Clinical features and prognosis of ANCA-associated vasculitis patients who were double-seropositive for myeloperoxidase-ANCA and proteinase 3-ANCA.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients with dual positivity for proteinase 3-ANCA (PR3-ANCA) and myeloperoxidase-ANCA (MPO-ANCA) are uncommon. We aimed to investigate these idiopathic double-positive AAV patients' clinical features, histological characteristics, and prognosis. We reviewed all the electronic medical records of patients diagnosed with AAV to obtain clinical data and renal histological information from January 2010 to December 2020 in a large center in China. Patients were assigned to the MPO-AAV group or PR3-AAV group or idiopathic double-positive AAV group by ANCA specificity. We explored features of idiopathic double-positive AAV. Of the 340 patients who fulfilled the study inclusion criteria, 159 (46.76%) were female, with a mean age of 58.41 years at the time of AAV diagnosis. Similar to MPO-AAV, idiopathic double-positive AAV patients were older and had more severe anemia, lower Birmingham Vasculitis Activity Score (BVAS) and C-reactive protein (CRP) levels, less ear, nose, and throat (ENT) involvement, higher initial serum creatinine and a lower estimated glomerular filtration rate (eGFR) when compared with PR3-AAV (P < 0.05). The proportion of normal glomeruli of idiopathic double-positive AAV was the lowest among the three groups (P < 0.05). The idiopathic double-positive AAV patients had the worst remission rate (58.8%) among the three groups (P < 0.05). The relapse rate of double-positive AAV (40.0%) was comparable with PR3-AAV (44.8%) (P > 0.05). Although there was a trend toward a higher relapse rate of idiopathic double-positive AAV (40.0%) compared with MPO-AAV (23.5%), this did not reach statistical significance (P > 0.05). The proportion of patients who progressed to ESRD was 47.1% and 44.4% in the idiopathic double-positive AAV group and MPO-AAV group respectively, without statistical significance. Long-term patient survival also varied among the three groups (P < 0.05). Idiopathic double-positive AAV is a rare clinical entity with hybrid features of MPO-AAV and PR3-AAV. MPO-AAV is the "dominant" phenotype in idiopathic double-positive AAV.

Bone-Differentiation-Associated Circ-Spen Regulates Death of Mouse Bone Marrow Mesenchymal Stem Cells by Inhibiting Apoptosis and Promoting Autophagy.

The role of estrogen receptor ß (ERß) in bone health is closely associated with its function in vivo, and ERß-/- mice have been widely utilized to explore the related influences. In this study, ERß-/- female mice were established to investigate the differential expression of circular RNAs (circRNAs) by RNA-Sequencing (RNA-Seq). Among these circRNAs, mmu_circ_0011379 (named Circ-Spen) exhibited high expression in ERß-/- female mice. However, the precise mechanism by which Circ-Spen regulates bone health remained unclear. This study identified Circ-Spen as a positive regulator of mouse bone marrow mesenchymal stem cell (mBMSC) viability. The expression of Circ-Spen was markedly increased in ERß-/- mice femurs tested by RT-qPCR. Moreover, Circ-Spen exhibited an enhanced expression during the bone formation process of mBMSCs. Qualitative experiments also demonstrated that Circ-Spen possessed a circular structure and was localized within the nucleus of mBMSCs. Functionally, it inhibited apoptosis via caspase-3, BCL-2, and BAX, while also promoting autophagy through BECN1 and P62 in mBMSCs tested by MTT assays, transmission electron microscopy (TEM), and Western blotting. These findings reveal the potential of targeting Circ-Spen as a promising therapeutic strategy for rejuvenating senescent mBMSCs and enhancing the efficiency of mBMSC transplantation, which lays the foundation for advancements in the field of bone therapy.

Variations in grain yield and nutrient status of different maize cultivars by application of zinc sulfate.

Although maize is sensitive to zinc (Zn) deficiencies, the responses of maize cultivars to the foliar application of Zn sulfate (ZnSO4) may vary significantly. Here, we quantified the responses of grain yields and nitrogen (N), phosphorus (P), and potassium (K) absorption to ZnSO4 using 22 modern maize cultivars. The results revealed that 40.9% of the cultivars were not affected by foliar ZnSO4, whereas only 45.5% of the cultivars responded positively to ZnSO4, which was evidenced by increased grain numbers and shortened bald tip lengths. The impact of Zn fertilizer might be manifested in the dry biomass, from the 8-leaf stage (BBCH 18). For Zn-deficiency resistant cultivars, the foliar application of ZnSO4 enhanced N accumulation by 44.1%, while it reduced P and K absorption by 13.6% and 23.7%, respectively. For Zn-deficiency sensitive maize cultivars, foliar applied ZnSO4 improved the accumulation of N and K by 27.3% and 25.0%, respectively; however, it lowered their utilization efficiency. Hence, determining the optimized application of Zn fertilizer, while avoiding Zn toxicity, should not be based solely on the level of Zn deficiency in the soil, but also, take into consideration the sensitivity of some cultivars to Zn, Furthermore, the supplementation of Zn-deficiency sensitive maize cultivars with N and K is key to maximizing the benefits of Zn fertilization.

