Ferroptosis Contributes to Microvascular Dysfunction in Diabetic Retinopathy.

Ferroptosis is a new form of cell death characterized by iron-dependent lipid peroxidation. Whether ferroptosis is involved in retinal microvascular dysfunction under diabetic condition is not known. Herein, the expression of ferroptosis-related genes in patients with proliferative diabetic retinopathy and in diabetic mice was determined with quantitative RT-PCR. Reactive oxygen species, iron content, lipid peroxidation products, and ferroptosis-associated proteins in the cultured human retinal microvascular endothelial cells (HRMECs) and in the retina of diabetic mice were examined. The association of ferroptosis with the functions of endothelial cells in vitro was evaluated. After administration of ferroptosis-specific inhibitor, Fer-1, the retinal microvasculature in diabetic mice was assessed. Characteristic changes of ferroptosis-associated markers, including glutathione peroxidase 4, ferritin heavy chain 1, long-chain acyl-CoA synthetase 4, transferrin receptor protein 1, and cyclooxygenase-2, were detected in the retinal fibrovascular membrane of patients with proliferative diabetic retinopathy, cultured HRMECs, and the retina of diabetic mice. Elevated levels of reactive oxygen species, lipid peroxidation, and iron content were found in the retina of diabetic mice and in cultured HRMECs. Ferroptosis was found to be associated with HRMEC dysfunction under high-glucose condition. Inhibition of ferroptosis with specific inhibitor Fer-1 in diabetic mice significantly reduced the severity of retinal microvasculopathy. Ferroptosis contributes to microvascular dysfunction in diabetic retinopathy, and inhibition of ferroptosis might be a promising strategy for the therapy of early-stage diabetic retinopathy.

Prevalence and characteristics of somatic symptom disorder in the elderly in a community-based population: a large-scale cross-sectional study in China.

INTRODUCTION AND OBJECTIVES: The aging population is expected to reach 2 billion by 2050, but the impact of somatic symptom disorder (SSD) on the elderly has been insufficiently addressed. We aimed to clarify the prevalence of SSD in China and to identify physical and psychological differences between the elderly and non-elderly. METHODS: In this prospective multi-center study, 9020 participants aged (2206 non-elderly adults and 6814 elderly adults) from 105 communities of Shanghai were included (Assessment of Somatic Symptom in Chinese Community-Dwelling People, clinical trial number NCT04815863, registered on 06/12/2020). The Somatic Symptom Scale-China (SSS-CN) questionnaire was used to measure SSD. Depressive and anxiety disorders were assessed by the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7), respectively. RESULTS: The prevalence of SSD in the elderly was higher than that in the non-elderly (63.2% vs. 45.3%). The elderly suffered more severe SSD (20.4% moderate and severe in elderly vs. 12.0% in non-elderly) and are 1.560 times more likely to have the disorder (95%CI: 1.399-1.739; p < .001) than the non-elderly. Comorbidity of depressive or anxiety disorders was 3.7 times higher than would be expected in the general population. Additionally, the results of adjusted multivariate analyses identified older age, female sex, and comorbid physical diseases as predictive risk factors of SSD in the elderly group. CONCLUSIONS: With higher prevalence of common physical problems (including hypertension, diabetes mellitus and cardio/cerebrovascular disease), the elderly in Shanghai are more vulnerable to have SSD and are more likely to suffer from comorbid depressive and anxiety disorders. SSD screening should be given more attention in the elderly, especially among older females with several comorbid physical diseases.

Reverse "cheese wire" fenestration for abdominal aortic dissection repair: a case report and literature review.

