Causes Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma.

BACKGROUND & AIMS: The nuclear receptor coactivator 5 (NCOA5) is a putative type 2 diabetes susceptibility gene. NCOA5 haploinsufficiency results in the spontaneous development of nonalcoholic fatty liver disease (NAFLD), insulin resistance, and hepatocellular carcinoma (HCC) in male mice; however, the cell-specific effect of NCOA5 haploinsufficiency in various types of cells, including macrophages, on the development of NAFLD and HCC remains unknown. METHODS: Control and myeloid-lineage-specific Ncoa5 deletion (Ncoa5ΔM/+) mice fed a normal diet were examined for the development of NAFLD, nonalcoholic steatohepatitis (NASH), and HCC. Altered genes and signaling pathways in the intrahepatic macrophages of Ncoa5ΔM/+ male mice were analyzed and compared with those of obese human individuals. The role of platelet factor 4 (PF4) in macrophages and the underlying mechanism by which PF4 affects NAFLD/NASH were explored in vitro and in vivo. PF4 expression in HCC patient specimens and prognosis was examined. RESULTS: Myeloid-lineage-specific Ncoa5 deletion sufficiently causes spontaneous NASH and HCC development in male mice fed a normal diet. PF4 overexpression in Ncoa5ΔM/+ intrahepatic macrophages is identified as a potent mediator to trigger lipid accumulation in hepatocytes by inducing lipogenesis-promoting gene expression. The transcriptome of intrahepatic macrophages from Ncoa5ΔM/+ male mice resembles that of obese human individuals. High PF4 expression correlated with poor prognosis of HCC patients and increased infiltrations of M2 macrophages, regulatory T cells, and myeloid-derived suppressor cells in HCCs. CONCLUSIONS: Our findings reveal a novel mechanism for the onset of NAFLD/NASH and HCC initiated by NCOA5-deficient macrophages, suggesting the NCOA5-PF4 axis in macrophages as a potential target for developing preventive and therapeutic interventions against NAFLD/NASH and HCC.

Jian-Pi-Yi-Shen formula alleviates renal fibrosis by restoring NAD+ biosynthesis in vivo and in vitro.

BACKGROUND: Patients with chronic kidney disease (CKD) lack efficacious treatment. Jian-Pi-Yi-Shen formula (JPYSF) has demonstrated significant clinical efficacy in treating CKD for decades. However, its renoprotective mechanism has not been fully elucidated. This study aimed to determine whether JPYSF could delay renal fibrosis progression in CKD by restoring nicotinamide adenine dinucleotide (NAD+) biosynthesis. METHODS: Adenine-diet feeding was used to model CKD in C57BL/6 mice. JPYSF was orally administered for 4 weeks. Human proximal tubular epithelial cells (HK-2) cells were stimulated with transforming growth factor-ß1 (TGF-ß1) with or without JPYSF treatment. Renal function of mice was assessed by serum creatinine and blood urea nitrogen levels. Renal histopathological changes were assessed using Periodic acid-Schiff and Masson's trichrome staining. Cell viability was assessed using a cell counting kit-8 assay. NAD+ concentrations were detected by a NAD+/NADH assay kit. Western blotting, immunohistochemistry, and immunofluorescence were employed to examine fibrosis-related proteins and key NAD+ biosynthesis enzymes expression in the CKD kidney and TGF-ß1-induced HK-2 cells. RESULTS: JPYSF treatment could not only improve renal function and pathological injury but also inhibit renal fibrosis in CKD mice. Additionally, JPYSF reversed fibrotic response in TGF-ß1-induced HK-2 cells. Moreover, JPYSF rescued the decreased NAD+ content in CKD mice and TGF-ß1-induced HK-2 cells through restoring expression of key enzymes in NAD+ biosynthesis, including quinolinate phosphoribosyltransferase, nicotinamide mononucleotide adenylyltransferase 1, and nicotinamide riboside kinase 1. CONCLUSIONS: JPYSF alleviated renal fibrosis in CKD mice and reversed fibrotic response in TGF-ß1-induced HK-2 cells, which may be related to the restoration of NAD+ biosynthesis.

A Hierarchical Control Strategy for a Rigid-Flexible Coupled Hexapod Bio-Robot.

The motion process of legged robots contains not only rigid-body motion but also flexible motion with elastic deformation of the legs, especially for heavy loads. Hence, the characteristics of the flexible components and their interactions with the rigid components need to be considered. In this paper, a hierarchical control strategy for robots with rigid-flexible coupling characteristics is proposed. This strategy involves (1) leg force prediction based on real-time motion trajectories and feedforward compensation for the error caused by flexible components; (2) building upon the centroid dynamics model of the rigid-body chassis, the centroid trajectories (centroid angular momentum (CAM) and centroid linear momentum (CLM)) and the body trajectory are taken into account to derive the optimal drive torque for maintaining body stability; (3) finally, the precise force control of the hydraulic drive units is achieved through the sliding mode control algorithm, integrating the dynamic model of the flexible legs. The proposed methods are validated on a giant hexapod robot weighing 3.5 tons, demonstrating that the introduced approach can reduce the robot's vibrations.

