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Clustered regularly interspaced short palindromic repeats (CRISPR) technology emerges a remarkable potential for cure of refractory cancer like metastatic breast cancer. However, how to efficiently deliver the CRISPR system with non-viral carrier remains a major issue to be solved. Here, we report a kind of targeted core-shell nanoparticles (NPs) carrying dual plasmids (pHR-pCas9) for precise CCCTC-binding factor (CTCF) gene insert to circumvent metastatic breast cancer. The targeted core-shell NPs carrying pHR-pCas9 can accomplish γGTP-mediated cellular uptake and endosomal escape, facilitate the precise insert and stable expression of CTCF gene, inhibit the migration, metastasis, and colonization of metastatic breast cancer cells. Besides, the finding further reveals that the inhibitory mechanism of metastasis could be associated with up-regulating CTCF protein, followed by down-regulating stomatin (STOM) protein. The study offers a universal nanostrategy enabling the robust non-viral delivery of gene-editing system for treatment of severe illness.

A universal strategy for green and in situ synthesis of carbon dot-based pickling solution with high inhibition efficiency.

Background: G-protein-coupled receptor 43 (GPR43) is a posttranscriptional regulator involved in cholesterol metabolism. This study aimed to investigate the possible roles of GPR43 activation in podocyte lipotoxicity in diabetic nephropathy (DN) and explore the potential mechanisms. Methods: The experiments were conducted by using diabetic GPR43-knockout mice and a podocyte cell culture model. Lipid deposition and free cholesterol levels in kidney tissues were measured by BODIPY staining and quantitative cholesterol assays, respectively. The protein expression of GPR43, LC3II, p62, beclin1, low-density lipoprotein receptor (LDLR) and early growth response protein 1 (EGR1) in kidney tissues and podocytes was measured by real-time PCR, immunofluorescent staining and Western blotting. Results: There were increased LDL cholesterol levels in plasma and cholesterol accumulation in the kidneys of diabetic mice. However, GPR43 gene knockout inhibited these changes. An in vitro study further demonstrated that acetate treatment induced cholesterol accumulation in high glucose-stimulated podocytes, which was correlated with increased cholesterol uptake mediated by LDLR and reduced cholesterol autophagic degradation, as characterized by the inhibition of LC3 maturation, p62 degradation and autophagosome formation. Gene knockdown or pharmacological inhibition of GPR43 prevented these effects on podocytes. Furthermore, GPR43 activation increased extracellular regulated protein kinases 1/2 (ERK1/2) activity and EGR1 expression in podocytes, which resulted in an increase in cholesterol influx and autophagy inhibition. In contrast, after GPR43 deletion, these changes in podocytes were improved, as shown by the in vivo and in vitro results. Conclusion: GPR43 activation-mediated lipotoxicity contributes to podocyte injury in DN by modulating the ERK/EGR1 pathway.

Epidemiological studies have shown that higher intake of flavonoid is inversely associated with CHD risk. However, which flavonoid subclass could reduce CHD risk has remained controversial. The present meta-analysis of prospective cohort studies aimed to quantitatively assess the associations between flavonoid subclasses and CHD risk. A systematic literature search was implemented from PubMed and Web of Science databases up to March 2021, and eligible studies were identified. Multivariate-adjust relative risks (RR) with corresponding 95 % CI were pooled by using a random-effects model. A restricted cubic spline regression model was performed for non-linear dose–response analysis. A total of 19 independent prospective cohort studies with 894 471 participants and 34 707 events were included. The results showed that dietary intakes of anthocyanins (RR = 0·90; 95 % CI: 0·83, 0·98), proanthocyanidins (RR = 0·78; 95 % CI: 0·65, 0·94), flavonols (RR = 0·88; 95 % CI: 0·79, 0·98), flavones (RR = 0·94; 95 % CI: 0·89, 0·99) and isoflavones (RR = 0·90; 95 % CI: 0·83, 0·98) were negatively associated with CHD risk. Dose–response analysis showed that increment of 50 mg/d anthocyanins, 100 mg/d proanthocyanidins, 25 mg/d flavonols, 5 mg/d flavones and 0·5 mg/d isoflavones were associated with 5 % reduction in CHD risk, respectively. Sensitivity and subgroup analyses were used to further support these associations. The present results indicate that dietary intakes of fruits and vegetables abundant five flavonoid subclasses, namely anthocyanins, proanthocyanidins, flavonols, flavones and isoflavones, are associated with a lower risk of CHD.

The improvement of lightweight and safety is the development requirement of automobile parts. Therefore, the demand of thin-walled parts with ultra-high strength is more urgent. However, with the increase of strength, the springback phenomenon of parts is particularly serious, which greatly affects the forming quality of parts. Generally, the springback of automobile parts should be controlled within 5%. Thus, the accurate simulation and prediction of springback can provide important support for the manufacture of ultra-high strength automobile thin-walled parts. In this paper, the bending springback of the medium-Mn steel, as one of the third-generation automobile steels, was studied based on experiment and simulation under different conditions. Tensile tests were carried out to evaluate comprehensive mechanical properties with high strength and high plasticity. Cyclic loading-unloading tests were conducted to analyze the changing rules of unloading elastic modulus and inelastic recovery with strain. The correlation model between unloading elastic modulus and true plastic strain was further established and the model parameters were obtained. Furthermore, V-shaped bending tests were carried out under different conditions to analyze the effects of rolling direction, bending angle, and punch fillet radius on springback. The effect of rolling direction on springback angle is negligible. The bending angle has a positive effect on springback angle, while the punch fillet radius has a negative effect. Finally, the material model with constant and variable elastic moduli were developed by using user-defined material subroutines for the medium-Mn steel. V-shaped bending tests under constant and variable elastic moduli were simulated and compared with the experimental result. The simulated result with variable elastic modulus was closer to the experimental one, which proves the importance of considering the change of unloading elastic modulus in the numerical simulation of medium-Mn steel. The research result of this paper is helpful to enhance the simulation accuracy of springback of medium-Mn steel part and promote its industrial application.