BACKGROUND: Aortic dissection is one of the most common emergency condition leading to internal organs or lower limb ischemia and aortic rupture. Herein, we described a reverse "cheese wire" endovascular fenestration repair (CWFER) in a patient with complicated abdominal aortic dissection which had never been reported. CASE PRESENTATION: A 62-year-old male presented abdominal tear-like pain and acute ischemia of the right lower extremity during the endovascular treatment of celiac trunk aneurysms. Computed tomography angiography (CTA) and digital subtraction angiography (DSA) showed abdominal aortic type B dissection with acute ischemia of the right lower extremity preoperatively. After a detailed preoperative examination, the patient then was performed a reverse CWFER. So far, the patient has been followed-up for 6 months, postoperative CTA demonstrated good stent-graft expansion and perfusion of bilateral common iliac arteries; also, no endoleak was detected. CONCLUSIONS: The right iliac artery in this patient supplied by false lumen, which lead to acute ischemia of the right lower extremity, needed to be treated as an emergency and dealt with promptly. CWFER is a very high-risk treatment that requires the rich experience of vascular surgeon and accurate assessment of aortic dissection. After interventional treatment, the patient recovered uneventfully after 6 months' follow-up.

Effects of Peppermint Essential Oil on Learning and Memory Ability in APP/PS1 Transgenic Mice.

OBJECTIVE: To explore the effect and mechanism of peppermint essential oil on learning and memory ability of APP/PS1 transgenic mice. METHODS: Morris water maze test and shuttle box test were used to explore the changes in learning and memory ability of APP/PS1 transgenic mice after sniffing essential oil. The cellular status of neurons in the hippocampal CA1 region of the right hemisphere, Aß deposition, oxidative stress level, and serum metabonomics were detected to explore its mechanism. RESULTS: Sniffing peppermint essential oil can improve the learning and memory ability of APP/PS1 transgenic mice. Compared with the model group, the state of neurons in the hippocampal CA1 region of the peppermint essential oil group returned to normal, and the deposition of Aß decreased. The MDA of brain tissue decreased significantly, and the activity of SOD and GSH-PX increased significantly to the normal level. According to the results of metabonomics, it is speculated that peppermint essential oil may improve cognitive function in AD by regulating arginine and proline metabolism, inositol phosphate metabolism, and cysteine and methionine metabolism.

3C protease of enterovirus 71 cleaves promyelocytic leukemia protein and impairs PML-NBs production.

BACKGROUND: Enterovirus 71 (EV71) usually infects infants causing hand-foot-mouth disease (HFMD), even fatal neurological disease like aseptic meningitis. Effective drug for preventing and treating EV71 infection is unavailable currently. EV71 3C mediated the cleavage of many proteins and played an important role in viral inhibiting host innate immunity. Promyelocytic leukemia (PML) protein, the primary organizer of PML nuclear bodies (PML-NBs), can be induced by interferon and is involved in antiviral activity. PML inhibits EV71 replication, and EV71 infection reduces PML expression, but the molecular mechanism is unclear. METHODS: The cleavage of PMLIII and IV was confirmed by co-transfection of EV71 3C protease and PML. The detailed cleavage sites were evaluated further by constructing the Q to A mutant of PML. PML knockout cells were infected with EV71 to identify the effect of cleavage on EV71 replication. Immunofluorescence analysis to examine the interference of EV71 3C on the formation of PML-NBs. RESULTS: EV71 3C directly cleaved PMLIII and IV. Furthermore, 3C cleaved PMLIV at the sites of Q430-A431 and Q444-S445 through its protease activity. Overexpression of PMLIV Q430A/Q444A variant exhibited stronger antiviral potential than the wild type. PMLIV Q430A/Q444A formed normal nuclear bodies that were not affected by 3C, suggesting that 3C may impair PML-NBs production via PMLIV cleavage and counter its antiviral activities. PML, especially PMLIV, which sequesters viral proteins in PML-NBs and inhibits viral production, is a novel target of EV71 3C cleavage. CONCLUSIONS: EV71 3C cleaves PMLIV at Q430-A431 and Q444-S445. Cleavage reduces the antiviral function of PML and decomposes the formation of PML-NBs, which is conducive to virus replication.

A Retrospective Study Comparing the Effectiveness and Safety of EXOSEAL Vascular Closure Device to Manual Compression in Patients Undergoing Percutaneous Transbrachial Procedures.

