DEAD-box helicase 1 inhibited CD8+ T cell antitumor activity by inducing PD-L1 expression in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) does not respond well to current treatments, even immune checkpoint inhibitors. PD-L1 (programmed cell death ligand 1 or CD274 molecule)-mediated immune escape of tumor cells may be a key factor affecting the efficacy of immune checkpoint inhibitor (ICI) therapy. However, the regulatory mechanisms of PD-L1 expression and immune escape require further exploration. Here, we observed that DDX1 (DEAD-box helicase 1) was overexpressed in HCC tissues and associated with poor prognosis in patients with HCC. Additionally, DDX1 expression correlated negatively with CD8+ T cell frequency. DDX1 overexpression significantly increased interferon gamma (IFN-γ)-mediated PD-L1 expression in HCC cell lines. DDX1 overexpression decreased IFN-γ and granzyme B production in CD8+ T cells and inhibited CD8+ T cell cytotoxic function in vitro and in vivo. In conclusion, DDX1 plays an essential role in developing the immune escape microenvironment, rendering it a potential predictor of ICI therapy efficacy in HCC.

A Green and Wide-Scope Approach for Chiroptical Sensing of Organic Molecules through Biomimetic Recognition in Water.

Optical chirality sensing has attracted a lot of interest due to its potential in high-throughput screening in chirality analysis. A molecular sensor is required to convert the chirality of analytes into optical signals. Although many molecular sensors have been reported, sensors with wide substrate scope remain to be developed. Herein, we report that the amide naphthotube-based chirality sensors have an unprecedented wide scope for chiroptical sensing of organic molecules. The substrates include, but are not limited to common organic products in asymmetric catalysis, chiral molecules with inert groups or remote functional groups from their chiral centers, natural products and their derivatives, and chiral drugs. The effective chirality sensing is based on biomimetic recognition in water and on effective chirality transfer through guest-induced formation of a chiral conformation of the sensors. Furthermore, the sensors can be used in real-time monitoring on reaction kinetics in water and in determining absolute configurations and ee values of the products in asymmetric catalysis.

RNA-binding protein trinucleotide repeat-containing 6A regulates the formation of circular RNA circ0006916, with important functions in lung cancer cells.

Circular RNAs (circRNAs) are widespread and diverse endogenous RNAs distinct from traditional linear RNAs, which may regulate gene expression in eukaryotes. However, the function of human circRNAs, including their potential role in lung cancer, remains largely unknown. We screened the circRNA circ0006916, which was evidently down-regulated in 16HBE-T cells (anti-benzopyrene-trans-7, 8-dihydrodiol-9, 10-epoxide-transformed human bronchial epithelial cells), and in A549 and H460 cell lines. Silencing of circ0006916, but not its parental gene homer scaffolding protein 1 (HOMER1), promoted cell proliferation via speeding up the cell cycle process rather than by inhibiting apoptosis; conversely, overexpression of circ0006916 had the opposite effect. Luciferase-screening assay indicated that circ0006916 bound to miR-522-3p and inhibited pleckstrin homology domain and leucine rich repeat protein phosphatase 1 (PHLPP1) activity. We also explored the effect of the RNA-binding protein trinucleotide repeat-containing 6A (TNRC6A) on circ0006916 production. Circ0006916 expression was decreased after silencing TNRC6A. TNRC6A bound to the intron regions around the circRNA-forming exons of circ0006916, as shown by RNA immunoprecipitation assay combined with sequencing analysis. The association of circ0006916 with TNRC6A was further verified by RNA pull-down assays. We then constructed a carrier and confirmed that TNRC6A binding to the flanked intron region of circ0006916 was necessary for generation of circ0006916. These results demonstrate that TNRC6A regulates the biogenesis of the circRNA circ0006916, which has a regulatory role in cell growth.

Bis-Naphthalene Cleft with Aggregation-Induced Emission Properties through Lone-Pair⋠⋠⋠π Interactions.

A rigid molecular cleft shows unique aggregation-induced emission (AIE) by restricting the motion of aldehyde through intermolecular lone pair⋅⋅⋅π interactions, which are tuned by side chains. This AIE luminogen was demonstrated to work as a fluorescent sensor for aniline and an optical chirality sensor for chiral amine.