PurposeTo estimate the effectiveness of an Epstein–Barr virus (EBV) serology-based screening program to reduce nasopharyngeal carcinoma (NPC) mortality in a cluster randomized controlled trial in an NPC high-risk population.MethodsSixteen towns in Sihui and Zhongshan Cities, China were selected; eight were randomly allocated to the screening group and eight to the control group. Cantonese residents aged 30-69 years with no history of NPC were included January 1, 2008 to December 31, 2015. Residents in the screening towns were invited to undergo serum EBV VCA/EBNA1 IgA antibody tests; others received no intervention. Screening lasted through December 31, 2015; the population was followed through December 31, 2017.ResultsA total of 175,037 residents in the screening group and 184,526 residents in the control group were included. NPC incidence was similar in screening and control groups. A 28% reduction in NPC mortality was observed in the screening versus control arms in the overall study population (8.0 NPC deaths per 1000 person years versus 11.1; adjusted rate ratio [aRR]=0.72; 95% confidence interval=0.48-1.09; p=0.12). A stronger benefit was observed among individuals aged >50 (aRR=0.63; p=0.048) compared to those ConclusionIn this near 10-year trial, serology EBV VCA and EBNA1 IgA antibody testing led to a reduction in NPC mortality, particularly among individuals aged ⩾50. EBV antibody-based screening for NPC is effective at reducing NPC mortality in high-risk populations.Trial registration numberNCT00941538

Rationale: Albuminuria is an early clinical feature in the progression of diabetic nephropathy (DN). Podocyte insulin resistance is a main cause of podocyte injury, playing crucial roles by contributing to albuminuria in early DN. G protein-coupled receptor 43 (GPR43) is a metabolite sensor modulating the cell signalling pathways to maintain metabolic homeostasis. However, the roles of GPR43 in podocyte insulin resistance and its potential mechanisms in the development of DN are unclear. Methods: The experiments were conducted by using kidney tissues from biopsied DN patients, streptozotocin (STZ) induced diabetic mice with or without global GPR43 gene knockout, diabetic rats treated with broad-spectrum oral antibiotics or fecal microbiota transplantation, and cell culture model of podocytes. Renal pathological injuries were evaluated by periodic acid-schiff staining and transmission electron microscopy. The expression of GPR43 with other podocyte insulin resistance related molecules was checked by immunofluorescent staining, real-time PCR, and Western blotting. Serum acetate level was examined by gas chromatographic analysis. The distribution of gut microbiota was measured by 16S ribosomal DNA sequencing with faeces. Results: Our results demonstrated that GPR43 expression was increased in kidney samples of DN patients, diabetic animal models, and high glucose-stimulated podocytes. Interestingly, deletion of GPR43 alleviated albuminuria and renal injury in diabetic mice. Pharmacological inhibition and knockdown of GPR43 expression in podocytes increased insulin-induced Akt phosphorylation through the restoration of adenosine 5'-monophosphate-activated protein kinase α (AMPKα) activity. This effect was associated with the suppression of AMPKα activity through post-transcriptional phosphorylation via the protein kinase C-phospholipase C (PKC-PLC) pathway. Antibiotic treatment-mediated gut microbiota depletion, and faecal microbiota transplantation from the healthy donor controls substantially improved podocyte insulin sensitivity and attenuated glomerular injury in diabetic rats accompanied by the downregulation of the GPR43 expression and a decrease in the level of serum acetate. Conclusion: These findings suggested that dysbiosis of gut microbiota-modulated GPR43 activation contributed to albuminuria in DN, which could be mediated by podocyte insulin resistance through the inhibition of AMPKα activity.

Background: Our previous study demonstrated that the disruption of cholesterol homeostasis promotes tubulointerstitial injury in diabetic nephropathy (DN). This study aimed to further investigate the effects of gut microbiota dysbiosis on this process and explored its potential mechanism. Methods: Diabetic rats treated with broad-spectrum oral antibiotics or faecal microbiota transplantation (FMT) from the healthy donor group and human kidney 2 (HK-2) cells stimulated with sodium acetate were used to observe the effects of gut microbiota on cholesterol homeostasis. The gut microbiota distribution was measured by 16S rDNA sequencing with faeces. Serum acetate level was examined by gas chromatographic analysis. Protein expression of G protein coupled receptor 43 (GPR43) and molecules involved in cholesterol homeostasis were assessed by immunohistochemical staining, immunofluorescence staining, and Western Blotting. Results: Depletion of gut microbiota significantly attenuated albuminuria and tubulointerstitial injury. Interestingly, serum acetate levels were also markedly decreased in antibiotics-treated diabetic rats and positively correlated with the cholesterol contents in kidneys. An in vitro study demonstrated that acetate significantly increased cholesterol accumulation in HK-2 cells, which was caused by increased expression of proteins mainly modulating cholesterol synthesis and uptake. As expected, FMT effectively decreased serum acetate levels and alleviated tubulointerstitial injury in diabetic rats through overriding the disruption of cholesterol homeostasis. Furthermore, GPR43 siRNA treatment blocked acetate-mediated cholesterol homeostasis dysregulation in HK-2 cells through decreasing the expression of proteins governed cholesterol synthesis and uptake. Conclusion: Our studies for the first time demonstrated that the acetate produced from gut microbiota mediated the dysregulation of cholesterol homeostasis through the activation of GPR43, thereby contributing to the tubulointerstitial injury of DN, suggesting that gut microbiota reprogramming might be a new strategy for DN prevention and therapy.

