LDHA contributes to nicotine induced cardiac fibrosis through autophagy flux impairment.

Cardiac fibrosis is a typical feature of cardiac pathological remodeling, which is associated with adverse clinical outcomes and has no effective therapy. Nicotine is an important risk factor for cardiac fibrosis, yet its underlying molecular mechanism remains poorly understood. This study aimed to identify its potential molecular mechanism in nicotine-induced cardiac fibrosis. Our results showed nicotine exposure led to the proliferation and transformation of cardiac fibroblasts (CFs) into myofibroblasts (MFs) by impairing autophagy flux. Through the use of drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) technology, it was discovered that nicotine directly increased the stability and protein levels of lactate dehydrogenase A (LDHA) by binding to it. Nicotine treatment impaired autophagy flux by regulating the AMPK/mTOR signaling pathway, impeding the nuclear translocation of transcription factor EB (TFEB), and reducing the activity of cathepsin B (CTSB). In vivo, nicotine treatment exacerbated cardiac fibrosis induced in spontaneously hypertensive rats (SHR) and worsened cardiac function. Interestingly, the absence of LDHA reversed these effects both in vitro and in vivo. Our study identified LDHA as a novel nicotine-binding protein that plays a crucial role in mediating cardiac fibrosis by blocking autophagy flux. The findings suggest that LDHA could potentially serve as a promising target for the treatment of cardiac fibrosis.

On-site rapid detection of perfluorooctanoic acid by visual immunochromatographic strip biosensor in domestic water and real human samples.

The International Agency for Research on Cancer (IARC) classifies PFOA as a Class 1 carcinogen. Here, a new naked-eye PFOA immunochromographic strip was developed to recognize PFOA in domestic water and real human samples within 10 min based on a novel custom designed anti-PFOA monoclonal antibody (mAb) 2A3, which was firstly an immune rapid detection method for PFOA has been proposed. Using computer simulation techniques such as quantum computing to assist in designing the structural formula of PFOA semi antigen, which hapten was firstly proposed. The half maximal inhibitory concentration of PFOA monoclonal antibody (mAb) 2A3 was 2.4 µg/mL. Using mAb 2A3, we developed an immunochromatographic strip (ICS) for detecting PFOA in real samples. The developed method generated results in 10 min, with visual detection limits of 20, 20, and 200 µg/mL and limit of detection of 50, 200, and 500 µg/mL for water, blood and urine samples, respectively. The established ICS and indirect competitive enzyme-linked immunosorbent assay were used to analyze the actual samples, and the results were confirmed by LC-MS/MS. Our study findings showed that the ICS and ic-ELISA can quickly detect PFOA in actual samples.

FOXM1 promotes the progression of non-small cell lung cancer by inhibiting miR-509-5p expression via binding to the miR-509-5p promoter region.

Background: Forkhead box M1 (FOXM1) functions as a transcription factor and is consistently overexpressed in various cancers, including non-small-cell lung-, breast-, cervical-, and colorectal cancer. Its overexpression is associated with poor prognosis in patients with non-small-cell lung cancer, although the detailed mechanisms by which FOXM1 promotes the development of non-small-cell lung cancer remain unclear. Objective: The mechanism of FOXM1 in migration, invasion, apoptosis, and viability of lung cancer cells was investigated. Methods: Transwell assay, scratch test, and flow cytometry were employed to study the effects of FOXM1 on migration, invasion, and apoptosis in A549 cells. A quantitative polymerase chain reaction was used to determine the impact of FOXM1 on miR-509-5p expression in A549 cells. Dual-luciferase reporter gene assay and chromatin immunoprecipitation were adopted to investigate the molecular mechanisms of FOXM1 on miR-509-5p expression. Results: FDI-6 (a FOXM1 inhibitor) reduced the protein abundance of FOXM1, thereby increasing the expression of miR-509-5p in A549 cells. Moreover, FDI-6 treatment significantly reduced migration, invasion, and viability of A549 cells while promoting cell apoptosis. Furthermore, miR-509-5p inhibitor obviously alleviated the biological effects of FDI-6 on A549 cells, suggesting that FOXM1 primarily exerted its cancer promoting effect by regulating miR-509-5p. Mechanistically, FOXM1 directly bound to the miR-509-5p promoter to inhibit miR-509-5p expression. Conclusion: FOXM1 directly binds to the promoter region of miR-509-5p to form a negative feedback loop, thereby inhibiting miR-509-5p expression and promoting the development of non-small-cell lung cancer. This study is expected to complement research on the pathogenesis of non-small-cell lung cancer and promote the development of novel therapeutic targets for this disease.