Spontaneous regression of adrenal metastasis from renal cell carcinoma after sunitinib withdrawal: case report and literature review.

BACKGROUND: The spontaneous regression of metastatic renal cell carcinoma is a rare phenomenon, with an estimated incidence of < 1%. We report a case of post-nephrectomy renal cell carcinoma adrenal metastasis, followed by the spontaneous regression of the metastasis after withdrawal of sunitinib. CASE PRESENTATION: The patient was a 55-year-old male with clear cell type renal cell carcinoma who previously underwent a left laparoscopic radical nephrectomy. After 51 months of follow up, a recurrence in the left renal fossa was observed and subsequently excised. Four months after excision, an abdominal Computerized tomography (CT) identified an adrenal metastasis of 1.6 cm. The patient was treated with sunitinib. However, the treatment was discontinued because of gastrointestinal side effects and fatigue. Eleven months after the discontinuation of sunitinib treatment, a progression in the adrenal metastasis growth (5.7 cm) was observed, whereas 16 months after the discontinuation, a regression of the adrenal metastasis growth (3.4 cm) was observed. During subsequent follow-ups, a gradual reduction in the size of the adrenal metastasis (1.8 cm) was observed. After 44 months from the discontinuation of sunitinib treatment, the patient was still alive and followed up in the outpatient department. CONCLUSIONS: Sunitinib is a multi-targeted inhibitor of vascular endothelial growth factor (VEGF) receptors. This compound reduces tumor angiogenesis and has been approved worldwide for the treatment of advanced renal cell carcinoma. To our knowledge, this is the fourth case of the spontaneous regression of metastatic renal cell carcinoma after the discontinuation of sunitinib treatment.

A novel regulatory network among LncRpa, CircRar1, MiR-671 and apoptotic genes promotes lead-induced neuronal cell apoptosis.

Lead is a metal that has toxic effects on the developing nervous system. However, the mechanisms underlying lead-induced neurotoxicity are not well understood. Non-coding RNAs (ncRNAs) play an important role in epigenetic regulation, but few studies have examined the function of ncRNAs in lead-induced neurotoxicity. We addressed this in the present study by evaluating the functions of a long non-coding RNA (named lncRpa) and a circular RNA (named circRar1) in a mouse model of lead-induced neurotoxicity. High-throughput RNA sequencing showed that both lncRpa and circRar1 promoted neuronal apoptosis. We also found that lncRpa and circRar1 induced the upregulation of apoptosis-associated factors caspase8 and p38 at the mRNA and protein levels via modulation of their common target microRNA miR-671. This is the first report of a regulatory interaction among a lncRNA, circRNA, and miRNA mediating neuronal apoptosis in response to lead toxicity.

Correlations between inflammatory cytokines, muscle damage markers and acute postoperative pain following primary total knee arthroplasty.

BACKGROUND: Despite the success of total knee arthroplasty (TKA) in reducing knee pain and improving functional disability, the management of acute postoperative pain is still unsatisfactory. This study was aimed to quantitatively analyze the possible correlations between inflammatory cytokines, muscle damage markers and acute postoperative pain following primary TKA. METHODS: Patients scheduled for unilateral primary TKA were consecutively included, the serial changes of the numerical rating scale (NRS) at rest (NRSR) and at walking (NRSW), serum inflammatory cytokines and muscle damage markers were assessed before surgery (T0) and at postoperative day 1, 2, 3 and 5 (T1-T4, respectively); while pain disability questionnaire (PDQ) and synovial fluid inflammatory cytokines were evaluated at T0. The correlations between inflammatory cytokines, muscle damage markers and pain scores were examined, and Bonferroni correction was applied for multiple comparisons. RESULTS: Ninety six patients were included for serum markers and pain evaluations at T0-T4, while 54 (56.25%) for synovial fluid cytokines at T0. The NRSR at T1 and T2 were positively correlated with preoperative NRSW, while the NRSW at T1 to T4 were positively correlated with preoperative NRSR, NRSW and PDQ (all p < 0.05). The NRSR was positively correlated with serum PGE2, IL-6, and CK at T1; the NRSW was positively correlated with serum CRP at T1, with PGE2 and IL-6 at T1 to T3, with CK at T2 and T4, and with Mb and LDH at T1 to T4 (all p < 0.003). Meanwhile, positive correlations were observed between preoperative NRSW and synovial fluid PGE2, IL-6, IL-8, or TNF-α, as well as between PDQ and PGE2 (all p < 0.003), but no associations between postoperative pain scores and preoperative synovial fluid cytokines was found (all p ≥ 0.003). Additionally, the NRSR at T1 and T2, and NRSW at T1 to T4 were positively correlated with body mass index (all p < 0.05). CONCLUSIONS: Serum inflammatory cytokines and muscle damage markers are positively correlated with acute postoperative pain following primary TKA, and the key cytokines (CRP, PGE2, and IL-6) and markers (Mb, CK and LDH) may serve as the targets for developing novel analgesic strategies.