Gut microbiota dysbiosis and intestinal barrier impairment in diarrhea caused by cold drink and high-fat diet.

Cold drink and high-fat diet (CDHFD) are common diet patterns. However, the potential risks remain unclear. We investigated the effects of CDHFD in adult mice and explored the mechanisms of action. Twenty adult male mice were randomly divided into control and model groups, and the control group was fed a normal diet, whereas the model group was fed CDHFD for 28 days. We found that mice in the model group developed diarrhea symptoms accompanied by fatigue and weakness. Analysis of the intestinal flora revealed that the model group had a lower diversity and richness of microorganism species in the gut than the control group. Furthermore, the characteristic analysis indicated that CDHFD downregulated specific bacteria, such as norank_f_Muribaculaceae, Muribaculum, and Odoribacter, which are known to be associated with the systemic inflammatory response and mucosal barrier function. Blood tests showed that immune cells and inflammatory cytokines were significantly elevated in the model group, along with increased LPS induced by CDHFD. Pathological investigations demonstrated that CDHFD damages the intestinal mucosa while affecting the expression of tight junction proteins, including ZO-1, Claudin-1, Claudin-2, and Occludin, which may be attributed to the activation of the TRAF6/IκB/p65 signaling pathway. In conclusion, impaired gut microbial and mechanical barrier function is responsible for CDHFD-induced diarrhea. In this study, we constructed a model of diet-induced diarrhea by simulating human dietary patterns, evaluated the long-term effects of CDHFD on human intestinal barriers and immune systems, and revealed its mechanism of action based on chronic inflammation. This study validated the model's fit to provide an effective screening model for drug or functional food development.

Single-cell transcriptomics uncover hub genes and cell-cell crosstalk in patients with hypertensive nephropathy.

Hypertensive nephropathy (HTN) is one of the leading causes of end-stage renal disease, yet the molecular mechanisms are still unknown. To explore novel mechanisms and gene targets for HTN, the gene expression profiles of renal biopsy samples obtained from 2 healthy living donor controls and 5 HTN patients were determined by single-cell RNA sequencing. Key hub genes expression were validated by the Nephroseq v5 platform. The HTN endothelium upregulated cellular adhesion genes (ICAM2 and CEACAM1), inflammatory genes (ETS2 and IFI6) and apoptosis related genes (CNN3). Proximal tubules in HTN highly expressed hub genes including BBOX1, TPM1, TMSB10, SDC4, and NUP58, which might be potential novel targets for proximal tubular injury. The upregulated genes in tubules of HTN were mainly participating in inflammatory signatures including IFN-γ signature, NF-κB signaling, IL-12 signaling and Wnt signaling pathway. Receptor-ligand interaction analysis indicated potential cell-cell crosstalk between endothelial cells or mesangial cells with other renal resident cells in HTN. Together, our data identify a distinct cell-specific gene expression profile, pathogenic inflammatory signaling and potential cell-cell communications between endothelial cells or mesangial cells with other renal resident cells in HTN. These findings may provide a promising novel landscape for mechanisms and treatment of human HTN.

Progress of Polymer-Based Dielectric Composites Prepared Using Fused Deposition Modeling 3D Printing.

Polymer-based dielectric composites are of great importance in advanced electronic industries and energy storage because of their high dielectric constant, good processability, low weight, and low dielectric loss. FDM (Fused Deposition Modeling) is a greatly accessible additive manufacturing technology, which has a number of applications in the fabrication of RF components, but the unavoidable porosity in FDM 3D-printed materials, which affects the dielectric properties of the materials, and the difficulty of large-scale fabrication of composites by FDM limit its application scope. This study's main focus is on how the matrix, filler, interface, and FDM 3D printing parameters influence the electrical properties of FDM-printed polymer-based dielectric composites. This review article starts with the fundamental theory of dielectrics. It is followed by a summary of the factors influencing dielectric properties in recent research developments, as well as a projection for the future development of FDM-prepared polymer-based dielectric composites. Finally, improving the comprehensive performance of dielectric composites is an important direction for future development.

Efficacy and safety of combined Chinese and Western medicine in the treatment of knee osteoarthritis: a prospective, multicenter cohort study.