LncRNA PWRN1 inhibits the progression of hepatocellular carcinoma by activating PKM2 activity.

Hepatocellular carcinoma (HCC) is one of the most prevalent and leading causes of cancer-related mortality worldwide. Long non-coding RNAs (lncRNAs) have been demonstrated to play vital roles in cancer development and progression. The lncRNA PWRN1 (PWRN1), acts as a tumor suppressor factor, which is low expressed in some cancers. However, the molecular mechanisms underlying the effects of PWRN1, especially the regulatory relationship with RNA binding protein in HCC remain largely unknown. In the present study, we demonstrated that PWRN1 was significantly down-regulated in HCC and correlated with better prognosis; furthermore, gain-of-function experiments showed that PWRN1 inhibited the proliferation of HCC cells. We further found that PWRN1 up-regulated pyruvate kinase activity and thus hinders the proliferation of HCC in vitro and in vivo. Mechanistically, pyruvate kinase M2 (PKM2) was bound to it and maintained the high activity state of PKM2, thereby hindering PKM2 from entering the nucleus in the form of low-activity dimers, reducing the expression of c-Myc downstream gene LDHA, leading to a decrease in lactate levels, and inhibiting the growth of tumor cells. In addition, PWRN1 was found to inhibit aerobic glycolysis. Finally, TEPP-46, a pyruvate kinase activator, appeared to inhibit HCC proliferation by maintaining tetramer stability and increasing pyruvate kinase activity. Taken together, our results provide new insights into the biology hindering HCC proliferation and indicate that PWRN1 in combination with PKM2 activators might represent a novel therapeutic target for HCC.

Formononetin attenuates cigarette smoke-induced COPD in mice by suppressing inflammation, endoplasmic reticulum stress, and apoptosis in bronchial epithelial cells via AhR/CYP1A1 and AKT/mTOR signaling pathways.

Chronic obstructive pulmonary disease (COPD) is a chronic, progressive, and lethal lung disease with few treatments. Formononetin (FMN) is a clinical preparation extract with extensive pharmacological actions. However, its effect on COPD remains unknown. This study aimed to explore the effect and underlying mechanisms of FMN on COPD. A mouse model of COPD was established by exposure to cigarette smoke (CS) for 24 weeks. In addition, bronchial epithelial BEAS-2B cells were treated with CS extract (CSE) for 24 h to explore the in vitro effect of FMN. FMN significantly improved lung function and attenuated pathological lung damage. FMN treatment reduced inflammatory cell infiltration and pro-inflammatory cytokines secretion. FMN also suppressed apoptosis by regulating apoptosis-associated proteins. Moreover, FMN relieved CS-induced endoplasmic reticulum (ER) stress in the mouse lungs. In BEAS-2B cells, FMN treatment reduced CSE-induced inflammation, ER stress, and apoptosis. Mechanistically, FMN downregulated the CS-activated AhR/CYP1A1 and AKT/mTOR signaling pathways in vivo and in vitro. FMN can attenuate CS-induced COPD in mice by suppressing inflammation, ER stress, and apoptosis in bronchial epithelial cells via the inhibition of AhR/CYP1A1 and AKT/mTOR signaling pathways, suggesting a new therapeutic potential for COPD treatment.

Combination of fractional carbon dioxide laser with recombinant human collagen in periocular skin rejuvenation.

BACKGROUND: The most visible sign of facial aging is often seen in the periocular area. However, periocular rejuvenation remains challenging due to the particularity of periocular anatomic locations. AIMS: We aimed to evaluate the efficacy and safety of the fractional-ablative CO2 laser-facilitated recombinant human collagen permeation in periocular rejuvenation. PATIENTS/METHODS: This 3-month prospective single-blinded and self-controlled trial enrolled 26 patients with periocular aging who underwent the treatments of fractional-ablative CO2 laser along with laser-facilitated recombinant human collagen permeation. Following the treatments, the patients were quantitatively assessed by various periocular skin aging indices before and after the treatment and monitored for any related adverse events. RESULTS: The patients showed significant improvements with the periocular skin aging indices 3 months after the treatments, which were detailed with a 47.3% decrease in lower eyelid skin rhytids, a 41.4% decrease in the lower eyelid skin texture, a 35.0% decrease in the static crow's feet, a 29.3% decrease in the amount of upper eyelid laxity, and a 20.2% increase in the MRD1 as compared with baseline (p < 0.05). Moreover, total skin thickness under ultrasound was increased in both upper and lower eyelids (5.6% and 3.3%, p < 0.05, respectively). Moreover, six patients (23.1%, 6/26) had erythema for 2 weeks, and two (2/26, 7.7%) had mild hyperpigmentation for 3 months. CONCLUSIONS: Fractional-ablative CO2 laser combined with laser-facilitated recombinant human collagen permeation can be a safe and effective treatment for periocular rejuvenation.