The Effect of Staged Transverse Preputial Island Flap Urethroplasty for Proximal Hypospadias with Severe Chordee.

PURPOSE: We compare the effects of staged tranverse preputial island flap urethroplasty and the Byars 2-stage procedure in patients with proximal hypospadias and severe chordee. MATERIALS AND METHODS: We studied 87 consecutive children referred for proximal hypospadias with severe chordee between March 2011 and March 2014. Of the cases 42 were repaired with staged tranverse preputial island flap (group 1) and 45 were managed by 2-stage Byars urethroplasty (group 2). Mean ± SD age at first stage surgery was 26.6 ± 13.3 months in group 1 and 24.8 ± 14.7 months in group 2. Postoperative complications in both groups were assessed regarding fistulas, urethral strictures, diverticula, meatal stenosis and glanular dehiscence. RESULTS: After the second stage 2 patients (4.8%) in group 1 and 10 (23.2%) in group 2 had urethrocutaneous fistulas (p <0.05). One patient (2.4%) in group 1 and 2 patients (4.4%) in group 2 had urethral strictures (p >0.05). All patients with stricture were cured by repeated dilation and no patient required reoperation. One patient (2.4%) in group 1 and no patient in group 2 had diverticulum (p >0.05). No patient in either group had signs or symptoms of meatal stenosis or residual chordee. Three patients (7.1%) in group 1 and 12 (26.7%) in group 2 needed reoperation (p <0.05). CONCLUSIONS: Two-stage urethroplasty, particularly tranverse preputial island flap partial urethroplasty, is appropriate for treating patients with proximal hypospadias and severe chordee. Use of the tranverse preputial island flap can decrease complications associated with the second stage and significantly improve the success rate.

Theoretical Studies on Palladium-Mediated Enantioselective C-H Iodination.

DFT calculations have been carried out to investigate the reaction mechanism for Pd(II)-mediated enantioselective C-H iodination. Iodination of the aryl ortho C-H bond of benzylamines catalyzed by Pd(II) diacetate complexes in the presence of the L-MPAA ligand experiences three main steps: first, C-H bond activation; second, oxidative addition of iodine on Pd(II) and reductive elimination of iodobenzene; third, catalyst regeneration through ligand exchange. The C-H bond activation is found to be the rate-determining step of the overall iodination due to higher activation energy. The reaction barrier for the formation of iodinated (R)-benzylamine is lower than that of (S)-benzylamine, which confirms the R enantioselectivity in iodination at room temperature. The retainment of the coordination of one acetic acid on Pd(II) and the chelating MPAA ligand during the catalyzed reaction are suggested to give space economy to facilitate the C-H bond activation. The NHTf functional group on the substrate is found to be very important for ortho C-H iodination at ambient condition. Our calculated results are consistent with the experimental observations.

Surface-printed microdot array chips coupled with matrix-assisted laser desorption/ionization mass spectrometry for high-throughput single-cell patterning and phospholipid analysis.