BACKGROUND: This study aimed to assess the safety and efficacy of EXOSEAL vascular closure device (EVCD) insertion by comparing its performance with manual compression (MC) in achieving hemostasis at the brachial artery puncture site. METHODS: A retrospective study of brachial artery access by using either MC or EVCD for achieving hemostasis from March 2016 to October 2017 was conducted. Patients with Stanford type B aortic dissection (TBAD) undergoing percutaneous transbrachial procedures were included. Time to hemostasis (TTH) was the primary efficacy end point. Seven-day incidence of major access site-related complications was the primary safety end point. TTH and major and minor complications associated with treatment of these 2 groups were also evaluated. RESULTS: A total of 157 patients with TBAD undergoing percutaneous transbrachial procedures entered the analysis. Of these, 107 patients underwent EVCD insertion and 50 patients underwent MC. The baseline characteristics of the 2 groups were similar. TTH was significantly shorter for EVCD over MC (P < 0.05). The TTH ≥10 min in the MC group was 100.0% (n = 50), but in the EVCD group, it was ≤2 min, 87.9% (n = 107); 2-5 min, 7.5% (n = 107); and ≥10 min, 4.7% (n = 107). The EVCD group had several major complications, while the MC group had none. Two patients (1.9%, n = 107) required vascular repair, one patient (0.6%, n = 107) required blood transfusion, and 1 patient (0.6%, n = 107) developed upper limb numbness and weakness after EVCD deployment. Minor complication such as the occurrence of hematoma (≤5 cm) in the MC group was 4 (8.0%) but was also 4 (3.7%) in the EVCD group, showing statistically significant difference (P = 0.030). The incidence of ecchymosis was 8 (7.5%) in the EVCD group when compared with 13 (26.0%) in the MC group, which showed statistically significant difference (P = 0.001). Other major and minor complications showed no significant differences between these 2 groups. CONCLUSIONS: After invasive procedures by 6F percutaneous access via the brachial artery in preprocedurally fully anticoagulated patients, TTH was significantly reduced in patients who underwent EVCD when compared with patients who underwent MC. MC is a safer and more convenient way to achieve hemostasis but has higher incidence of minor complications.

Outcome of Surgical Treatment for Carotid Body Tumors in Different Shambling Type Without Preoperative Embolization: A Single-Center Retrospective Study.

BACKGROUND: Carotid body tumor (CBT) is the most common head and neck paragangliomas. Surgical resection is the golden standard management for CBT. While preoperative embolization is still controversial, long-term outcomes and perioperative results are still deficient. We, here, presented the outcomes of surgical treatment for CBT without preoperative embolization at our institution. METHODS: In this retrospective study, we collected data from 101 patients who received surgical treatment for CBTs without preoperative embolization from 2011 to 2016. In addition, we attempted to conduct 2 years of follow-up under the guidance of both neurologist and vascular surgeon. Patients' demographics, clinical characteristics, complications, and follow-up results were all analyzed with descriptive statistics. RESULTS: Complete resection of the CBT was achieved in 101 cases (100%). Postoperative adverse events (AEs) mostly observed during hospitalization were as follows: tongue bias (I: 4, 36.4%; II: 8, 19.5%; III: 13, 26.5%), hoarseness (I: 1, 9.1%; II: 4, 9.8%; III: 7, 14.3%), dysphagia (I: 0; II: 2, 4.9%; III: 7, 14.3%), and hematoma (I: 0; II: 0; III: 1, 2.0%). No other serious AEs were observed. The total incidence of AEs in type I patients was 5 (45.5%), 14 (34.1%) in type II, and 28 (57.1%) in type III, and the type III group has significantly higher than the other two groups. At the end of 2 years of follow-up, there were no AEs in type I patients. The number of patients with AEs in type III was greater than that in type II, although there was no significant difference. Based on our findings, 3 most commonly injured cranial nerves (CNs) after surgical resection of CBT were CN XII (hypoglossal nerve, 21.9%), CN X (vagus nerve, 20.3%), and recurrent laryngeal nerve (18.8%). CONCLUSIONS: Surgical management without preoperative embolization for CBT patients is a safe and effective therapeutic approach.