Airborne observations over the North Atlantic Ocean reveal the importance of gas-phase urea in the atmosphere.

Reduced nitrogen (N) is central to global biogeochemistry, yet there are large uncertainties surrounding its sources and rate of cycling. Here, we present observations of gas-phase urea (CO(NH2)2) in the atmosphere from airborne high-resolution mass spectrometer measurements over the North Atlantic Ocean. We show that urea is ubiquitous in the lower troposphere in the summer, autumn, and winter but was not detected in the spring. The observations suggest that the ocean is the primary emission source, but further studies are required to understand the responsible mechanisms. Urea is also observed aloft due to long-range transport of biomass-burning plumes. These observations alongside global model simulations point to urea being an important, and currently unaccounted for, component of reduced-N to the remote marine atmosphere. Airborne transfer of urea between nutrient-rich and -poor parts of the ocean can occur readily and could impact ecosystems and oceanic uptake of carbon dioxide, with potentially important climate implications.

Anemia is a risk factor for rapid eGFR decline in type 2 diabetes.

Objective: To investigate the association between anemia and progression of diabetic kidney disease (DKD) in type 2 diabetes. Methods: This was a retrospective study. A total of 2570 in-patients with type 2 diabetes hospitalized in Jinan branch of Huashan hospital from January 2013 to October 2017 were included, among whom 526 patients were hospitalized ≥ 2 times with a median follow-up period of 2.75 years. Annual rate of eGFR decline was calculated in patients with multiple admissions. A rate of eGFR decline exceeding -5 ml/min per 1.73 m2 per year was defined as rapid eGFR decline. The prevalence of DKD and clinical characteristics were compared between anemia and non-anemia patients. Correlation analysis was conducted between anemia and clinical parameters. Comparison of clinical features were carried out between rapid eGFR decline and slow eGFR decline groups. The risk factors for rapid DKD progression were analyzed using logistic regression analysis. Results: The prevalence of anemia was 28.2% among the 2570 diabetic patients, while in patients with DKD, the incidence of anemia was 37.8%. Patients with anemia had greater prevalence of DKD, higher levels of urinary albumin-to-creatinine ratio (UACR), serum creatinine, BUN, urine α1-MG, urine ß2-MG, urine NAG/Cr, hsCRP, Cystatin C, homocysteine and lower eGFR, as compared to the patients without anemia. Anemia was correlated with age, UACR, eGFR, urinary NAG/Cr, hsCRP and diabetic retinopathy (DR). Logistic regression analysis of 526 patients with type 2 diabetes during the follow-up period showed that anemia was an independent risk factor for rapid eGFR decline. Conclusion: Anemia is associated with worse renal function and is an independent risk factor for rapid eGFR decline in type 2 diabetes.

Bioaccessibility and bioavailability evaluation of heavy metal(loid)s in ginger in vitro: Relevance to human health risk assessment.

Ginger is a common spice in everyday diet. However, over time, it may absorb and accumulate heavy metal(loid)s (HMs) from the soil, posing a potential health risk to humans. In this study, we evaluated the pollution level, bioavailability, mobility evaluation, and health risk of Cr, Pb, Cd, and As in the soil-ginger system of five major ginger-producing cities in Shandong Province, China. Research indicated the concentrations of the Cr, Pb, Cd, and As in the soil were close to or even higher than background value, except Weifang. With the concentrations of Cr, Pb, Cd, and As in ginger being 0.08-0.47, 0.03-0.16, 0.002-0.03, and 0.006-0.028 mg/kg, the four HMs concentrations were within the limits of 0.1-0.5 mg/kg based on the Chinese health standard (GB2762-2017) of HMs in food. The bioavailability of HMs in soils was evaluated using diethylenetriaminepentaacetic acid (DTPA) and nitric acid (HNO3) extraction and the results showed that Pb and Cd have high bioavailability. Mobility evaluation of HMs from soil to ginger based on Pearson's correlation and the partial least squares-path method (PLS-PM) model showed that the soil's physicochemical properties influence the HMs migration process (especially Cd and Pb) in the soil-ginger system, and the PLS-PM model has good adaptability to Cd and Pb (gof > 0.5). The mean total carcinogenic risk (TCR) of bioaccessible gastric and intestinal HMs were 4.64 × 10-6 and 3.13 × 10-6, which were much lower than that of total HMs (2.60 × 10-5), indicating that existing models based on total HMs may overestimate the health risk of HMs. The bioaccessible concentrations should be considered to improve the accuracy of assessment results.