RATIONALE: Single-cell analysis is very important in several research fields for the heterogeneity of individual cells, which has been well accepted. However, restricted by the size and low content of a single cell, current studies have encountered challenges in high-throughput, high-space resolution and sensitivity, and multicomponent analysis. A methodology of a surface-printed microdot array chip coupled with matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) is presented in this study for high-throughput single-cell patterning and phospholipid analysis. METHODS: The poly-L-lysine (PLL) used as ink molecule was printed on an oxygen plasma processed indium tin oxide (ITO)-coated glass slide to form a microdot array by micro-contact printing technology. The cell array was then formed on the PLL microarray through electrostatic adsorption force. 9-Aminoacridine (9-AA) matrix was applied on the cell array before it was analyzed by MALDI-TOF MS. MALDI mass spectrometry imaging (MALDI-MSI) was then used for high-throughput, quick measurement, and multicomponent analysis of the cell array. RESULTS: The single-cell capture efficiency of the cell array formed on the PLL microarray was about 40%. Twelve phospholipids were detected at the single-cell level, and the structures were further confirmed by MS/MS. The MALDI-MSI of selected ions showed a conformity with the cell array. The relative signal intensity data of selected ions were extracted from every pixel in the image within several minutes. The heterogeneity between individual cells was revealed from the relative signal intensity of phospholipids in 1-3 cells. CONCLUSIONS: Compared to the existing related approaches, high-throughput, quick measurement, and multicomponent single-cell analysis have been realized by our method. Through different ink molecules used for micro-contact printing, the established platform could have the potential to capture and analyze specific cells. Copyright © 2016 John Wiley & Sons, Ltd.

Design, synthesis and evaluation of acridine derivatives as multi-target Src and MEK kinase inhibitors for anti-tumor treatment.

Clinical studies have shown enhanced anticancer effects of combined inhibition of Src and MEK kinases. Development of multi-target drugs against Src and MEK is of potential therapeutic advantage against cancers. As a follow-up of our previous studies, and by using molecular docking method, we designed and synthesized a new series of 9-anilinoacridines containing phenyl-urea moieties as potential novel dual Src and MEK inhibitors. The anti-proliferative assays against K562 and HepG-2 tumor cells showed that most of the derivatives displayed good cytotoxicity in vitro. In particular, kinase inhibition assays showed that compound 8m inhibited Src (59.67%) and MEK (43.23%) at 10 µM, and displayed moderate inhibitory activity against ERK and AKT, the downstream effectors of both Src and MEK. Moreover, compound 8m was found to induce K562 cells apoptosis. Structure-activity relationships of these derivatives were analyzed. Our study suggested that acridine scaffold, particularly compound 8m, is of potential interest for developing novel multi-target Src and MEK kinase inhibitors.

No clear benefit or drawback to the use of closed drainage after primary total knee arthroplasty: a systematic review and meta-analysis.

BACKGROUND: Closed drainage after primary total knee arthroplasty (TKA) has been used routinely for many decades, but controversies have arisen in recent years. The purposes of this study were to compare the clinical outcomes of closed drainage with nondrainage after primary TKA; and to assess the benefit and drawback of closed drainage. METHODS: Electronic databases (PubMed/Medline, CENTRAL, Embase and Web of Science) were systematically searched for randomised controlled trials (RCTs) that investigated the efficacy and risks of closed drainage after primary TKA. Two investigators independently reviewed studies for eligibility, assessed the risk of bias and extracted the data. A meta-analysis was then performed using Review Manager Software. RESULTS: Twelve RCTs totalling 889 TKAs were identified. No significant differences in infection rate or blood loss were found between the closed drainage and nondrainage TKAs, and there was also no significant difference in haematoma formation, deep venous thrombosis, postoperative VAS score or range of motion between the two groups. CONCLUSIONS: There appears to be no clear benefit or drawback to the use of closed drainage after primary TKA. Improving the use of closed drainage might provide better outcomes.

The Efficacy and Safety of Combination of Intravenous and Topical Tranexamic Acid in Revision Hip Arthroplasty: A Randomized, Controlled Trial.