Causal associations between female reproductive behaviors and psychiatric disorders: a lifecourse Mendelian randomization study.

BACKGROUND: The timings of reproductive life events have been examined to be associated with various psychiatric disorders. However, studies have not considered the causal pathways from reproductive behaviors to different psychiatric disorders. This study aimed to investigate the nature of the relationships between five reproductive behaviors and twelve psychiatric disorders. METHODS: Firstly, we calculated genetic correlations between reproductive factors and psychiatric disorders. Then two-sample Mendelian randomization (MR) was conducted to estimate the causal associations among five reproductive behaviors, and these reproductive behaviors on twelve psychiatric disorders, using genome-wide association study (GWAS) summary data from genetic consortia. Multivariable MR was then applied to evaluate the direct effect of reproductive behaviors on these psychiatric disorders whilst accounting for other reproductive factors at different life periods. RESULTS: Univariable MR analyses provide evidence that age at menarche, age at first sexual intercourse and age at first birth have effects on one (depression), seven (anxiety disorder, ADHD, bipolar disorder, bipolar disorder II, depression, PTSD and schizophrenia) and three psychiatric disorders (ADHD, depression and PTSD) (based on p<7.14×10-4), respectively. However, after performing multivariable MR, only age at first sexual intercourse has direct effects on five psychiatric disorders (Depression, Attention deficit or hyperactivity disorder, Bipolar disorder, Posttraumatic stress disorder and schizophrenia) when accounting for other reproductive behaviors with significant effects in univariable analyses. CONCLUSION: Our findings suggest that reproductive behaviors predominantly exert their detrimental effects on psychiatric disorders and age at first sexual intercourse has direct effects on psychiatric disorders.

Huangqi-Danshen decoction protects against cisplatin-induced acute kidney injury in mice.

Background: Acute kidney injury (AKI) induced by cisplatin remains a major impediment to the clinical application of cisplatin, necessitating urgent exploration for promising solutions. Huangqi-Danshen decoction (HDD), a Chinese herbal preparation, has been shown by our group to have a reno-protective effect in adenine-induced chronic kidney disease mice and diabetic db/db mice. However, the effect of HDD on cisplatin-induced AKI and its underlying mechanisms are unknown. Methods: The AKI model was established by intraperitoneal injection of cisplatin (20 mg/kg) in C57BL/6 mice. The mice in the treatment group were administrated with HDD (6.8 g/kg/d) for 5 consecutive days before cisplatin challenge. After 72 h cisplatin injection, blood and kidney tissue were subsequently collected for biochemical detection, histopathological evaluation, Western blot analysis, immunohistochemical staining, and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling assay. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used to detect changes in renal metabolites. Results: The results showed that HDD significantly reduced serum creatinine and blood urea nitrogen levels and alleviated renal histopathological injury in cisplatin-induced AKI mice. And HDD treatment demonstrated a significant inhibition in apoptosis, inflammation, and oxidative stress in AKI mice. Moreover, non-target metabolomics revealed that HDD significantly restored 165 altered metabolites in AKI mice. Subsequent enrichment analysis and pathway analysis of these metabolites indicated that nicotinate and nicotinamide metabolism was the primary pathway affected by HDD intervention. Further investigation showed that HDD could upregulate nicotinamide adenine dinucleotide (NAD+) biosynthesis-related enzymes quinolinate phosphoribosyltransferase, nicotinamide mononucleotide adenylyltransferase 1, and nicotinamide phosphoribosyltransferase to replenish NAD+ content in the kidney of AKI mice. Conclusion: In summary, HDD exerted a protective effect against cisplatin-induced AKI and suppressed apoptosis, inflammation, and oxidative stress in the kidney of AKI mice, which may be attributed to the modulation of NAD+ biosynthesis.

Mechanism of regulating macrophages/osteoclasts in attenuating wear particle-induced aseptic osteolysis.

Joint replacement surgery is the most effective treatment for end-stage arthritis. Aseptic loosening caused by periprosthetic osteolysis is a common complication after joint replacement. Inflammation induced by wear particles derived from prosthetic biomaterials is a major cause of osteolysis. We emphasize that bone marrow-derived macrophages and their fusion-derived osteoclasts play a key role in this pathological process. Researchers have developed multiple intervention approaches to regulate macrophage/osteoclast activation. Aiming at wear particle-induced periprosthetic aseptic osteolysis, this review separately discusses the molecular mechanism of regulation of ROS formation and inflammatory response through intervention of macrophage/osteoclast RANKL-MAPKs-NF-κB pathway. These molecular mechanisms regulate osteoclast activation in different ways, but they are not isolated from each other. There is also a lot of crosstalk among the different mechanisms. In addition, other bone and joint diseases related to osteoclast activation are also briefly introduced. Therefore, we discuss these new findings in the context of existing work with a view to developing new strategies for wear particle-associated osteolysis based on the regulation of macrophages/osteoclasts.