Astaxanthin ameliorates lipopolysaccharide-induced acute lung injury via inhibition of inflammatory reactions and modulation of the SOCS3/JAK2/STAT3 signaling pathways in mice.

Acute lung injury (ALI) is a systemic inflammatory process. A large number of studies have shown that astaxanthin (ASTA) has strong anti-inflammatory effects and almost non-toxic side effects. The purpose of this study was to explore the effect of ASTA on lipopolysaccharide (LPS)-induced ALI in mice and its underlying mechanism. The result showed that compared with the LPS group, the expression levels of the respiratory resistance (Re), inspiratory resistance (Ri), dynamic lung compliance (Cdyn), wet/dry weight (W/D) ratio, albumin (BA/SA) ratio and myeloperoxidase (MPO) activity in the ASTA pretreatment group were significantly reduced, and total cell, neutrophil and macrophage counts were significantly decreased. HE staining results showed that alveolar interstitial edema, bleeding and erythrocyte exudation were reduced. Compared with the LPS group, the percentage of Th17 cells and the content of interleukin (IL)-17 and tumor necrosis factor-α (TNF-α) in the ASTA pretreatment group were significantly decreased, while the content of the transforming growth factor (TGF)-ß and the percentage of Treg cells were significantly increased. Western blot analysis showed that ASTA could up-regulate the expression level of the suppressor of cytokine signaling-3 (SOCS3) and down-regulate the expression levels of phosphorylated Janus kinase 2 (p-JAK2), phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in lung tissue. The results showed that ASTA had a protective effect on LPS-induced acute lung injury in mice, and its protective mechanism was through activating the SOCS3/JAK2/STAT3 signaling pathway, promoting Treg cell differentiation and reducing inflammatory reactions and Th17 cell differentiation, which provided a theoretical basis for the clinical treatment of ALI.

Macrophage-derived exosomal miR-4532 promotes endothelial cells injury by targeting SP1 and NF-κB P65 signalling activation.

Atherosclerosis is a complex pathological process involving macrophages, endothelial cells and vascular smooth muscle cells that can lead to ischemic heart disease; however, the mechanisms underlying cell-to-cell communication in atherosclerosis are poorly understood. In this study, we focused on the role of exosomal miRNAs in crosstalk between macrophages and endothelial cells and explored the rarely studied molecular mechanisms involved. Our in vitro result showed that macrophage-derived exosomal miR-4532 significantly disrupted human umbilical vein endothelial cells (HUVECs) function by targeting SP1 and downstream NF-κB P65 activation. In turn, increased endothelin-1 (ET-1), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and decreased endothelial nitric oxide synthase (eNOS) expression in HUVECs increased attraction of macrophages, exacerbating foam cell formation and transfer of exosomal miR-4532 to HUVECs. MiR-4532 overexpression significantly promoted endothelial injury and pretreatment with an inhibitor of miR-4532 or GW4869 (exosome inhibitor) could reverse this injury. In conclusion, our data reveal that exosomes have a critical role in crosstalk between HUVECs and macrophages. Further, exosomal miR-4532 transferred from macrophages to HUVECs and targeting specificity protein 1 (SP1) may be a novel therapeutic target in patients with atherosclerosis.

Risk factors for the in-hospital mortality of CRRT-therapy patients with cardiac surgery-associated AKI: a single-center clinical study in China.