Upregulation of miR-330-5p is associated with carotid plaque's stability by targeting Talin-1 in symptomatic carotid stenosis patients.

BACKGROUND: The aim of this study was to investigate the relationship between Talin-1 and stability of carotid atherosclerosis plaque and also find out the role of miRNA, as an upstream regulator, in regulating the expression level of Talin-1. METHODS: Human carotid plaques were obtained from 20 symptomatic carotid stenosis patients who underwent carotid endarterectomy (CEA) in our hospital between October 2014 and August 2017. Western blot analysis and immunohistochemistry was carried out to detect the distribution and expression level of Talin-1 in each plaque sample. The content of miRNAs in carotid plaque was decected by quantitative reverse transcription polymerase chain reaction (RT-qPCR), and the relative expression levels were calculated by 2-△△Ct method after the (cycle threshold) Ct value (power amplification knee point) was obtained. Dual-luciferase reporter assays were applied to verify the successful transfections. Finally, we compared all the groups with independent-samples t-test and one-way analysis of variance (ANOVA). RESULTS: Talin-1 was significantly downregulated in human unstable carotid plaque samples compared with stable carotid plaques (P < 0.05), and the distribution of Talin-1 was mainly found in the fibrous cap of carotid plaque. The overexpression of miRNA-330-5p was found in unstable carotid plaque, which significantly induced the inhibition of expression level of Talin-1. CONCLUSION: Upregulated miR-330-5p may lead to unstable carotid plaques by targeting Talin-1 in symptomatic carotid stenosis patients. This might be a new target for the treatment of atherosclerotic diseases through future studies.

Management of wide-based renal artery aneurysms using noncovered stent-assisted coil embolization.

OBJECTIVE: This study describes the safety and midterm efficacy of a noncovered stent-assisted embolization (SAE) technique in treating patients with wide-base renal artery aneurysms (RAAs). METHODS: Between February 2011 and June 2014, 34 RAAs in 28 consecutive patients were treated with noncovered SAE in our center. RESULTS: Technical success was 100%. During an average follow-up of 19 months, the systolic and diastolic blood pressures were significantly decreased. Serum creatinine was significantly decreased, and the glomerular filtration rate was significantly increased at the 6 and 12 month follow-up compared with the baseline. The aneurysm sac thrombosis ratio was obviously increased at 1, 6, and 12 months of follow-up. Complications occurred in four patients, including one major, two minor, and one late complication. Computed tomography angiography or digital subtraction angiography demonstrated that the primary patency at 1, 6, and 12 months was 100%, 96%, and 100%, respectively, and primary assisted and secondary patency was 100%, without endoleaks. CONCLUSIONS: SAE can be safely and effectively performed in patients with wide-based RAAs or those with critical anatomy. It showed a midterm reduction of blood pressure and improvement of renal function in RAA patients.

Downregulation of Talin-1 expression associates with increased proliferation and migration of vascular smooth muscle cells in aortic dissection.

BACKGROUND: This study aimed to assessed whether Talin-1 is involved in the pathogenesis of aortic dissection via regulating vascular smooth muscle cell (VSMC) biological function. METHODS: Human aortic samples were obtained from organ donors who died from nonvascular diseases as normal controls and from patients undergoing surgical repair of thoracic aortic dissection. The expression level and distribution of Talin-1 were detected using westernblot analysis and immunohistochemistry in each sample. We inhibited the expression of Talin-1 via RNA interference in VSMCs. VSMC proliferation was detected by Cell-counting Kit-8 analyses. Scratch test and flow cytometry were used to identify the migration and apoptosis ability. Antibody microarray analysis and qRT-PCR were used to detect some protein and mRNA changes which were induced by Talin-1 downregulation. RESULTS: Talin-1 was significantly downregulated in the media of aortic dissection samples compared with controls (P < 0.05). Talin-1 knockdown significantly induced VSMC proliferation and migration in vitro. Proteins which involved in cell cycle can be regulated by downregulating Talin-1. Down regulation of Talin-1 can significanly increased the expression of anaphase-promoting complex subunit 2 (APC2) and decreased p19 alternative reading frame (p19ARF), Cullin-3, and beta actin's expression. CONCLUSIONS: Talin-1 induces VSMCs proliferation and migration. It downregulated in aortic dissection, which might play a potential role in the development of aortic dissection.