Epidemiological studies indicate that higher intakes of flavonoids are associated with reduced stroke risk, however, which subtypes play significant roles to protect against stroke remain unclear. A systematic literature search in PubMed and Web of Science databases was performed up to Oct. 2021. Flavonoids or their subtypes (flavanol, flavanone, flavone, flavan-3-ol, isoflavone, or anthocyanin) were paired with stoke as the search term. Multivariate-adjusted relative risks (RRs) with 95% confidence intervals (CIs) for the highest versus the lowest category were pooled by using a random-effects model. Dose-response analysis was implemented by using a restricted cubic spline regression model. Ten independent prospective cohort studies with 387,076 participants and 9,564 events were included. Higher intakes of flavanones were inversely associated with stroke risk (RR = 0.85; 95%CI: 0.78, 0.93). Dose-response analysis showed that 50 mg/day increment of flavanones was associated with 11% reduction in stroke risk (RR = 0.89; 95%CI: 0.84, 0.94). Flavan-3-ols was marginally inversely associated with stroke risk (RR = 0.92; 95%CI: 0.82, 1.02). Dose-response analysis showed that 200 mg/day increment of flavan-3-ols was associated with 14% reduction in stroke risk (RR = 0.86; 95%CI: 0.75, 0.98). The non-significant association was observed with respect to other flavonoid subclasses. This study demonstrated higher intakes of flavanones and flavan-3-ols were associated with a lower risk of stroke. Dietary intakes of lemon and citrus rich in flavanones and flavan-3-ols might have beneficial functions for the protection against stroke. The findings of these associations of the present study need to be confirmed in other regions and ethnic origins.

Objective Plasma Epstein-Barr virus (EBV) DNA is considered a biomarker for nasopharyngeal carcinoma (NPC). However, its long-term role in NPC development is unclear. Materials and methods A total of 1363 participants seropositive for EBV VCA-IgA and EBNA1-IgA in a community-based NPC screening program in southern China were tested for plasma EBV DNA levels by real-time qPCR between 2008 and 2015. New NPC cases were confirmed by active follow-up approach and linkage to local cancer registry through the end of 2016. Cox proportional hazards regression analysis was performed to calculate the hazard ratios (HRs) for NPC risk with plasma EBV DNA. Results Thirty patients were newly diagnosed during a median 7.5 years follow-up. NPC incidence increased with the plasma EBV DNA load ranging from 281.46 to 10,074.47 per 100,000 person-years in participants with undetectable and ≥ 1000 copies/ml levels; the corresponding cumulative incidence rates were 1.73 and 50%. Furthermore, plasma EBV DNA loads conferred an independent risk for NPC development after adjustment for other risk factors, with HRs of 7.63 for > 3–999 copies/ml and 39.79 for ≥1000 copies/ml. However, the HRs decreased gradually after excluding NPC cases detected in the first 2 to 3 years and became statistically nonsignificant by excluding cases detected during the first 4 years. Conclusion Elevated plasma EBV DNA can predict NPC risk over 3 years. Monitoring plasma EBV DNA can be used as a complementary approach to EBV serological antibody-based screening for NPC.

Mg alloys oxidize easily in air atmosphere during explosive welding. In this study, explosive welding of Mg/Al composites was shielded using inert gas to improve composite quality. Mg-AZ31B/Al-1060 composite plates were produced under helium atmosphere and compared with identical plates produced under air atmosphere with the same parameters. Microscopic morphology, elemental distribution and the mechanical properties of the bonding interface were evaluated. The interface morphology of the composites welded under helium differs significantly from those welded under air due to the different pressure of shock waves in gaseous media, and almost no oxide formed on the interface of helium bonded composite. In addition, the gain of shear and tensile strength of the helium bonded samples were observed. Therefore, the inert gas plays an important role in improving the properties of Mg-Al composite plates. Inert gas-shielding can be applied as an effective manufacturing method in live wave metal explosive welding.

Thermal deposition and temperature distribution on the interface of explosive welding composites affect the formation of molten regions and the interface morphology. This study is primarily devoted to discussing the effect of thermal conduction on the distribution of interfacial temperature. Two-dimensional models with thermal conductivity coefficient were established based on the Johnson-Cook constitutive equation and Gruneisen state equation by using the smooth-particle hydrodynamics (SPH) method in Fortran. The simulation results show that the melting of interface metals occurred in all the case even it was too small to observe, which verified the interface melting metal has similar characteristics of incompressible fluid during the welding process. Furthermore, the temperature distribution was significantly different from the adiabatic model with the help of high cooling rate when the plate thickness is less than 1 mm, which suggested the thermal conduction cannot be neglected in the analysis of temperature and melting under this condition.