OBJECTIVE: We retrospectively analyzed risk factors on in-hospital mortality in CRRT-therapy patients with open cardiac surgery (CS)-induced acute kidney injury (AKI), to provide the clinical basis for predicting and lowering the in-hospital mortality after CS. METHODS: 84 CS-AKI patients with CRRT were divided into survival and death groups according to discharge status, and the perioperative data were analyzed with R version 4.0.2. RESULTS: There were significant differences between the two groups, including: urea nitrogen, Sequential Organ Failure Assessment (SOFA) score and vasoactive-inotropic score (VIS) on the first day after operation; VIS just before CRRT; SOFA score and negative balance of blood volume 24 h after CRRT; the incidence rate of bleeding, severe infection and MODS after operation; and the interval between AKI and CRRT. Univariate logistic regression analysis showed that SOFA score and VIS on the first day after operation; VIS just before CRRT; VIS and negative balance of blood volume 24 h after CRRT; the incidence rate of bleeding, infection and multiple organ dysfunction syndrome (MODS) after operation; bootstrap resampling analysis showed that SOFA score and VIS 24 h after CRRT, as well as the incidence of bleeding after operation were the independent risk factors. CONCLUSION: Maintaining stable hemodynamics and active prevention of bleeding are expected to decrease the in-hospital mortality.

Diagnostic Efficacy and Clinical Value of Ultrasonography in Difficult Airway Assessment: Based on a Prospective Cohort Study.

Objective: A case-control study was conducted to explore the diagnostic efficacy and clinical value of ultrasound in difficult airway assessment. Methods: A total of 220 patients undergoing elective surgery under general anesthesia were prospectively enrolled in our hospital from April 2018 to April 2021. General data were collected one day before operation, including sex, age, height, weight, body mass index (BMI), modified Mallampati test (MMT), inter-incisor distance (IID) and thyromental distance (TMD), the upper lip bite test (ULBT), and thyromental height (TMH). DSH, DSE, DSV, HMD, and tongue width and thickness were measured by ultrasound in the supine position before anesthesia induction on the day of operation. The above data were measured by the same anesthesiologist. After anesthesia, the patients were exposed to laryngoscope by the same senior doctor who did not participate in the data analysis, and the Cormack-Lehane (CL) grade was recorded and endotracheal intubation was completed. The relationship between DSE, DSH, DSV, HMD, and tongue width and thickness and laryngoscope exposure difficulty and tracheal intubation difficulty was analyzed. The critical value of each index for predicting laryngoscope exposure difficulty and tracheal intubation difficulty was obtained by the receiver operating characteristic curve (ROC) and Jordan index. According to the critical value, the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of each index were calculated. Results: On comparing the general conditions of the four groups, this study prospectively included 220 patients undergoing elective surgery under general anesthesia for tracheal intubation in our hospital from April 2018 to April 2021, of which 8 cases were excluded from the study because of loss of incisors, 5 cases were excluded from the study due to unclear development of the anterior vocal cords under ultrasound, 7 cases were excluded from the study, and finally 200 patients were included in the study, including 104 males and 96 females. Among the 200 patients, difficult laryngoscope exposure was found in 26 cases (13.00%) and difficult tracheal intubation in 17 cases (8.50%). Tracheal intubation was performed in 17 patients with a visual laryngoscope and light rod, respectively. The weight and BMI of patients in the DL group were higher than in the NDL group, and the difference was statistically significant (P < 0.05); the weight and BMI of patients in the DI group were higher than in the NDI group, and the difference was statistically significant (P < 0.05); there was no significant difference in sex, age, and height between the DL group and the NDL group and the DI group and the NDI group (P > 0.05). Compared with the NDL group, IID, TMD, and TMH in the DL group were lower, and the difference was statistically significant (P < 0.05); there was no significant difference in ULBT (P > 0.05). DSE, DSH, and DSV were higher than in the NDL group, and the difference was statistically significant (P < 0.05), the HMD was lower than in the NDL group, and the difference was statistically significant (P < 0.05);the width and thickness of tongue were higher than in the NDL group, and the difference was statistically significant (P < 0.05). On comparing the DI NDI groups, the IID, TMD, and TMH in group DI were lower than in group NDI, and the difference was statistically significant (P < 0.05), but there was no significant difference in ULBT (P > 0.05); DSE, DSH, and DSV were higher than in the NDI group, and the difference was statistically significant (P < 0.05); the HMD was lower than in the NDI group, and the difference was statistically significant (P < 0.05); the width and thickness of tongue were higher than in the NDL group, and the difference was statistically significant (P < 0.05). The AUC of BMI, TMH, DSE, DSV, HMD, and tongue width and thickness all ranged from 0.70 to 0.9. Laryngoscope exposure difficulty diagnostic value was medium. The AUC of TMD, MMT, ULBT, IID, and DSH ranged from 0.5 to 0.7. The diagnostic value of laryngoscope exposure difficulty was low. According to the ROC curve, the AUC value of HMD, DSE, and tongue thickness in ultrasonic indicators was higher than that of traditional indicators and the AUC value of TMH was the highest in traditional indicators. When the HMD cutoff value was 5.29 cm; the accuracy, sensitivity, specificity, PPV, and NPV were 73.6%, 96.7%, 71.6%, 31.8%, and 97.4%, respectively. Compared with tongue width, tongue thickness has a better predictive performance. The accuracy of DSH, DSV, DSE, and tongue width and thickness in predicting difficult laryngoscope exposure was lower than HMD and the difference was statistically significant (P < 0.05). The patients in the DI and NDI groups indicated that the AUC of ULBT, TMD, and IID was between 0.5 and 0.7, the diagnostic values of BMI, MMT, TMH, DSE, DSH, DSV, HMD, and tongue width and thickness were between 0.7 and0.9, and the diagnostic value for tracheal intubation difficulty was moderate. According to the ROC curve, HMD, DSE, and tongue thickness in ultrasonic indexes were higher compared to traditional indexes. Among the traditional indexes, the AUC value of TMH is the largest. In ultrasonic indexes, when the critical value of HMD DSE is 4.85 cm, the AUC value is 0.893, and its accuracy, sensitivity, specificity, PPV, and NPV are 81.6%, 93.8%, 80.6%, 30.2%, and 99.5%, respectively. In ultrasonic indexes, the prediction performance is better, followed by the tongue thickness prediction performance. The accuracy of DSH, DSV, DSE, and tongue width and thickness in predicting difficult tracheal intubation was lower than in HMD, and the difference was statistically significant (P < 0.05). Conclusion: Ultrasonic measurements such as DSH, DSE, DSV, HMD, and tongue width and thickness have predictive value for difficult airway;when the ultrasonic measurement of HMD is ˂5.29 cm, we should pay attention to the difficulty of laryngoscope exposure, and when DSE is ˂4.85 cm, we should watch out for difficult tracheal intubation. In terms of other ultrasound indexes, HMD is more valuable in predicting difficult airway.