BACKGROUND: Revision total hip arthroplasty (THA) is associated with substantial blood loss and a high probability of blood transfusion in the perioperative period. This study aimed to evaluate the efficacy and safety of combination of intravenous (IV) and topical tranexamic acid (TXA) in revision THA. METHODS: Eighty-four consecutive patients undergoing revision THA were randomized into combined group and IV-TXA group. Patients in the combined group were given intravenously 15 mg/kg TXA as a preoperative, and topical TXA solution was applied at a concentration of 3 g TXA per 100-mL saline during the different procedure points. Patients in the IV-TXA group were given intravenously 15 mg/kg TXA alone. RESULTS: The mean total blood loss, drainage volume, and maximum hemoglobin drop were significantly lower in the combined group than the IV-TXA group (P < .001, P < .001, P < .001, respectively). Compared with the IV-TXA group, the amount of blood transfusions and number of blood transfusions required were decreased dramatically in the combined group (P = .027, P < .001, respectively). One deep vein thrombosis and 4 calf muscular vein thrombosis in the combined group and 3 calf muscular vein thrombosis in the IV-TXA were detected by the Doppler ultrasound. No pulmonary embolism was observed and no significant differences were found in other complications between the 2 groups. CONCLUSION: This study showed that combined administration of IV and topical TXA in revision THA can effectively decrease total blood loss and number of blood transfusions required without increasing the risk of deep vein thrombosis or/and pulmonary embolism compared with IV-TXA alone.

Functional role and mechanism of lncRNA LOC728228 in malignant 16HBE cells transformed by anti-benzopyrene-trans-7,8-dihydrodiol-9,10-epoxide.

Lung cancer is a major health problem, and is considered one of the deadliest cancers in humans. It is refractory to current treatments, and the mechanisms of lung cancer are unknown. Long noncoding RNAs (lncRNAs) are involved in various biological processes and human diseases. However, the exact functional roles and mechanisms of lncRNAs are largely unclear. In this study, we attempted to identify lung-cancer-related lncRNAs. We found changes in lncRNA expression in the anti-benzo(a) pyrene-7,8-diol-9,10-epoxide (anti-BPDE)-transformed human bronchial epithelial cell line (16HBE-T cells) using microarrays and qRT-PCR. Of these lncRNAs, LOC728228 was upregulated relative to its expression in control untransformed16HBE (16HBE-N) cells. LOC728228 knockdown inhibited cell proliferation, caused G0/G1-phase cell-cycle arrest, reduced cellular migration, suppressed colony formation in vitro, and inhibited tumor growth in a nude mouse xenograft model. LOC728228 knockdown also suppressed cyclin D1 expression, and the depletion of cyclin D1 induced G0/G1-phase cell-cycle arrest and inhibited cell proliferation, thus influencing the malignant potential of cancer cells. In summary, our results suggest that lncRNA LOC728228 has an oncogene-like function and plays a vital role in human lung cancer.

[Correlation Study on Chinese Medical Syndrome Types of Chronic Atrophic Gastritis Patients, Hp, and IL-1ß Polymorphism].

OBJECTIVE: To explore the correlation between Chinese medical (CM) syndrome types of chronic atrophic gastritis (CAG) patients and Helicobacter pylori (Hp) infection, polymorphisms of IL-1B, and IL-1ß. METHODS: Totally 192 CAG patients and 202 healthy subjects (as the healthy control group) were recruited in this case-control study. The Hp infection was tested by 13C-urea breath test and colloidal gold-labeled assay (GICA). The concentration of peripheral blood IL-1ß was measured by ELISA. The polymorphisms of IL-1B gene in the promoter region were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Pi-Wei weakness syndrome (PWWS) was dominant in CAG patients (31.77%, 61/192 cases). The Hp infection ratio in CAG patients was 53.65% (103/192 cases), of which, Pi-Wei damp-heat syndrome(PWDHS, 64.86%, 24/37 cases) and Gan-Wei disharmony syndrome (GWDS, 66.67%, 24/36 cases) were dominant. Compared with the health control group, the plasma concentration of IL-1ß was obviously elevated in CAG patients with PWDHS, GWDS, and static blood obstructing collaterals syndrome (SBOCS) (all P < 0.05). Additionally, there was no difference in the distribution of polymorphisms in the promoter region of IL-1 B gene between the CAG patients and the healthy control group (P > 0.05). CONCLUSIONS: The incidence risk of CAG was not associated with IL-1B polymorphism. But CM syndrome types of CAG patients was associated with Hp infection and peripheral blood IL-1ß levels.