Purpose: To conduct a real-world evaluation of the efficacy and safety of combined Chinese and Western medicine in treating knee osteoarthritis (KOA). Methods: A multicenter, prospective cohort study design was employed, enrolling 450 KOA patients (Kellgren-Lawrence score of 3 or less). The patients were divided into a Western medicine treatment group (WM group) and a combined Western and traditional Chinese medicine treatment group (WM-CM group). A 6-week treatment plan was administered, and follow-up visits occurred at 2 weeks, 4 weeks, and 6 weeks after initiating treatment. The primary outcome indicator was the total Western Ontario and McMaster Universities Arthritis Index (WOMAC) score after 6 weeks of treatment. Secondary outcome indicators included WOMAC subscales for pain, stiffness, and joint function, visual analogue scale (VAS) score, physical component summary (PCS), mental component summary (MCS), and clinical effectiveness. The incidence of drug-related adverse events was used as a safety evaluation indicator. Results: A total of 419 patients were included in the final analysis: 98 in the WM group and 321 in the WM-CM group. The baseline characteristics of the two groups were comparable, except for the incidence of stiffness symptoms and stiffness scores. After 6 weeks of treatment, the WM-CM group exhibited superior results to the WM group in improving the total WOMAC score (24.71 ± 1.38 vs. 16.36 ± 0.62, p < 0.001). The WM-CM group also outperformed the WM group in WOMAC pain and joint function scores, VAS score, PCS score, MCS score, and clinical effectiveness (p < 0.05), which was consistent with the findings of the main evaluation index. Subgroup analysis indicated that the combined Chinese and Western medicine treatment showed more pronounced benefits in patients under 65 years of age and in those with a Kellgren-Lawrence (K-L) classification of 0-I. Throughout the study, no adverse effects were observed in either group. Conclusion: The combination of Chinese and Western medicine demonstrated superiority over Western medicine alone in relieving knee pain symptoms, improving knee function, and enhancing the quality of life for KOA patients with a K-L score of 3 or less. Moreover, the treatment exhibited a good safety profile. Clinical Trial Registration: (https://www.chictr.org.cn/), identifier (ChiCTR1900027175).

Fused-Deposition Modeling 3D Printing of Short-Cut Carbon-Fiber-Reinforced PA6 Composites for Strengthening, Toughening, and Light Weighting.

Additive manufacturing of carbon-fiber-reinforced polymer (CFRP) has been widely used in many fields. However, issues such as inconsistent fiber orientation distribution and void formation during the layer stacking process have hindered the further optimization of the composite material's performance. This study aimed to address these challenges by conducting a comprehensive investigation into the influence of carbon fiber content and printing parameters on the micro-morphology, thermal properties, and mechanical properties of PA6-CF composites. Additionally, a heat treatment process was proposed to enhance the interlayer bonding and tensile properties of the printed composites in the printing direction. The experimental results demonstrate that the PA6-CF25 composite achieved the highest tensile strength of 163 MPa under optimal heat treatment conditions: 120 °C for 7.5 h. This corresponds to a significant tensile strength enhancement of 406% compared to the unreinforced composites, which represents the highest reported improvement in the current field of CFRP-fused deposition 3D printing. Additionally, we have innovatively developed a single-layer monofilament CF-OD model to quantitatively analyze the influence of fiber orientation distribution on the properties of the composite material. Under specific heat treatment conditions, the sample exhibits an average orientation angle µ of 0.43 and an orientation angle variance of 8.02. The peak frequency of fiber orientation closely aligns with 0°, which corresponds to the printing direction. Finally, the study explored the lightweight applications of the composite material, showcasing the impressive specific energy absorption (SEA) value of 17,800 J/kg when implementing 3D-printed PA6-CF composites as fillers in automobile crash boxes.

Expression of LRG-1 in mice with hypertensive renal damage and its significance. / LRG-1åœ¨é«˜è¡€åŽ‹è‚¾æŸå®³å°é¼ ä¸­çš„è¡¨è¾¾åŠå ¶æ„ä¹‰.