Health risk assessment of heavy metal(loid)s in the farmland of megalopolis in China by using APCS-MLR and PMF receptor models: Taking Huairou District of Beijing as an example.

The quality of agricultural soils is important for agricultural production and food safety. The contamination of agricultural soils by heavy metal(loid)s (HMs) has aroused global attention. Fifty-two topsoil samples with 8 HMs were gathered to assess the health risks of farmland soil in Huairou District, Beijing. As a significantly enriched pollutant, the results revealed that Hg had greater ecological risks relative to other HMs. We found that the positive matrix factorization (PMF) model appears to be more physically plausible in identifying complex pollution sources compared to the absolute principal components score-multiple linear regression (APCS-MLR) model, which had a higher fit coefficient (r2 = 0.69-0.99). Five HMs from pollution sources, including agricultural activities, traffic source, natural source, fuel burning, and industrial production, were identified by integrating the PMF model with Pearson's correlation analysis, revealing corresponding contribution rates of 29.40%, 22.54%, 20.16%, 15.20%, and 12.70%, respectively. The probabilistic health risk evaluation results showed an absence of non-carcinogenic risks in all populations, but the carcinogenic risk could not be ignored, especially in children. In addition, the source-oriented health risks showed that agricultural activities made the largest contribution to the health risks of all populations. This research provides scientific evidence for preventing HMs contamination and control of farmland.

Isolated metastasis of mediastinal carcinoid to the left ventricle: A case report.

Carcinoid tumors are uncommon neuroendocrine tumors that produce high levels of serotonin and are mainly located in the gastrointestinal tract and bronchopulmonary system but very rarely in the mediastinum. These are slow-growing tumors that most commonly present metastatic lesions in the liver, followed by the bones, lungs, and peritoneum. Solid cardiac metastases from carcinoid tumors have seldom been reported. In this case report, we present a patient with a rare localized metastasis in the left ventricle with an antecedent history of resected carcinoid tumor of the anterior mediastinum.

Potent antitumor activity of a glutamyltransferase-derived peptide via an activation of oncosis pathway.