Background: Neo-adjuvant chemotherapy is an effective strategy for improving treatment of breast cancers. However, the efficacy of this treatment strategy is limited for treatment of triple negative breast cancer (TNBC). Gene therapy may be a more effective strategy for improving the prognosis of TNBC. Methods: A novel 25 nucleotide sense strand of miRNA was designed to treat TNBC by silencing the Slug gene, and encapsulated into DSPE-PEG2000-tLyp-1 peptide-modified functional liposomes. The efficacy of miRNA liposomes was evaluated on invasive TNBC cells and TNBC cancer-bearing nude mice. Furthermore, functional vinorelbine liposomes were constructed to investigate the anticancer effects of combined treatment. Results: The functional miRNA liposomes had a round shape and were nanosized (120 nm). Functional miRNA liposomes were effectively captured by TNBC cells in vitro and were target to mitochondria. Treatment with functional liposomes silenced the expression of Slug and Slug protein, inhibited the TGF-β1/Smad pathway, and inhibited invasiveness and growth of TNBC cells. In TNBC cancer-bearing mice, functional miRNA liposomes exerted a stronger anticancer effect than functional vinorelbine liposomes, and combination therapy with these two formulations resulted in nearly complete inhibition of tumor growth. Preliminary safety evaluations indicated that the functional miRNA liposomes did not affect body weight or cause damage to any major organs. Furthermore, the functional liposomes significantly increased the half-life of the drug in the blood of cancer-bearing nude mice, and increased drug accumulation in breast cancer tissues. Conclusion: In this study, we constructed novel functional miRNA liposomes. These liposomes silenced Slug expression and inhibited the TGF-β1/Smad pathway in TNBC cells, and enhanced anticancer efficacy in mice using combined chemotherapy. Hence, the present study demonstrated a promising strategy for gene therapy of invasive breast cancer.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the developed world. Podocyte injury is a critical cellular event involved in the progression of DN. Our previous studies demonstrated that platelet-derived microparticles (PMPs) mediated endothelial injury in diabetic rats. This study aimed to investigate whether PMPs are deposited in podocytes and to assess their potential effects on podocyte injury in DN.The deposition of PMPs in podocytes was assessed by immunofluorescent staining and electron microscopy. The changes in renal pathology and ultra-microstructure were assessed by periodic acid-Schiff staining and electron microscopy, respectively. The expression of inflammatory cytokines and extracellular matrix proteins was measured by immuno-histochemical staining and western blot.PMPs were widely deposited in podocytes of glomeruli in diabetic patients and animal models and closely associated with DN progression. Interestingly, aspirin treatment significantly inhibited the accumulation of PMPs in the glomeruli of diabetic rats, alleviated mesangial matrix expansion and fusion of foot processes, and decreased the protein expression of inflammatory cytokines and extracellular matrix secretion. An in vitro study further confirmed the deposition of PMPs in podocytes. Moreover, PMP stimulation induced the phenotypic transition of podocytes through decreased podocin protein expression and increased protein expression of α-SMA and fibronectin, which was correlated with increased production of inflammatory cytokines.Our findings demonstrated for the first time that the deposition of PMPs in podocytes contributed to the development of DN.

Background and Aims The G-protein-coupled receptor 43 (GPR43) is a post-transcriptional regulator involved in cholesterol metabolism. Our previous studies demonstrated that intracellular cholesterol accumulation contributed to podocyte injury in diabetic nephropathy (DN). This study aimed to investigate possible roles of GPR43 activation in lipid nephrotoxicity in DN and to explore its potential mechanisms. Method The experiments were conducted by using diabetic GPR43 knockout mice and cell culture model of podocytes. Renal pathological changes were checked by periodic acid schiff staining, immunohistochemical staining and transmission electron microscopy (TEM). The lipid deposition and free cholesterol contents in kidney tissues were detected by Oil Red O staining, BODIPY staining, and cholesterol quantitative assay. The protein expressions of GPR43, LC3II, p62 and related molecules of LDLR pathway in kidney tissues and podocytes were detected by real-time PCR, immunofluorescent staining, and Western blotting. Results There were decreased plasma level of LDL-cholesterol and cholesterol accumulation in kidney tissues of diabetic GPR43 knockout mice. In vitro study demonstrated that acetate, a stimulator of GPR43, increased LDLR-mediated cholesterol uptake in podocytes, accompanied with reduced cholesterol autophagic degeneration, characterized by inhibited LC3 maturation, p62 degradation, and autophagosome formation. These may evoke synergistic effects attributing to cellular cholesterol accumulation in podocytes. While genetic knockdown or pharmacological inhibition of GPR43 inhibited this effect in podocytes. Furthermore, the activation of GPR43 led to the activation of ERK1/2/EGR1 pathway in podocytes, whereas blocking ERK1/2 activity or reducing EGR1 expression reversed cholesterol influx and the inhibition of autophagy mediated by GPR43 activation in podocytes. Meanwhile, deletion of the GPR43 improved autophagy and inhibited the ERK1/2-EGR1 pathway of podocyte in diabetic mice in vivo. Conclusion Activation of the GPR43 mediated lipid nephrotoxicity contributes to podocyte injury in DN, which was mainly through the activation of ERK/EGR1 pathways. These findings suggested that the GPR43 receptor could be a potential therapeutic target for the prevention of DN progression.

Background and Aims Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the developed world. Podocyte injury has been shown to be a critical cellular event in the progression of DN. Our previous studies demonstrated that platelet-derived microparticles (PMPs) mediated endothelial injury in diabetic rats. Therefore, this study aimed to investigate whether the PMPs deposit in podocytes and its potential effects on podocyte injury in DN. Method Deposition of PMPs in podocytes was checked by immunofluorescent staining and electron microscopy. Renal pathological change and ultra-microstructure were respectively checked by periodic acid-schiff staining and electron microscopy. The protein expression of inflammatory cytokines and extracellular matrix was measured by immunohistochemical staining and Western blot. Results The PMPs were found to be widely deposited in podocytes of glomeruli in diabetic patients and animal models and closely associated with progression of DN. Interestingly, aspirin treatment significantly inhibited accumulation of PMPs in glomeruli of diabetic rats, accompanied with alleviated mesangial matrix expansion, fusion of foot processes, decreased protein expression of inflammatory cytokines and extracellular matrix secretion. The in vitro study further confirmed the deposition of PMPs in podocytes. Moreover, PMPs stimulation induced phenotype transition of podocytes through decreased protein expression of podocin and increased protein expression of α-SMA and fibronectin, which was correlated with increased production of inflammatory cytokines. Conclusion Our findings for the first time demonstrated that deposition of PMPs in podocytes contributed to the development of DN.