Dynamic Changes in Gut Microbiota-Derived Metabolite Trimethylamine-N-Oxide and Risk of Type 2 Diabetes Mellitus: Potential for Dietary Changes in Diabetes Prevention.

BACKGROUND: A gut-microbial metabolite, trimethylamine N-oxide (TMAO), has been associated with type 2 diabetes mellitus (T2DM). Few previous prospective studies have addressed associations between the changes in TMAO and T2DM incidence. METHODS: Data were derived from a longitudinal cohort conducted from 2019 to 2021 in rural areas of Fuxin County, Liaoning Province, China, and 1515 diabetes-free participants aged above 35 years were included. The concentrations of serum TMAO and its precursors were measured at two time points, namely in 2019 and 2021. TMAO and TMAO changes (ΔTMAO) were separately tested in a logistic regression model. For further examination, the odds ratios (ORs) for T2DM were calculated according to a combination of TMAO levels and ΔTMAO levels. RESULTS: During a median follow-up of 1.85 years, 81 incident cases of T2DM (5.35%) were identified. Baseline TMAO levels exhibited a nonlinear relationship, first decreasing and then increasing, and only at the highest quartile was it associated with the risk of T2DM. The OR for T2DM in the highest quartile of serum TMAO was 3.35 (95%CI: 1.55-7.26, p = 0.002), compared with the lowest quartile. As for its precursors, only choline level was associated with T2DM risk and the OR for T2DM in the Q3 and Q4 of serum choline was 3.37 (95%CI: 1.41-8.05, p = 0.006) and 4.72 (95%CI: 1.47-15.13, p = 0.009), respectively. When considering both baseline TMAO levels and ΔTMAO over time, participants with sustained high TMAO levels demonstrated a significantly increased risk of T2DM, with a multivariable-adjusted OR of 8.68 (95%CI: 1.97, 38.34). CONCLUSION: Both initial serum TMAO levels and long-term serum TMAO changes were collectively and significantly associated with the occurrence of subsequent T2DM events. Interventions aimed at normalizing TMAO levels, such as adopting a healthy dietary pattern, may be particularly beneficial in T2DM prevention.

Breast Milk Enema and Meconium Evacuation Among Preterm Infants: A Randomized Clinical Trial.

Importance: Delayed meconium evacuation and delayed achievement of full enteral feeding among premature infants are associated with poor short- and long-term outcomes. Identifying a more effective and safer enema for meconium evacuation is imperative for improving neonatal care. Objective: To examine whether breast milk enemas can shorten the time to complete meconium evacuation and achievement of full enteral feeding for preterm infants. Design, Setting, and Participants: This randomized, open-label, parallel-group, single-center clinical trial was conducted from September 1, 2019, to September 30, 2022, among 286 preterm infants with a gestational age of 23 to 30 weeks in the neonatal ward of the Shengjing Hospital of China Medical University in Shenyang. Interventions: Preterm infants were randomly assigned to receive either breast milk enemas or normal saline enemas 48 hours after birth. Main Outcome and Measures: The primary outcomes were time to complete meconium evacuation and time to achieve full enteral feeding. Secondary outcomes were duration of hospitalization, weight at discharge, and duration of total parenteral nutrition. Intention-to-treat and per-protocol analyses were conducted. Results: In total, 286 preterm infants (mean [SD] gestational age, 198.8 [7.9] days; 166 boys [58.0%]) were eligible and included in this study. A total of 145 infants were randomized to the normal saline group, and 141 were randomized to the breast milk group. The time to achieve complete meconium evacuation was significantly shorter in the breast milk group than in the normal saline group (-2.2 days; 95% CI, -3.2 to -1.2 days). The time to achieve full enteral feeding was also significantly shorter in the breast milk group than in the normal saline group (-4.6 days; 95% CI, -8.0 to -1.2 days). The duration of total parenteral nutrition was significantly shorter in the breast milk group than in the normal saline group (-4.6 days; 95% CI, -8.6 to -1.0 days). There were no clinically notable differences in any other secondary or safety outcomes between the 2 groups. Conclusions and Relevance: In this randomized clinical trial testing the effects of breast milk enema on meconium evacuation, breast milk reduced the time to achieve complete meconium evacuation and achieve full enteral feeding for preterm infants with a gestational age of 23 to 30 weeks. Subgroup analyses highlight the need for tailored interventions based on gestational age considerations. Trial Registration: isrctn.org Identifier: ISRCTN17847514.