Hepatocellular carcinoma (HCC) still presents poor prognosis with high mortality rate, despite of the improvement in the management. The challenge for precision treatment was due to the fact that little targeted therapeutics are available for HCC. Recent studies show that metabolic and circulating peptides serve as endogenous switches for correcting aberrant cellular plasticity. Here we explored the antitumor activity of low molecular components in human umbilical serum and identified a high abundance peptide VI-13 by peptidome analysis, which was recognized as the part of glutamyltransferase signal peptide. We modified VI-13 by inserting four arginines and obtained an analog peptide VI-17 to improve its solubility. Our analyses showed that the peptide VI-17 induced rapid context-dependent cell death, and exhibited a higher sensitivity on hepatoma cells, which is attenuated by polyethylene glycol but not necrotic inhibitors such as z-VAD-fmk or necrostatin-1. Morphologically, VI-17 induced cell swelling, blebbing and membrane rupture with release of cellular ATP and LDH into extracellular media, which is hallmark of oncotic process. Mechanistically, VI-17 induced cell membrane pore formation, degradation of α-tubulin via influx of calcium ion. These results indicated that the novel peptide VI-17 induced oncosis in HCC cells, which could serve as a promising lead for development of therapeutic intervention of HCC.

Bioinspired Microenvironment Responsive Nanoprodrug as an Efficient Hydrophobic Drug Self-Delivery System for Cancer Therapy.

Artemisinin compounds have shown satisfactory safety records in anti-malarial clinical practice over decades and have revealed value as inexpensive anti-tumor adjuvant chemotherapeutic drugs. However, the rational design and precise preparation of nanomedicines based on the artemisinin drugs are still limited due to their non-aromatic and fragile chemical structure. Herein, a bioinspired coordination-driven self-assembly strategy was developed to manufacture the artemisinin-based nanoprodrug with a significantly increased drug loading efficacy (∼70 wt %) and decreased preparation complexity compared to conventional nanodrugs. The nanoprodrug has suitable size distribution and robust colloidal stability for cancer targeting in vivo. The nanoprodrug was able to quickly disassemble in the tumor microenvironment with weak acidity and a high glutathione concentration, which guarantees a better tumor inhibitory effect than direct administration and fewer side effects on normal tissues in vivo. This work highlights a new strategy to harness a robust, simplified, organic solvent-free, and highly repeatable route for nanoprodrug manufacturing, which may offer opportunities to develop cost-effective, safe, and clinically available nanomedicines.

Nicotine Causes Mitochondrial Dynamics Imbalance and Apoptosis Through ROS Mediated Mitophagy Impairment in Cardiomyocytes.

Nicotine contained in traditional cigarettes, hookahs, and e-cigarettes is an important risk factor for cardiovascular disease. Our previous study showed that macroautophagic flux impairment occurred under nicotine stimulation. However, whether nicotine influences mitochondrial dynamics in neonatal rat ventricular myocytes (NRVMs) is unclear. The purpose of this study was to explore the effects and potential mechanism of nicotine on mitophagy, mitochondrial dynamics, apoptosis, and the relationship between these processes in NRVMs. Our results showed that nicotine exposure increased mitochondria-derived superoxide production, decreased mitochondrial membrane potential, and impaired PINK1/Parkin-mediated mitophagic flux in NRVMs. Interestingly, nicotine significantly promoted dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and suppressed mitofusin (MFN)-mediated fusion, which was also observed in the bafilomycin A1-treated group. These results suggest that mitophagic flux impairment may contribute to Drp-1-mediated mitochondrial fission. Finally, nicotine caused excessive mitochondrial fission and contributed to apoptosis, which could be alleviated by mdivi-1, an inhibitor of Drp1. In addition to CTSB, as we previously reported, the enzyme activity of cathepsin L (CTSL) was also decreased in lysosomes after stimulation with nicotine, which may be the main cause of the hindered mitophagic flux induced by nicotine in NRVMs. Pretreatment with Torin 1, which is an inhibitor of mTOR, activated CTSL and ameliorated nicotine-induced mTOR activation and mitophagy impairment, decreased mitochondria-derived superoxide production, and blunted mitochondrial fission and apoptosis. Pretreatment with the ROS scavenger N-acetyl-cysteine (NAC) or inhibitors of p38 and JNK, which could also alleviate mitophagy impairment, exhibited similar effects as Torin1 on mitochondria. Taken together, our study demonstrated that nicotine treatment may lead to an increase in Drp1-mediated mitochondrial fission by blocking mitophagic flux by weakening the enzyme activity of CTSL and activating the ROS/p38/JNK signaling pathway. Excessive mitochondrial fission induced by nicotine ultimately leads to apoptosis. Torin1 restored the decreased CTSL enzyme activity by removing excessive ROS and alleviated the effects of nicotine on mitophagic flux, mitochondrial dynamics, and apoptosis. These results may provide new evidence on the relationship between mitophagic flux and mitochondrial dynamics and new perspectives on nicotine's effects on mitochondrial dynamics in cardiomyocytes.