OBJECTIVES: Long-term elevated blood pressure may lead to kidney damage, yet the pathogenesis of hypertensive kidney damage is still unclear. This study aims to explore the role and significance of leucine-rich alpha-2-glycoprotein-1 (LRG-1) in hypertensive renal damage through detecting the levels of LRG-1 in the serum and kidney of mice with hypertensive renal damage and its relationship with related indexes. METHODS: C57BL/6 mice were used in this study and randomly divided into a control group, an angiotensin II (Ang II) group, and an Ang II+irbesartan group. The control group was gavaged with physiological saline. The Ang II group was pumped subcutaneously at a rate of 1.5 mg/(kg·d) for 28 days to establish the hypertensive renal damage model in mice, and then gavaged with equivalent physiological saline. The Ang II+irbesartan group used the same method to establish the hypertensive renal damage model, and then was gavaged with irbesartan. Immunohistochemistry and Western blotting were used to detect the expression of LRG-1 and fibrosis-related indicators (collagen I and fibronectin) in renal tissues. ELISA was used to evaluate the level of serum LRG-1 and inflammatory cytokines in mice. The urinary protein-creatinine ratio and renal function were determined, and correlation analysis was conducted. RESULTS: Compared with the control group, the levels of serum LRG-1, the expression of LRG-1 protein, collagen I, and fibronectin in kidney in the Ang II group were increased (all P<0.01). After treating with irbesartan, renal damage of hypertensive mice was alleviated, while the levels of LRG-1 in serum and kidney were decreased, and the expression of collagen I and fibronectin was down-regulated (all P<0.01). Correlation analysis showed that the level of serum LRG-1 was positively correlated with urinary protein-creatinine ratio, blood urea nitrogen, and blood creatinine level in hypertensive kidney damage mice. Serum level of LRG-1 was also positively correlated with serum inflammatory factors including TNF-α, IL-1ß, and IL-6. CONCLUSIONS: Hypertensive renal damage mice display elevated expression of LRG-1 in serum and kidney, and irbesartan can reduce the expression of LRG-1 while alleviating renal damage. The level of serum LRG-1 is positively correlated with the degree of hypertensive renal damage, suggesting that it may participate in the occurrence and development of hypertensive renal damage.

Single-cell RNA sequencing reveals the transcriptomic landscape of kidneys in patients with ischemic acute kidney injury.

BACKGROUND: Ischemic acute kidney injury (AKI) is a common syndrome associated with considerable mortality and healthcare costs. Up to now, the underlying pathogenesis of ischemic AKI remains incompletely understood, and specific strategies for early diagnosis and treatment of ischemic AKI are still lacking. Here, this study aimed to define the transcriptomic landscape of AKI patients through single-cell RNA sequencing (scRNA-seq) analysis in kidneys. METHODS: In this study, scRNA-seq technology was applied to kidneys from two ischemic AKI patients, and three human public scRNA-seq datasets were collected as controls. Differentially expressed genes (DEGs) and cell clusters of kidneys were determined. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, as well as the ligand-receptor interaction between cells, were performed. We also validated several DEGs expression in kidneys from human ischemic AKI and ischemia/reperfusion (I/R) injury induced AKI mice through immunohistochemistry staining. RESULTS: 15 distinct cell clusters were determined in kidney from subjects of ischemic AKI and control. The injured proximal tubules (PT) displayed a proapoptotic and proinflammatory phenotype. PT cells of ischemic AKI had up-regulation of novel pro-apoptotic genes including USP47 , RASSF4 , EBAG9 , IER3 , SASH1 , SEPTIN7 , and NUB1 , which have not been reported in ischemic AKI previously. Several hub genes were validated in kidneys from human AKI and renal I/R injury mice, respectively. Furthermore, PT highly expressed DEGs enriched in endoplasmic reticulum stress, autophagy, and retinoic acid-inducible gene I (RIG-I) signaling. DEGs overexpressed in other tubular cells were primarily enriched in nucleotide-binding and oligomerization domain (NOD)-like receptor signaling, estrogen signaling, interleukin (IL)-12 signaling, and IL-17 signaling. Overexpressed genes in kidney-resident immune cells including macrophages, natural killer T (NKT) cells, monocytes, and dendritic cells were associated with leukocyte activation, chemotaxis, cell adhesion, and complement activation. In addition, the ligand-receptor interactions analysis revealed prominent communications between macrophages and monocytes with other cells in the process of ischemic AKI. CONCLUSION: Together, this study reveals distinct cell-specific transcriptomic atlas of kidney in ischemic AKI patients, altered signaling pathways, and potential cell-cell crosstalk in the development of AKI. These data reveal new insights into the pathogenesis and potential therapeutic strategies in ischemic AKI.

Genistein Modified with 8-Prenyl Group Suppresses Osteoclast Activity Directly via Its Prototype but Not Metabolite by Gut Microbiota.

Postmenopausal osteoporosis is a significant threat to human health globally. Genistein, a soy-derived isoflavone, is regarded as a promising anti-osteoporosis drug with the effects of promoting osteoblastogenesis and suppressing osteoclastogenesis. However, its oral bioavailability (6.8%) is limited by water solubility, intestinal permeability, and biotransformation. Fortunately, 8-prenelylated genistein (8PG), a derivative of genistein found in Erythrina Variegate, presented excellent predicted oral bioavailability (51.64%) with an improved osteoblastogenesis effect, although its effects on osteoclastogenesis and intestinal biotransformation were still unclear. In this study, an in vitro microbial transformation platform and UPLC-QTOF/MS analysis method were developed to explore the functional metabolites of 8PG. RANKL-induced RAW264.7 cells were utilized to evaluate the effects of 8PG on osteoclastogenesis. Our results showed that genistein was transformed into dihydrogenistein and 5-hydroxy equol, while 8PG metabolites were undetectable under the same conditions. The 8PG (10-6 M) was more potent in inhibiting osteoclastogenesis than genistein (10-5 M) and it down-regulated NFATC1, cSRC, MMP-9 and Cathepsin K. It was concluded that 8-prenyl plays an important role in influencing the osteoclast activity and intestinal biotransformation of 8PG, which provides evidence supporting the further development of 8PG as a good anti-osteoporosis agent.