Integrative Analysis of miRNA and circRNA Expression Profiles and Interaction Network in HSV-1-Infected Primary Corneal Epithelial Cells.

PURPOSE: Circular RNAs (circRNAs) are products of alternative splicing with roles as competitive endogenous RNAs or microRNA sponges, regulating gene expression and biological processes. However, the involvement of circRNAs in herpes simplex keratitis remains largely unexplored. METHODS: This study examines circRNA and miRNA expression profiles in primary human corneal epithelial cells infected with HSV-1, compared to uninfected controls, using microarray analysis. Bioinformatic analysis predicted the potential function of the dysregulated circRNAs and microRNA response elements (MREs) in these circRNAs, forming an interaction network between dysregulated circRNAs and miRNAs. RESULTS: A total of 332 circRNAs and 16 miRNAs were upregulated, while 80 circRNAs and six miRNAs were downregulated (fold change ≥2.0 and p < 0.05). Gene ontology (GO) and KEGG pathway analyses were performed on parental genes of dysregulated circRNAs to uncover potential functions in HSV-1 infection. Notably, miR-181b-5p, miR-338-3p, miR-635, and miR-222-3p emerged as pivotal miRNAs interacting with multiple dysregulated circRNAs. CONCLUSIONS: This comprehensive study offers insights into differentially expressed circRNAs and miRNAs during HSV-1 infection in corneal epithelial cells, shedding light on circRNA-miRNA interactions' potential role in herpes simplex keratitis pathogenesis.

Metabonomics Study in Mice With Learning and Memory Impairment on the Intervention of Essential Oil Extracted From Cinnamomum camphora Chvar. Borneol.

Our objective was to explore the mechanism of essential oil that was extracted from Cinnamomum camphora chvar. Borneol (Borneol essential oil) for improving learning and memory impairment in mice. Brain tissue and plasma samples of a normal group, a model group, a Borneol essential oil group and a reference group were detected using gas chromatography time-of-flight mass spectrometry (GC-TOFMS) in order to find differential metabolites and analyze metabolic pathways. Results showed that there were 11 different metabolites --including glycine and azelaic acid --in plasma samples, and that there were 26 different metabolites--including adenine and aspartic acid --in brain tissue samples. These metabolites are involved in phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, beta-alanine metabolism, glyoxylate acid and dicarboxylate metabolism, and aminoacyl-tRNA biosynthesis. Thus, Borneol essential oil may improve learning and memory impairment by regulating amino acid metabolism and/or neurotransmitter changes.

Achieving acetone efficient deep decomposition by strengthening reactants adsorption and activation over difunctional Au(OH)Kx/hierarchical MFI catalyst.