Clinical implications of aldo-keto reductase family 1 member C3 and its relationship with lipocalin 2 in cancer of the uterine cervix.

OBJECTIVE: Over-expression of the aldo-keto reductase family 1 member C3 (AKR1C3) has been demonstrated in many human cancers. Lipocalin 2 (LCN2) is reported to inhibit cervical cancer metastasis but little is known regarding its relationship with AKR1C3 in the development and progression of uterine cervical cancer. This study aimed to investigate the involvement of AKR1C3 and its relationship with LCN2 in cervical cancer. METHODS: The roles of AKR1C3 and LCN2 were investigated using the lentivirus shRNA system in SiHa and Caski cervical cancer cells. LCN2 and matrix metalloproteinase-2 (MMP-2) promoters were constructed to demonstrate transcriptional regulation by shAKR1C3 and shLCN2, respectively. The influences of metastatic phenotypes were analyzed by wound healing, Boyden chamber, and immunofluorescence assays. The activity of MMP-2 was determined by zymography assay. The impacts of AKR1C3 and LCN2 on patient prognosis were evaluated using tissue microarrays by Cox regression and Kaplan-Meier models. RESULTS: Silencing of the AKR1C3 gene increased the expression of LCN2 and decreased the migratory and invasive abilities and changed the cytoskeleton of cervical cancer cells. When AKR1C3 was over-expressed, it decreased LCN2 promoter activity and LCN2 expression and increased cell migration. The mRNA level and enzyme activity of MMP-2 increased in silenced LCN2 cells. Positive AKR1C3 and negative LCN2 were correlated with higher recurrence and poorer survival of cervical cancer patients. CONCLUSIONS: Silencing of AKR1C3 increases LCN2 expression and inhibits metastasis in cervical cancer. Both AKR1C3 and LCN2 serve as molecular targets for cancer therapy to improve the clinical outcome of cervical cancer patients.

4-(Methylnitrosamino)-1-(3-pyridyl) -1-butanone induces circulating microRNA deregulation in early lung carcinogenesis.

OBJECTIVE: To study the alteration of circulating microRNAs in 4-(methylnitrosamino)-1-(3-pyridyl) -1-butanone (NNK)-induced early stage lung carcinogenesis. METHODS: A lung cancer model of male F344 rats was induced with systemic NNK and levels of 8 lung cancer-associated miRNAs in whole blood and serum of rats were measured by quantitative RT-PCR of each at weeks 1, 5, 10, and 20 following NNK treatment. RESULTS: No lung cancer was detected in control group and NNK treatment group at week 20 following NNK treatment. The levels of some circulating miRNAs were significantly higher in NNK treatment group than in control group. The miR-210 was down-regulated and the miR-206 was up-regulated in NNK treatment group. The expression level of circulating miRNAs changed from week 1 to week 20 following NNK treatment. CONCLUSION: The expression level of circulating miRNAs is related to NNK-induced early stage lung carcinogenesis in rats and can therefore serve as its potential indicator.

[Analysis for the blood mineral content of children aged 3 to 12 years in 7 cities and 2 towns in China].