It is acknowledged that contrast-induced nephropathy (CIN) is a common cause of acute renal insufficiency after cardiac catheterization and affects mortality and morbidity. To date, it is unknown whether oral N-acetylcysteine (NAC) is able to prevent contrast-induced nephropathy (CIN) in patients undergoing coronary angioplasty. A meta-analysis of randomized controlled trials was performed to assess the effects of NAC in the prevention of CIN in patients following coronary angioplasty. A total of 19 studies published prior to January 2015 that investigated the efficacy of oral NAC for the prevention of CIN were collected from Medline, Cochrane and Embase databases and conference proceedings from cardiology and nephrology meetings. The primary point of investigation was CIN, and the secondary points were renal failure requiring dialysis, mortality and length of hospitalization. The meta-analysis was performed using fixed- or random-effect models according to heterogeneity. Up to January 2015, 19 randomized placebo-controlled clinical trials met the inclusion criteria for the meta-analysis, including 4,514 patients. The pooled data showed that oral NAC did not reduce the CIN incidence [relative risk 0.84, 95% confidence interval (CI) 0.65–1.10; P=0.20], without heterogeneity among trials (I2=29%). Thus, the present meta-analysis suggests that oral NAC therapy is not effective as an alternative treatment to prevent CIN in patients following angioplasty. Further high quality randomized clinical controlled trials are required to confirm the usage and availability of this treatment.

Background: Podocyte-derived microparticles (MPs) could be secreted from activated or apoptotic podocytes. An increased number of podocyte-derived MPs in the urine might reflect podocyte injury in renal diseases. This study aimed to observe the change of urinary podocyte-derived MP levels in patients with chronic kidney disease (CKD) and to further explore its correlation with the progression of CKD. Methods: A prospective, longitudinal study was conducted in eighty patients with biopsy-proven CKD. Podocyte-derived MPs (annexin V and podocalyxin positive) were detected by flow cytometry. The number of urinary podocyte-derived MPs was analyzed to evaluate the association with biochemical measurements and pathological glomerulosclerosis assessment. Patients with idiopathic membranous nephropathy (IMN) were followed up after the six-month treatment of prednisone combined with tacrolimus to evaluate the association of urinary podocyte-derived MP levels and the remission of IMN. Results: The CKD patients had higher urinary podocyte-derived MP levels compared with healthy controls (HCs). Baseline urinary levels of podocyte-derived MPs were positively correlated with 24-hour proteinuria, while were inversely correlated with the percentage of global glomerulosclerosis. The urinary podocyte-derived MPs levels had good discrimination for glomerulosclerosis [area under curve (AUC), 0.66]. The urinary podocyte-derived MPs levels in IMN patients were significantly decreased accompanied with the recovery of abnormal clinical parameters after six-month treatment. Conclusions: The urinary levels of podocyte-derived MPs were closely associated with podocyte injury and glomerulosclerosis, which could be useful for monitoring disease activity in CKD patients. Urinary podocyte-derived MPs might be a non-invasive biomarker for the evaluation of early CKD progression.

Background New non-invasive biomarkers are demanded to identify renal damage in various autoimmune-associated kidney diseases. Glomerular podocyte damage mediated by systemic lupus erythematosus (SLE) plays an important role in the pathogenesis and progression of lupus nephritis (LN). This study evaluated whether the podocyte-derived microparticles (MPs) were novel biomarkers of clinical and histological features in SLE patients with LN. Methods A cross-sectional study, including 34 SLE patients and 16 healthy controls, was designed. Urinary annexin V+ podocalyxin+ MPs of all participants were quantified by flow cytometry. The correlation of podocyte-derived MPs with clinical and histological parameters of SLE patients was analysed. Results The number of annexin V+ podocalyxin+ MPs from urine samples were markly increased in patients with SLE. Furthermore, the level of urinary podocyte-derived MPs was positively correlated with the SLE Disease Activity Index (SLEDAI) score, anti-dsDNA antibody titre, erythrocyte sedimentation rate, and proteinuria. Conversely, it was negatively correlated with the level of complement C3 and serum albumin. The number of urinary podocyte-derived MPs was significantly increased in SLE patients with high activity indices. Receiver operating characteristic (ROC) curves were calculated to assess the power for podocyte-derived MP levels in differentiating between SLE patients with and without LN. Podocyte-derived MP levels were able to differentiate between SLE patients with mild disease activity, as well as those with moderate and above disease activity. SLE patients showed increased podocyte-derived MP excretion into the urine. Conclusions These findings suggest that the change in urinary podocyte-derived MP levels could be useful for evaluating and monitoring SLE disease activity.