Clinical features and prognosis of MPO-ANCA and anti-GBM double-seropositive patients.

Background: Several lines of evidence implicate that there are distinct differences between patients with myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane (GBM) antibody double-seropositive patients (DPPs) and single-positive patients. Hence, we conducted a retrospective study from a single center in China to analyze the clinical and pathological features, and prognosis of DPPs. Methods: 109 patients with MPO-ANCA-associated vasculitis (MPO-AAV), 20 DPPs and 23 patients diagnosed with anti-GBM disease from a large center in China were included in this study. The ratio of patients with renal biopsy in three groups were 100%, 50% and 100%, respectively. Their clinical and pathological characteristics, and outcomes were analyzed. The intensity of immune deposits in the kidney at diagnosis was detected by immunofluorescence (IF). Furthermore, multivariate Cox hazard model analysis was used to assess the clinical and histological predictors of end-stage renal disease (ESRD) and death for DPPs. Results: In our study, we found that patients in the DPPs group were older than the other two groups (p = 0.007, MPO-AAV vs. DPPs; p < 0.001, DPPs vs. anti-GBM). The DPPs group had a higher value of serum creatinine (p = 0.041) and lower estimated glomerular filtration rate (eGFR) (p = 0.032) compared with MPO-AAV patients. On the contrary, the DPPs group had a lower serum creatinine (p = 0.003) compared with patients with anti-GBM group. The proportion of patients with cardiac system involvement in the DPPs group was higher than anti-GBM patients (p = 0.014). Cellular crescents could be generally observed in renal biopsy of DPPs and patients with anti-GBM glomerulonephritis. In addition, Bowman's capsule rupture was more common in DPPs than MPO-AAV patients (p = 0.001). MPO-AAV had a better renal and overall survival outcome than DPPs (p < 0.001). There was no significant difference of renal and overall survival outcome between DPPs and patients with anti-GBM disease. The incidence of ESRD in DPPs was negatively associated with lymphocyte count (HR 0.153, 95% CI 0.027 to 0.872, p = 0.034) and eGFR (HR 0.847, 95% CI 0.726 to 0.989, p = 0.036). Elevated serum creatinine was confirmed as a risk factor of both renal (HR 1.003, 95% CI 1.000 to 1.005, p = 0.019) and patient survival in DPPs (HR1.461, 95% CI 1.050 to 2.033, p = 0.024). Conclusion: In summary, compared with anti-GBM disease, DPPs tended to involve multi-organ damage rather than limited to the kidney. It is highlighted that serologic DPPs have a worse renal and patient prognosis than MPO-AAV. Moreover, we found that the risk factors of renal survival of DPPs include low lymphocyte count, elevated serum creatinine and reduced eGFR, and serum creatinine can predict patient survival.

Effects of Dendrobium officinale ultrafine powder on sub-health mice induced by unhealthy lifestyle based on neuroendocrine immune system.

Sub-health status, in which a person's mind and body exist in a low-quality state of being between disease and health, has become an urgent public health problem that cannot be ignored globally. One of the most apparent sub-health symptoms is fatigue, and it also shows a significant decrease in mental vitality and adaptability caused by disruption of the neuroendocrine-immune system. Dendrobium officinale (DOF) has a long history of use in China as a medicinal food with immune-regulating, anti-fatigue, anti-oxidant, and hypoglycemic effects. The ameliorative effects of Dendrobium officinale on sub-health mice are investigated in this present study, as well as its underlying mechanisms via neuroendocrine-immune (NEI) modulation. Forty male KM mice were divided into normal control group (NC), model control group (MC), and two doses of ultrafine DOF powder (DOFP) intervention groups: DOFP-L (0.1 g kg-1), DOFP-H (0.2 g kg-1) groups. Sub-health mice were induced by mimicking unhealthy human lifestyles, including cold water swimming, limbs restriction, an unhealthy diet, and sleep deprivation for seven weeks. The findings revealed that DOFP intervened sub-health mice have less bodyweight loss, normal fecal morphology, as well as lower face temperature and blood flow, which is similar to the normal mice. Moreover, sub-health mice treated with DOFP showed improved forelimb grip strength and exercise endurance in weight-loaded exhaustion swimming and cold water exhaustion swimming, combined with reduced content of lactic acid (LD), lactate dehydrogenase (LDH), blood urea nitrogen (BUN) in the plasma, increased storage of liver glycogen (LG), and muscle glycogen (MG), as well as increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), reduced malondialdehyde (MDA) levels in the liver. Additionally, DOFP could increase the counts of autonomous movements of sub-health mice, minimize tail suspension time, and perform well in the elevated plus maze and open field tests, all of which are associated with anti-depression and anti-anxiety. Moreover, mechanistic investigations revealed that DOFP could alleviate plasma corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol (CORT) related hormones in the HPA axis, increase the level of hypothalamic norepinephrine (NE) and plasma ß-endorphin (ß-EP) of sub-health mice, while downregulating the content of 5-hydroxytryptamine (5-HT), dopamine (DA), and the relative mRNA expression of 5-HT1A and CRH in hypothalamus, and increase immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM), and CD4+/CD8+ T cell ratio levels. In conclusion, DOFP can relieve symptoms such as fatigue and depression in sub-health mice by regulating the disorder of the neuroendocrine-immune network.