Health risk assessment based on source identification of heavy metals: A case study of Beiyun River, China.

Long-term retention and accumulation of heavy metals in rivers pose a great threat to the stability of ecosystems and human health. In this study, Beiyun River was taken as the example to quantitatively identify pollution sources and assess the pollution source-oriented health risk. A total of 8 heavy metals (Mn, Ni, Pb, Zn, As, Cr, Cd, and Cu) in Beiyun River were measured. Ordinary kriging (OK) and inverse distance weight (IDW) methods were used to predict the distribution of heavy metals. The results showed that the OK method is more accurate, and heavy metal pollution in the midstream and downstream is much more serious than that in the upstream. Principal component analysis-multiple linear regressions (PCA-MLR) and positive matrix factorization (PMF) methods were used to quantitatively identify pollution sources. The coefficient of determination (R2) of PMF is closer to 1, and the analyzed pollution source is more refined. Furthermore, the result of source identification was imported into the health risk assessment to calculate the hazard index (HI) and carcinogenic risk (CR) of various pollution sources. The results showed that the HI and CR of As and Ni to local residents were serious in the Beiyun River. Industrial activities (23.0%) are considered to be the largest contribution of heavy metals in Beiyun River, followed by traffic source (17%), agricultural source (16%), and atmospheric deposition (16%). The source-oriented risk assessment indicated that the largest contribution of HI and CR is agricultural source in the Beiyun River, followed by industrial activities. This study provides a "target" for the precise control of pollution sources, which is of great significance for improving the fine management of the water environment in the basin.

[Regularities of acupoint combinations and characteristics of core acupoint application for acupuncture-moxibustion treatment of mammary gland hyperplasia based on complex network analysis].

OBJECTIVE: To analyze the acupoint combination regularities and application characteristics of core acupoints in acupuncture-moxibustion treatment of mammary gland hyperplasia (MGH) by using complex network technology, so as to provide reliable evidence for clinical selection of acupoints and treatment ideas. METHODS: The articles related to acupuncture treatment of MGH published from January of 1981 to May of 2020 were collected from databases as China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform (Wanfang), Chinese Journal of Science and Technology of VIP (VIP), PubMed, the Excerpta Medica Database (EMBASE), Cochrane Library, and Web of Science and Ovid database (OVID) according to the set inclusion and exclusion criteria of the present paper and by using keywords of "mammary gland hyperplasia", "mastalgia" or "fibrocystic breast change", "breast cystic hyperplasia ", etc. plus "acupuncture", "moxibustion", etc. Then, a correlative database model was established by using SPSS Modeler 18.0 to analyze their association regularities, followed by conducting a complex network analysis with Gephi 0.9.2 software. RESULTS: A total of 312 eligible articles containing 343 acupoint prescriptions and 113 acupoints were collected. The total frequency of use of the 113 acupoints was 1 998. The association regularity analysis showed a top relativity between Danzhong(CV17) and Zusanli(ST36). The analysis of the complex network topology revealed that CV17, Qimen(LR14), Sanyinjiao(SP6), Taichong(LR3), ST36, Jianjing(GB21), Rugen(ST18), Wuyi(ST15), Neiguan(PC6), Ashi-points, Fenglong (SP40), Guanyuan(CV4), Taixi(KI3), Tianzong(SI11), Ganshu (BL18), and Hegu(LI14) are the core acupoints for treatment of MGH. The principle for composing acupoint prescriptions is mainly the combination of acupoints on the left and right sides, the upper and lower parts, front and back parts of the body, respectively, and those of the outer and inner meridians, and those of the same name meridians and Zangfu-organ syndrome differentiation. The needle-insertion direction is mostly toward the focus. CONCLUSION: The composition of acupoint prescriptions for treating MGH with acupuncture and moxibustion is mainly based on the combination of specific acupoints among which the confluent acupoints are most frequently used, followed by the combination of acupoints distributing at the chest, back, upper and lower limbs, and the local acupoints.