Some studies have shown that gut microbiota along with its metabolites is closely associated with diabetic mellitus (DM). In this study we explored the relationship between gut microbiota and kidney injuries of early diabetic nephropathy (DN) and its underlying mechanisms. Male SD rats were intraperitoneally injected with streptozotocin to induce DM. DM rats were orally administered compound broad-spectrum antibiotics for 8 weeks. After the rats were sacrificed, their blood, urine, feces, and renal tissues were harvested for analyses. We found that compared with the control rats, DM rats had abnormal intestinal microflora, increased plasma acetate levels, increased proteinuria, thickened glomerular basement membrane, and podocyte foot process effacement in the kidneys. Furthermore, the protein levels of angiotensin II, angiotensin-converting enzyme, and angiotensin II type 1 receptor in the kidneys of DM rats were significantly increased. Administration of broad-spectrum antibiotics in DM rats not only completely killed most intestinal microflora, but also significantly lowered the plasma acetate levels, inhibited intrarenal RAS activation, and attenuated kidney damage. Finally, we showed that plasma acetate levels were positively correlated with intrarenal angiotensin II protein expression (r = 0.969, P

The differentiation therapy of breast cancer stem cells (CSCs) represents a significant strategy to treat cancer, but inefficient delivery to CSCs hinders the efficacy of differentiation agents. In this work, we report a type of functional dendrisomes constructed by the synthesized amphiphilic dendrimers, which enhance cellular uptake by breast CSCs, differentiate breast CSCs by carrying all-trans retinoic acid (ATRA), and increase the anticancer efficacy by carrying ATRA and docetaxel (DTX) in vitro and in breast cancer-bearing mice. The study further reveals the mechanism of cellular uptake by breast CSCs and uncovers the differentiation mechanism by analyzing relevant signal molecules, transcription factors, and cell cycle-associated signaling pathways during differentiation therapy in breast CSCs. Hence, this study offers a novel type of functional dendrisomes for differentiation therapy of breast CSCs and has significant clinical implications. Vesicles formed from branched molecules, known as dendrisomes, can be used to reprogram cancer stem cells inside breast cancer tumors. Researchers are experimenting with all-trans retinoic acid (ATRA) that encourages cancer stem cells to differentiate into less malignant forms. Wan-Liang Lu from Peking University in Beijing, China, and colleagues has developed a protocol that improves cellular uptake of ATRA by encapsulating it in a biocompatible polymer. The team synthesized spherical vesicles with greater durability and drug delivery capability than typical lipid vesicles by using polyester-based chains with branched structures as membranes. The experiments on breast-cancer bearing mice demonstrated that dendrisomes containing a mixture of ATRA, cholesterol, lipids, and anticancer agent could successfully enter cancer stem cells and initiate differentiation over 48 h. The research represents a significant contribution to differentiation therapy of cancer stem cells. We report a kind of functional dendrisomes constructed by amphiphilic dendrimers, which enable to enhance cellular uptake by breast cancer stem cells (CSCs), to differentiate breast CSCs by carrying all-trans retinoic acid (ATRA), and to increase anticancer efficacy by carrying ATRA and docetaxel in vitro and in breast cancer-bearing mice. The study further reveals endocytosis mechanism, and uncovers differentiation mechanism by analyzing relevant signal molecules, transcription factors, and cell cycle associated signaling pathway. Hence, the present study offers a novel type of functional dendrisomes for differentiation therapy of breast CSCs, and has a significant clinical implication.

BACKGROUND Wearable activity trackers offer potential to optimize behavior and support self-management. To assist older adults in benefiting from mobile technologies, theory-driven deployment strategies are needed to overcome personal, technological, and sociocontextual barriers in technology adoption. OBJECTIVE To test the effectiveness of a social group–based strategy to improve the acceptability and adoption of activity trackers by middle-aged and older adults. METHODS A cluster randomized controlled trial was conducted among 13 groups of middle-aged and older adults (≥45 years) performing group dancing (ie, square dancing) as a form of exercise in Guangzhou from November 2017 to October 2018. These dancing groups were randomized 1:1 into two arms, and both received wrist-worn activity trackers and instructions at the baseline face-to-face assessment. Based on the Information-Motivation-Behavior Skill framework, the intervention arm was also given a tutorial on the purpose of exercise monitoring (Information), encouraged to participate in exercise and share their exercise records with their dancing peers (Motivation), and were further assisted with the use of the activity tracker (Behavior Skill). We examined two process outcomes: acceptability evaluated by a 14-item questionnaire, and adoption assessed by the uploaded step count data. Intention-to-treat analysis was applied, with the treatment effects estimated by multilevel models. RESULTS All dancing groups were followed up for the postintervention reassessment, with 61/69 (88%) participants of the intervention arm (7 groups) and 56/80 (70%) participants of the control arm (6 groups). Participants’ sociodemographic characteristics (mean age 62 years, retired) and health status were comparable between the two arms, except the intervention arm had fewer female participants and lower cognitive test scores. Our intervention significantly increased the participants’ overall acceptability by 6.8 points (95% CI 2.2-11.4), mainly driven by promoted motivation (adjusted group difference 2.0, 95% CI 0.5-3.6), increased usefulness (adjusted group difference 2.5, 95% CI 0.9-4.1), and better perceived ease of use (adjusted group difference 1.2, 95% CI 0.1-2.4), whereas enjoyment and comfort were not increased (adjusted group difference 0.9, 95% CI –0.4-2.3). Higher adoption was also observed among participants in the intervention arm, who were twice as likely to have valid daily step account data than their controlled counterparts (adjusted incidence relative risk [IRR]=2.0, 95% CI 1.2-3.3). The average daily step counts (7803 vs 5653 steps/day for the intervention and control, respectively) were similar between the two arms (adjusted IRR=1.4, 95% CI 0.7-2.5). CONCLUSIONS Our social group–based deployment strategy incorporating information, motivation, and behavior skill components effectively promoted acceptability and adoption of activity trackers among community-dwelling middle-aged and older adults. Future studies are needed to examine the long-term effectiveness and apply this social engagement strategy in other group settings or meeting places. CLINICALTRIAL Chinese Clinical Trial Registry ChiCTR-IOC-17013185; https://tinyurl.com/vedwc7h.