Realizing the simultaneous adsorption and activation of O2 and reactants over supported noble metal catalysts is crucial for the oxidation of organic hydrocarbons. Herein, we report a facile one-step ethylene glycol reduction method to synthesize difunctional Au(OH)Kx sites, which were anchored on a hierarchical hollow MFI support and adopted for acetone decomposition. The alkali ion-associated adjacent surface hydroxyl groups were coordinated with Au nanoparticles, resulting in partially oxidized Au1+ sites with improved dispersion. The results obtained from exclusive ex situ and in situ experiments illustrated that the proper content of K and hydroxyl groups significantly enhanced the adsorption of surface O2 and acetone molecules around the Au sites simultaneously, whereas the excess K species inhibited the catalytic performance by blocking the pore structure and decreasing the acidity of catalysts. The Au(OH)K0.7/h-MFI catalyst exhibited the highest efficiency for acetone oxidation, over which 1500 ppm acetone can be completely oxidized at just 280 °C with an extremely low activation energy of 32.5 kJ mol-1. The carbonate species were detected as the main intermediates during acetone decomposition over the difunctional Au(OH)Kx sites through a Langmuir - Hinshelwood (L - H) mechanism. This finding paves the way for designing and constructing efficient functional active sites for the complete oxidation of hydrocarbons.

Effect of Financial Incentives on Hypertension Control: A Multicenter Randomized Controlled Trial in China.

BACKGROUND: Poorly controlled hypertension is a great challenge to global public health. Incentive approaches, based on behavioral and economic concepts, may improve patients' adherence to treatment. METHODS: We conducted a 2-arm randomized controlled trial to test whether financial incentives can help patients with poorly controlled hypertension in China reduce their blood pressure (BP). Participants were randomized 1:1 to the control and intervention groups. All participants received WeChat-based standard education and support for hypertension management. The intervention group received financial incentives, including process- and outcome-based incentives. RESULTS: No statistically significant differences in BP reduction and hypertension control rates were found between the two groups from baseline to 12-month follow-up. Mean systolic BP decreased from 158.7 to 149.8 mm Hg in the intervention group and 159.7 to 149.5 mm Hg in the control group (P=0.639). Mean diastolic BP decreased from 93.7 to 86.6 mm Hg in the intervention group and 93.9 to 86.3 mm Hg in the control group (P=0.667). Hypertension control rates in the intervention and control groups were 20.8% and 15.8%, respectively (P=0.318). Medication adherence was 84.2% in the intervention group and 86.2% in the control group (P=0.705). CONCLUSIONS: Financial incentives were effective in the short term for BP control, but a sustained effect of incentive-based BP control was not identified beyond 3 months of intervention. Future studies that focus on identifying the appropriate amount and structure of financial incentives for BP control are warranted. REGISTRATION: URL: www.isrctn.org; Unique identifier: ISRCTN13467677.

HLF regulates ferroptosis, development and chemoresistance of triple-negative breast cancer by activating tumor cell-macrophage crosstalk.

Tumor-associated macrophages (TAMs) are major components of the tumor microenvironment (TME) which are closely associated with the tumor malignant progression. However, the regulatory mechanisms by which TAMs influence the progression of triple-negative breast cancer (TNBC) remain unclear. Here, we report that hepatic leukemia factor (HLF) acts as a novel oncoprotein in TNBC. We found that HLF was regulated by transforming growth factor-beta1 (TGF-ß1) that is secreted by TAMs. Then, HLF transactivated gamma-glutamyltransferase 1 (GGT1) to promote the ferroptosis resistance, thus driving TNBC cell proliferation, metastasis and cisplatin resistance. Reciprocally, IL-6 produced by TNBC cells activated the JAK2/STAT3 axis to induce TGF-ß1 secretion by TAMs, thus constituted a feed-forward circuit. The accuracy of TNBC patient prognosis could be improved by employing a combination of HLF and GGT1 values. Thus, our findings document that the interactive dialogue between TNBC cells and TAMs promotes sustained activation of HLF in tumor cells through the IL-6-TGF-ß1 axis. Subsequently, HLF promotes the ferroptosis resistance in TNBC cells via GGT1 and ultimately facilitates the malignant tumor progression. Our study provides a potential target for the treatment of TNBC.

Global landscape of SARS-CoV-2 genomic surveillance and data sharing.