Preparation, Characterization, and In Vitro Release of Curcumin-Loaded IRMOF-10 Nanoparticles and Investigation of Their Pro-Apoptotic Effects on Human Hepatoma HepG2 Cells.

Curcumin (CUR) has a bright future in the treatment of cancer as a natural active ingredient with great potential. However, curcumin has a low solubility, which limits its clinical application. In this study, IRMOF-10 was created by the direct addition of triethylamine, CUR was loaded into IRMOF-10 using the solvent adsorption method, and the two were characterized using a scanning electron microscope (SEM), X-ray diffraction (XRD), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TG) methods, and Brunauer-Emmett-Teller (BET) analysis. We also used the MTT method, 4',6-diamidino-2-phenylindole (DAPI) staining, the annexin V/PI method, cellular uptake, reactive oxygen species (ROS), and the mitochondrial membrane potential (MMP) to perform a safety analysis and anticancer activity study of IRMOF-10 and CUR@IRMOF-10 on HepG2 cells. Our results showed that CUR@IRMOF-10 had a CUR load of 63.96%, with an obvious slow-release phenomenon. The CUR levels released under different conditions at 60 h were 33.58% (pH 7.4) and 31.86% (pH 5.5). Cell experiments proved that IRMOF-10 was biologically safe and could promote curcumin entering the nucleus, causing a series of reactions, such as an increase in reactive oxygen species and a decrease in the mitochondrial membrane potential, thereby leading to cell apoptosis. In summary, IRMOF-10 is an excellent drug carrier and CUR@IRMOF-10 is an effective anti-liver cancer sustained-release preparation.

Interleukin-22 exacerbates angiotensin II-induced hypertensive renal injury.

Hypertensive renal injury (HRI) is a main cause of end-stage renal diseases, and CD4+ T cells and the secreted inflammatory cytokines contribute to the progress of HRI. However, the exact mechanisms remain unidentified in HRI, and there is still a shortage of effective treatments. Here, we aim to explore the role of interleukin-22 (IL-22) and its underlying mechanism in HRI. Serum IL-22 level and peripheral Th22 cells frequency in patients with HRI were detected by ELISA and flow cytometry respectively. Angiotension II (Ang II) was infused subcutaneously to C57BL/6 mice for 28 days. Hypertensive mice were treated with recombinant IL-22 (rIL-22), anti-IL-22 antibody, or JAK2/STAT3 pathway blocker AG-490 respectively. Blood pressure (BP), urinary albumin/creatinine ratio (UACR), serum creatinine (Scr) and renal histopathology were measured; renal Th22 cells proportion were evaluated; inflammatory factors were evaluated by ELISA; JAK2/STAT3 pathway and fibrosis related factors expression in kidney were detected by Western blot. Serum IL-22 and Th22 cells proportion in kidney of mice were elevated after Ang II infusion. Compared to Ang II-infused mice, treatment with rIL-22 resulted in further increased UACR, Scr, renal pathological damage, inflammation and renal fibrosis, accompanied by elevated BP and JAK2/STAT3 pathway activation. Conversely, anti-IL-22 antibody reduced inflammation, renal fibrosis and BP in Ang II treated mice. AG490 could compromised the above effects of rIL-22. Taken together, recombinant IL-22 may aggravate hypertensive renal damage mediated by Ang II in mice, which may be through promoting JAK2/STAT3 pathway activation. Anti-IL-22 antibody exerts the opposite effects. These data suggest the IL-22 signaling maybe a novel therapeutic target for the treatment of hypertensive renal injury.

Potential Plasma Metabolic Biomarkers of Tourette Syndrome Discovery Based on Integrated Nontargeted and Targeted Metabolomics Screening Plasma Metabolic Biomarkers of TS.