Background: Neo-adjuvant chemotherapy is an effective strategy for improving treatment of breast cancers. However, the efficacy of this treatment strategy is limited for treatment of triple negative breast cancer (TNBC). Gene therapy may be a more effective strategy for improving the prognosis of TNBC. Methods: A novel 25 nucleotide sense strand of miRNA was designed to treat TNBC by silencing the Slug gene, and encapsulated into DSPE-PEG2000-tLyp-1 peptide-modified functional liposomes. The efficacy of miRNA liposomes was evaluated on invasive TNBC cells and TNBC cancer-bearing nude mice. Furthermore, functional vinorelbine liposomes were constructed to investigate the anticancer effects of combined treatment. Results: The functional miRNA liposomes had a round shape and were nanosized (120 nm). Functional miRNA liposomes were effectively captured by TNBC cells in vitro and were target to mitochondria. Treatment with functional liposomes silenced the expression of Slug and Slug protein, inhibited the TGF-β1/Smad pathway, and inhibited invasiveness and growth of TNBC cells. In TNBC cancer-bearing mice, functional miRNA liposomes exerted a stronger anticancer effect than functional vinorelbine liposomes, and combination therapy with these two formulations resulted in nearly complete inhibition of tumor growth. Preliminary safety evaluations indicated that the functional miRNA liposomes did not affect body weight or cause damage to any major organs. Furthermore, the functional liposomes significantly increased the half-life of the drug in the blood of cancer-bearing nude mice, and increased drug accumulation in breast cancer tissues. Conclusion: In this study, we constructed novel functional miRNA liposomes. These liposomes silenced Slug expression and inhibited the TGF-β1/Smad pathway in TNBC cells, and enhanced anticancer efficacy in mice using combined chemotherapy. Hence, the present study demonstrated a promising strategy for gene therapy of invasive breast cancer.

Breast cancer is the most common malignant disease in women all over the world and its chemotherapy outcome is restricted by multidrug resistance. Here, a nanostructure by functional larotaxel liposomes decorated with guanine-rich quadruplex nucleotide-lipid derivative for treatment of resistant breast cancer is developed. The studies are performed on the resistant breast cancer cells and the cancer-bearing mice. The nucleotide-lipid derivative (DSPE-PEG2000 -C6 -GT28nt) is synthesized by introducing a hydrophobic hexyl linkage between GT-28nt (containing 17 guanines and 11 thymidines) and DSPE-PEG2000 -NHS, and is incorporated on the functional larotaxel liposomes for specific binding with nucleolin receptor on the resistant cancer cells. The studies demonstrate that the liposomes had long circulatory effect, targeted capability, and significant anticancer efficacy in resistant cancer-bearing mice. The studies further reveal their action mechanism, consisting of blocking depolymerization of microtubules, arresting cell cycle, blocking JAK-STAT signaling pathway, and inhibiting activity of antiapoptotic proteins. In conclusion, the functional larotaxel liposomes can be used for effective treatment of drug-resistant breast cancer, and this study also offers a novel targeted nanomedicine based on nucleotide-lipid derivative.

Reaction of copper(II) perchlorate with glutaroimide-dioxime (H3gido) in MeOH solution led to a quasi co-planar 12-metallacrown-4 complex [Cu5(Hgido)4(ClO4)2]·CH3OH(1). The structure of complex 1 has been confirmed by X-ray analysis: two types of similar 12-metallacrown-4 units are connected into 1D chain by perchlorate anions. The temperature dependent magnetic susceptibilities analysis indicates that the antiferromagnetic exchange interaction through the Cu(II)peripheral–Cu(II)central and Cu(II)peripheral–Cu(II)peripheral pathways are J1 = -41.3 and J2 = -14.2 cm−1, respectively. The field-dependent magnetization at 2 K confirms the ground state of St = 3/2.

Background Wearable activity trackers offer potential to optimize behavior and support self-management. To assist older adults in benefiting from mobile technologies, theory-driven deployment strategies are needed to overcome personal, technological, and sociocontextual barriers in technology adoption. Objective To test the effectiveness of a social group–based strategy to improve the acceptability and adoption of activity trackers by middle-aged and older adults. Methods A cluster randomized controlled trial was conducted among 13 groups of middle-aged and older adults (≥45 years) performing group dancing (ie, square dancing) as a form of exercise in Guangzhou from November 2017 to October 2018. These dancing groups were randomized 1:1 into two arms, and both received wrist-worn activity trackers and instructions at the baseline face-to-face assessment. Based on the Information-Motivation-Behavior Skill framework, the intervention arm was also given a tutorial on the purpose of exercise monitoring (Information), encouraged to participate in exercise and share their exercise records with their dancing peers (Motivation), and were further assisted with the use of the activity tracker (Behavior Skill). We examined two process outcomes: acceptability evaluated by a 14-item questionnaire, and adoption assessed by the uploaded step count data. Intention-to-treat analysis was applied, with the treatment effects estimated by multilevel models. Results All dancing groups were followed up for the postintervention reassessment, with 61/69 (88%) participants of the intervention arm (7 groups) and 56/80 (70%) participants of the control arm (6 groups). Participants’ sociodemographic characteristics (mean age 62 years, retired) and health status were comparable between the two arms, except the intervention arm had fewer female participants and lower cognitive test scores. Our intervention significantly increased the participants’ overall acceptability by 6.8 points (95% CI 2.2-11.4), mainly driven by promoted motivation (adjusted group difference 2.0, 95% CI 0.5-3.6), increased usefulness (adjusted group difference 2.5, 95% CI 0.9-4.1), and better perceived ease of use (adjusted group difference 1.2, 95% CI 0.1-2.4), whereas enjoyment and comfort were not increased (adjusted group difference 0.9, 95% CI –0.4-2.3). Higher adoption was also observed among participants in the intervention arm, who were twice as likely to have valid daily step account data than their controlled counterparts (adjusted incidence relative risk [IRR]=2.0, 95% CI 1.2-3.3). The average daily step counts (7803 vs 5653 steps/day for the intervention and control, respectively) were similar between the two arms (adjusted IRR=1.4, 95% CI 0.7-2.5). Conclusions Our social group–based deployment strategy incorporating information, motivation, and behavior skill components effectively promoted acceptability and adoption of activity trackers among community-dwelling middle-aged and older adults. Future studies are needed to examine the long-term effectiveness and apply this social engagement strategy in other group settings or meeting places. Trial Registration Chinese Clinical Trial Registry ChiCTR-IOC-17013185; https://tinyurl.com/vedwc7h.