Genomic surveillance has shaped our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. We performed a global landscape analysis on SARS-CoV-2 genomic surveillance and genomic data using a collection of country-specific data. Here, we characterize increasing circulation of the Alpha variant in early 2021, subsequently replaced by the Delta variant around May 2021. SARS-CoV-2 genomic surveillance and sequencing availability varied markedly across countries, with 45 countries performing a high level of routine genomic surveillance and 96 countries with a high availability of SARS-CoV-2 sequencing. We also observed a marked heterogeneity of sequencing percentage, sequencing technologies, turnaround time and completeness of released metadata across regions and income groups. A total of 37% of countries with explicit reporting on variants shared less than half of their sequences of variants of concern (VOCs) in public repositories. Our findings indicate an urgent need to increase timely and full sharing of sequences, the standardization of metadata files and support for countries with limited sequencing and bioinformatics capacity.

Global landscape of SARS-CoV-2 genomic surveillance, public availability extent of genomic data, and epidemic shaped by variants.

Genomic surveillance has shaped our understanding of SARS-CoV-2 variants, which have proliferated globally in 2021.We collected country-specific data on SARS-CoV-2 genomic surveillance, sequencing capabilities, public genomic data from multiple public repositories, and aggregated publicly available variant data. Then, different proxies were used to estimate the sequencing coverage and public availability extent of genomic data, in addition to describing the global dissemination of variants. We found that the COVID-19 global epidemic clearly featured increasing circulation of Alpha since the start of 2021, which was rapidly replaced by the Delta variant starting around May 2021. SARS-CoV-2 genomic surveillance and sequencing availability varied markedly across countries, with 63 countries performing routine genomic surveillance and 79 countries with high availability of SARS-CoV-2 sequencing. We also observed a marked heterogeneity of sequenced coverage across regions and countries. Across different variants, 21-46% of countries with explicit reporting on variants shared less than half of their variant sequences in public repositories. Our findings indicated an urgent need to expand sequencing capacity of virus isolates, enhance the sharing of sequences, the standardization of metadata files, and supportive networks for countries with no sequencing capability.

The Effects of Puerarin on Autophagy Through Regulating of the PERK/eIF2α/ATF4 Signaling Pathway Influences Renal Function in Diabetic Nephropathy.

BACKGROUND AND PURPOSE: Autophagy is the main protective mechanism against aging in podocytes, which are terminally differentiated cells that have a very limited capacity for mitosis and self-renewal. Here, a streptozotocin-induced DN C57BL/6 mouse model was used to investigate the effects of puerarin on the modulation of autophagy under conditions associated with endoplasmic reticulum stress (ERS). In addition, this study aimed to identify the potential underlying molecular mechanisms. METHODS AND RESULTS: DN C57BL/6 mouse model was induced by streptozotocin (150 mg/kg) injection. The mice were administered rapamycin and puerarin, respectively, daily for up to 8 weeks. After the serum and kidney samples were collected, the fasting blood glucose (FBG), parameters of renal function, histomorphology, and the podocyte functional proteins were analyzed. Moreover, the autophagy markers and the expressions of PERK/ATF4 pathway were studied in kidney. Results found that the FBG level in DN mice was significantly higher than in normal mice. Compared with DN model mice, puerarin-treated mice showed an increased expression of podocyte functional proteins, including nephrin, podocin, and podocalyxin. Furthermore, the pathology and structure alterations were improved by treatment with rapamycin and puerarin compared with the DN control. The results indicated an elevated level of autophagy in rapamycin and puerarin groups compared with the DN model, as demonstrated by the upregulated expression of autophagy markers Beclin-1, LC3II, and Atg5, and downregulated p62 expression. In addition, the levels of PERK, eIF2α, and ATF4 were reduced in the DN model, which was partially, but significantly, prevented by rapamycin and puerarin. CONCLUSION: This study emphasizes the renal-protective effects of puerarin in DN mice, particularly in the modulation of autophagy under ERS conditions, which may be associated with activation of the PERK/eIF2α/ATF4 signaling pathway. Therefore, PERK may be a potential target for DN treatment.