Objective: Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by abnormal movements, phonations, and tics, but an accurate TS diagnosis remains challenging and indeed depends on its description of clinical symptoms. Our study was conducted to discover and verify some metabolite biomarkers based on nontargeted and targeted metabolomics. Methods: We conducted untargeted ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) for preliminary screening of potential biomarkers on 30 TS patients and 10 healthy controls and then performed validation experiments based on targeted ultrahigh-performance liquid chromatography triple quadrupole-MS (UHPLC/MS/MS) on 35 TS patients and 14 healthy controls. Results: 1775 differentially expressed metabolites were identified by partial least squares discriminant analysis (PLS-DA), fold-change analysis, T-test, and hierarchical clustering analysis (adjusted p value <0.05 and |logFC| > 1). TS plasma samples were found to be differentiated from healthy samples in our approach. Furthermore, aspartate and asparagine metabolism pathways were considered to be a significant enrichment pathway in TS progression based on metabolite pathway enrichment analysis. For the 8 metabolites involved in this pathway that we detected, we then performed validation experiments based on targeted UHPLC/MS/MS. The t-test, Mann-Whitney U test, and receiver operating characteristic (ROC) curve analysis were used to determine potential biomarkers. Ultimately, L-arginine and L-pipecolic acid were validated as significantly differentiated metabolites (p < 0.05), with an AUC of 70.0% and 80.3%, respectively. Conclusion: L-pipecolic acid was defined as a potential biomarker for TS diagnosis by the combined application of nontargeted and targeted metabolomic analysis.

Astragaloside IV-targeting miRNA-1 attenuates lipopolysaccharide-induced cardiac dysfunction in rats through inhibition of apoptosis and autophagy.

Astragaloside IV (AS-IV), the major active constituent purified from Astragalus membranaceus, was previously reported to have protective effects against cardiac dysfunction. However, the underlying mechanism remains unknown. In the present study, we investigated the protective effect of AS-IV on lipopolysaccharide (LPS)-induced cardiac dysfunction and explored the potential mechanism by focusing on miRNA-1 (miR-1) at the animal and cellular levels. A series of methods were used, including echocardiography, flow cytometry, ELISA, immunofluorescence, transmission electron microscopy, RT-PCR, and western blotting. The results showed that both AS-IV and the miR-1 inhibitor improved cardiac dysfunction, reduced heart injury, inhibited apoptosis and autophagy, and regulated the expression of calcium- and mitochondrial energy metabolism-related proteins in the heart tissue of rats treated with LPS. Importantly, AS-IV downregulated the expression of miR-1 mRNA in heart tissue. All effects of AS-IV were at least partly abolished by miR-1 mimics. In the in vitro study, both AS-IV and the miR-1 inhibitor inhibited apoptosis and autophagy and regulated the expression of calcium- and mitochondrial energy metabolism-related proteins in heart cells treated with LPS. Similarly, AS-IV downregulated the expression of miR-1 mRNA in heart cells. All effects of AS-IV on cells were at least partly abolished by miR-1 mimics. Furthermore, miR-1 mimics exhibited effects similar to LPS both in animal and cellular studies. Taken together, these results suggest that AS-IV protects against LPS-induced cardiac dysfunction by inhibiting calcium-mediated apoptosis and autophagy by targeting miR-1, highlighting a new mechanism for the therapeutic effect of AS-IV on cardiac dysfunction.

Kanglexin, a new anthraquinone compound, attenuates lipid accumulation by activating the AMPK/SREBP-2/PCSK9/LDLR signalling pathway.

Hyperlipidaemia is one of the major risk factors for atherosclerosis, coronary heart disease, stroke and diabetes. In the present study, we synthesized a new anthraquinone compound, 1,8-dihydroxy-3-succinic acid monoethyl ester-6-methylanthraquinone, and named it Kanglexin (KLX). The aim of this study was to evaluate whether KLX has a lipid-lowering effect and to explore the potential molecular mechanism. In this study, Sprague-Dawley rats were fed a high fat diet (HFD) for 5 weeks to establish a hyperlipidaemia model; then, the rats were orally administered KLX (20, 40, and 80 mg kg-1·d-1) or atorvastatin calcium (AT, 10 mg kg-1·d-1) once a day for 2 weeks. KLX had prominent effects on reducing blood lipids, hepatic lipid accumulation, body weight and the ratio of liver weight/body weight. Furthermore, KLXdramatically reduced the total cholesterol (TC) and triglyceride (TG) levels and lipid accumulation in a HepG2 cell model of dyslipidaemia induced by 1 mmol/L oleic acid (OA). KLX may decrease lipid levels by phosphorylating adenosine monophosphate-activated protein kinase (AMPK) and the downstream sterol regulatory element binding protein 2 (SREBP-2)/proprotein convertase subtilisin/kexin type 9 (PCSK9)/low-density lipoprotein receptor (LDLR) signalling pathway in the HFD rats and OA-treated HepG2 cells. The effects of KLX on the AMPK/SREBP-2/PCSK9/LDLR signalling pathway were abolished when AMPK was inhibited by compound C (a specific AMPK inhibitor) in HepG2 cells. In summary, KLX has an efficient lipid-lowering effect mediated by activation of the AMPK/SREBP-2/PCSK9/LDLR signalling pathway. Our findings may provide new insight into and evidence for the discovery of a new lipid-lowering drug for the prevention and treatment of hyperlipidaemia, fatty liver, and cardiovascular disease in the clinic.