Controlled detonation of emulsion Explosive and Hexogen (a kind of high explosive, for short, RDX) was performed to prepare Fe-based oxides/SiO2 nanoparticles. XRD (X-ray diffraction), TEM (Transmission electron microscope) and VSM (Vibrating sample magnetometer) experiments were performed to characterize and investigate the ingredients and phase structure of the granules, morphology, and distribution of the particles and the magnetism of the powders respectively. Results indicated that Fe/Urea complex detonation via emulsion explosives was advantageous to prepare Fe-based oxides/SiO2 core-shell powders, the inner FeO/Fe core was properly coated by a silica outer shell with the core size of around 50 nm and shell thickness of around 5–10 nm. And most of the raw detonation dust were converted into SiO2 coating Fe particles with the remained core-shell structure after proper thermal treatment. Raw powders obtained by RDX detonation presented weaker magnetism than that via emulsion explosives detonation, but which was substantially improved after thermal treatment.

Lei Liu, Li-Min Mu, Yan Yan, Jia-Shuan Wu, Ying-Jie Hu, Ying-Zi Bu, Jing-Ying Zhang, Rui Liu, Xue-Qi Li, Wan-Liang Lu Beijing Key Laboratory of Molecular Pharmaceutics and New Drug System, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China Abstract: Currently, chemotherapy is less efficient in controlling the continued development of breast cancer because it cannot eliminate extrinsic and intrinsic refractory cancers. In this study, mitochondria were modified by functional epirubicin liposomes to eliminate refractory cancers through initiation of an apoptosis cascade. The efficacy and mechanism of epirubicin liposomes were investigated on human breast cancer cells in vitro and in vivo using flow cytometry, confocal microscopy, high-content screening system, in vivo imaging system, and tumor inhibition in mice. Mechanistic studies revealed that the liposomes could target the mitochondria, activate the apoptotic enzymes caspase 8, 9, and 3, upregulate the proapoptotic protein Bax while downregulating the antiapoptotic protein Mcl-1, and induce the generation of reactive oxygen species (ROS) through an apoptosis cascade. In xenografted mice bearing breast cancer, the epirubicin liposomes demonstrated prolonged blood circulation, significantly increased accumulation in tumor tissue, and robust anticancer efficacy. This study demonstrated that functional epirubicin liposomes could significantly induce programmed death of refractory breast cancer by activating caspases and ROS-related apoptotic signaling pathways, in addition to the direct killing effect of the anticancer drug itself. Thus, we present a simple nanomedicine strategy to treat refractory breast cancer. Keywords: mitochondria, drug delivery, apoptosis, efficacy, signaling pathway

Large-scale explosive welded composite plates are important materials for nuclear fusion reactor vessels, and have high requirements for mechanical properties and crack detection tests. In order to meet the requirements, titanium/steel explosive welded composite plates were manufactured under different gas media, and the effect of gaseous media on the interfacial microstructure and mechanical properties of the composite plates was evaluated. The results show that there are significant differences in the interface morphology and mechanical properties of the explosive welded composites under different gaseous media. Unlike traditional explosive welding under air, a low density helium medium smooths the welding process and creates a more stable periodic wave at the interface. In addition, helium gas as an inert gas effectively inhibits the formation of oxides at the interface and improves the mechanical properties and welding quality.

To date, most studies conducted on cilostazol have examined its effects as an agent of maintenance-dose therapy, but its loading effects on platelet inhibition have never been reported. This study aimed to determine the loading effects of 200 mg cilostazol in addition to aspirin and clopidogrel on platelet inhibition in patients undergoing percutaneous coronary intervention.Sixty consecutive patients undergoing coronary intervention were enrolled and assigned to receive 300 mg of aspirin and clopidogrel with or without 200 mg of cilostazol. All loading doses were given at least 3 hours before percutaneous coronary intervention and followed by dual or triple maintenance-dose therapy. Platelet function tests were performed just before and at 24 hours and 30 days after percutaneous coronary intervention by light transmittance aggregometry and VerifyNow® P2Y12 assay.There were no significant differences in baseline or angiographic characteristics between the 2 groups. The results of platelet function tests revealed that the adjunctive loading dose of 200 mg of cilostazol induced more potent platelet inhibition compared to a dual regimen at each time point. Cilostazol reduced the incidence of high post-treatment platelet reactivity (HPPR).Adjunctive 200 mg cilostazol can improve platelet responsiveness to clopidogrel in the pre- and postprocedural phases, reducing the prevalence of HPPR.