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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.

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.

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.

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.

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

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.

Objective: The objective of this study was to compare the accuracy of 320-row computed tomography angiography (CTA) with conventional coronary angiography. Methods: Two hundred seventy-four patients with coronary artery disease who received both invasive coronary angiography and 320-row CTA were included. Stenosis of 50% or greater was considered obstructive. Results: In patient-based analysis, accuracy of CTA was 89.4%, with sensitivity of 94.6% and specificity of 54.3%. In segment-based analysis, the overall (4110 segments) accuracy of CTA was 90.7%, with sensitivity of 66.5% and specificity of 95.8%. For the segments with plaques (1191 segments), accuracy of CTA was 80.1%, with sensitivity of 83.5% and specificity of 77.0%. For segments with no plaque (2919 segments), accuracy of CTA was 95.0%, with sensitivity of 0.7% and specificity of 100.0%. For the segments with stents (110 segments), the accuracy of CTA was 86.4%. Conclusions: A 320-row CTA has potential to detect coronary lesions with soft and intermediate plaques.

Background: The aim of the present study was to assess the association between M235T polymorphism and heart failure using a meta-analysis. Methods: A literature search of Google Scholar, PubMed, the Cochrane Library and the China National Knowledge Infrastructure database (January 1990–April 2012) was performed for relevant studies. Statistical analyses were carried out using the Stata 12.0 to combine all the relevant studies. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated in a fixed-effects model and a random-effects model when appropriate. The pooled ORs were performed under the allelic contrast (T vs M), the dominant (TT + MT vs. MM) and the recessive models (TT vs MT + MM). Begg’s test was used to measure publication bias. Results: A total of six case-control studies including 842 patients and 1054 controls were enrolled in this meta-analysis. Overall, there was a significant association between angiotensinogen (AGT) gene M235T polymorphism and risk of heart failure in the subgroup analysis under the allelic contrast (T vs M: OR = 1.48, 95% CI: 1.04–2.11) and the dominant model (TT+MT vs MM: OR=1.67, 95% CI: 1.13–2.46) in the Caucasian population. Conclusions: The current meta-analysis suggests that M235T polymorphism might be associated with increased risk of heart failure in Caucasians.

The MADS box-containing transcription factors MEF2A-D regulate the expression of most skeletal and cardiac muscle structural genes. Recently, a zinc finger protein called HZF1 was identified as a transcription factor, and found to be highly expressed in cardiac muscle. By screening the transcription regulatory region of HZF1, we found that myocyte enhancer factor 2 (MEF2) potentially recognizes and binds the regulatory region of the HZF1 gene. We also found that the knockdown of MEF2A endogenous expression in human aortic smooth muscle cells decreases the expression of HZF1, while the enforced expression of MEF2A in turn promotes the expression of HZF1. Furthermore, we employed the luciferase reporter system and chromatin immunoprecipitation (ChIP) to demonstrate that MEF2A does in fact bind the regulatory region of HZF1, which suggests that HZF1 is the direct target of MEF2A. Based on the fact that MEF2 proteins function as essential regulators of cardiac development and as important pathological factors for certain cardiac diseases, our finding that MEF2 positively regulates the expression of HZF1 may contribute to further research investigating the role of the zinc finger protein HZF1 in cardiac development and disease.

To evaluate the safety and optimal prior percutaneous coronary intervention (PCI) nadroparin dose in patients with acute coronary syndrome (ACS).A total of 236 ACS patients were randomly treated with subcutaneously nadroparin 0.075 ml/10 kg (group I, n = 120) and 0.1 ml/10 kg (group II, n = 116) respectively (bid for 48 hours). PCI was the performed 1 h after final nadroparin injection. No additional nadroparin was applied during PCI. Plasmic anti-Xa level was assayed before and at 1, 2, 4 and 8 hours after final nadroparin administration. Adverse clinical events (death, myocardial infarction, need for revascularization) and bleeding events were recorded up to 30 days post PCI.Baseline clinical characteristics as well as the MACE and severe bleeding events between the two groups were similar (all P0.05). Plasmic anti-Xa level of group II was significantly higher than that of group I post nadroparin application (P0.01).Anticoagulation effects and MACE as well as severe bleeding events up to 30 days post PCI were similar with either 0.075 ml/10 kg or 0.1 ml/10 kg nadroparin dose in ACS patients.