Kanglexin, a novel anthraquinone compound, protects against myocardial ischemic injury in mice by suppressing NLRP3 and pyroptosis.

Pyroptosis is a form of inflammatory cell death that could be driven by the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation following myocardial infarction (MI). Emerging evidence suggests the therapeutic potential for ameliorating MI-induced myocardial damages by targeting NLRP3 and pyroptosis. In this study, we investigated the myocardial protection effect of a novel anthraquinone compound (4,5-dihydroxy-7-methyl-9,10-anthraquinone-2-ethyl succinate) named Kanglexin (KLX) in vivo and in vitro. Male C57BL/6 mice were pre-treated either with KLX (20, 40 mg· kg-1per day, intragastric gavage) or vehicle for 7 consecutive days prior to ligation of coronary artery to induce permanent MI. KLX administration dose-dependently reduced myocardial infarct size and lactate dehydrogenase release and improved cardiac function as compared to vehicle-treated mice 24 h after MI. We found that MI triggered NLRP3 inflammasome activation leading to conversion of interleukin-1ß (IL-1ß) and IL-18 into their active mature forms in the heart, which could expand the infarct size and drive cardiac dysfunction. We also showed that MI induced pyroptosis, as evidenced by increased DNA fragmentation, mitochondrial swelling, and cell membrane rupture, as well as increased levels of pyroptosis-related proteins, including gasdermin D, N-terminal GSDMD, and cleaved caspase-1. All these detrimental alterations were prevented by KLX. In hypoxia- or lipopolysaccharide (LPS)-treated neonatal mouse ventricular cardiomyocytes, we showed that KLX (10 µM) decreased the elevated levels of terminal deoxynucleotidyl transferase dUTP nick end labeling- and propidium iodide-positive cells, and pyroptosis-related proteins. We conclude that KLX prevents MI-induced cardiac damages and cardiac dysfunction at least partly through attenuating NLRP3 and subsequent cardiomyocyte pyroptosis, and it is worthy of more rigorous investigations for its potential for alleviating ischemic heart disease.

Daming capsule, a hypolipidaemic drug, lowers blood lipids by activating the AMPK signalling pathway.

BACKGROUND/AIMS: Hyperlipidaemia is a major risk factor for cardiovascular and cerebrovascular diseases. Daming capsule (DMC), a medicine for lowering blood lipids, is marketed in China; however, its mechanism is unclear. The present study aimed to investigate the mechanism by which DMC reduces blood lipids. METHODS AND RESULTS: A rat model of hyperlipidaemia was established by feeding rats a high-fat diet (HFD), and the serum lipid levels were detected with an automatic biochemical analyser. DMC (162 mg/kg) and atorvastatin calcium (10 mg/kg) were orally administered to the hyperlipidaemic rats for 4 weeks. HFD feeding markedly induced increases in the levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-c); however, DMC treatment significantly decreased the levels of TC, TG, and LDL-c in rats serum. Meanwhile, the hepatic TC and TG levels, liver weight/body weight ratio, and body weight were significantly lower in the DMC-treated rats than in the HFD rats. Moreover, DMC significantly alleviated hepatomegaly, hepatic lipid deposition, and hepatic steatosis. The protein expression level of phospho-adenosine monophosphate-activated protein kinase (p-AMPK) (Thr172) in HFD rat livers was lower than that in normal rat livers, whereas it increased in the liver of the DMC-treated rats; however, the protein expression level of total-AMPK in the liver was not different among the groups. The AMPK-activating effect of DMC was blocked by Compound C (a specific AMPK inhibitor) in HepG2 cells. Additionally, DMC considerably increased peroxisome proliferator-activated receptor-alpha (PPARα) protein expression and lipoprotein lipase (LPL) transcription and concentration in the liver. This effect of DMC was also inhibited by Compound C in HepG2 cells. DMC also promoted LDL receptor (LDLR) protein expression by activating AMPK. We further found that DMC reduced the levels of TC and TG in oleic acid-treated HepG2 cells, and it restored the expression levels of p-AMPK, PPARα, LPL, and LDLR compared to the decreased levels observed in oleic acid-treated HepG2 cells. CONCLUSION: DMC lowered lipids in serum and the liver by activating AMPK. On the one hand, the activation of AMPK enhanced PPARα expression and LPL transcription to lead to the hydrolysis of TG; on the other hand, it increased LDLR protein expression to promote lipid metabolism.