OBJECTIVE: To investigate the status of blood mineral content of children aged 3 to 12 years in Chinese cities and countryside and explore the possible related influencing factors. METHODS: The multistage stratified cluster random sampling was used to select one kindergarten and one primary school in seven cities (Beijing and Guangzhou and so on) and two towns randomly. Firstly, we selected one bottom class, middle class, top class in one kindergarten and one second grade and fifth grade in one primary school randomly. Then all of the healthful students of these classes were investigated and the blood mineral content of calcium, magnesium, lead, iron, copper, and zinc were detected. RESULTS: In the research, 1 842 students were investigated. The means of calcium, magnesium, lead, iron, copper, and zinc were in the standard range. The blood lead content of the boys was higher than that of the girls. The blood mineral content of different ages had statistical significance. The blood calcium and blood copper contents of the preschool children were higher than those of the school children. However, the school children had significantly higher blood lead, iron, and zinc contents in comparison with those of the preschool children. The incidences of iron deficiency and zinc deficiency were 35.5% and 39.6%, respectively. The incidence of iron deficiency and zinc deficiency of different ages had statistical significance, and with the age increasing, the incidence showed a decreasing trend. The incidences of iron deficiency and zinc deficiency of children whose age was more than or equal to 3 years and less than 4 years were up to 47.1% and 64.6%, respectively. The incidence of iron deficiency of the children in the countryside area was significantly higher than those in the first-tier cities. However, the incidence of zinc deficiency of the children in the countryside area was significantly lower than those in the first-tier cities and second-tier cities. CONCLUSION: The status of iron deficiency and zinc deficiency of children aged 3 to 12 years in Chinese cities and countryside were still serious. We should pay more attention to the nutrition interventional research on iron and zinc.

Atrazine exposure promotes cardiomyocyte pyroptosis to exacerbate cardiotoxicity by activating NF-κB pathway.

Atrazine is a ubiquitous herbicide with persistent environmental presence and accumulation in the food chain, posing potential health hazards to organisms. Increasing evidence suggests that atrazine may have detrimental effects on various organ systems, including the nervous, digestive, and immune systems. However, the specific toxicity and underlying mechanism of atrazine-induced cardiac injury remain obscure. In this study, 4-week-old male C57BL/6 mice were administered atrazine via intragastric administration at doses of 50 and 200 mg/kg for 4 and 8 weeks, respectively. Our findings showed that atrazine exposure led to cardiac fibrosis, as evidenced by elevated heart index and histopathological scores, extensive myofiber damage, and interstitial collagen deposition. Moreover, atrazine induced cardiomyocyte apoptosis, macrophage infiltration, and excessive production of inflammatory factors. Importantly, atrazine upregulated the expressions of crucial pyroptosis proteins, including NLRP3, ASC, CASPASE1, and GSDMD, via the activation of NF-κB pathway, thus promoting cardiomyocyte pyroptosis. Collectively, our findings provide novel evidence demonstrating that atrazine may exacerbate myocardial fibrosis by inducing cardiomyocyte pyroptosis, highlighting its potential role in the development of cardiac fibrosis.

circular RNA circ-231 promotes protein biogenesis of TPI1 and PRDX6 through mediating the interaction of eIF4A3 with STAU1 to facilitate unwinding of secondary structure in 5' UTR, enhancing progression of human esophageal squamous cell carcinoma (ESCC).

Background: The nuclear cap-binding complex (CBC)-dependent translation (CT) is an important initial translation pathway for 5'-cap-dependent translation in normal mammal cells. Eukaryotic translation initiation factor 4A-III (eIF4A3), as an RNA helicase, is recruited to CT complex and enhances CT efficiency through participating in unwinding of secondary structure in the 5' UTR. However, the detailed mechanism for eIF4A3 implicated in unwinding of secondary structure in the 5' UTR in normal mammal cells is still unclear. Specially, we need to investigate whether the kind of mechanism in normal mammal cells extrapolates to cancer cells, e.g. ESCC, and further interrogate whether and how the mechanism triggers malignant phenotype of ESCC, which are important for identifying a potential therapeutic target for patients with ESCC. Methods: Bioinformatics analysis, RNA immunoprecipitation and RNA pulldown assays were performed to detect the interaction of circular RNA circ-231 with eIF4A3. In vitro and in vivo assays were performed to detect biological roles of circ-231 in ESCC. RNA immunoprecipitation, RNA pulldown, mass spectrometry analysis and co-immunoprecipitation assays were used to measure the interaction of circ-231, eIF4A3 and STAU1 in HEK293T and ESCC. In vitro EGFP reporter and 5' UTR of mRNA pulldown assays were performed to probe for the binding of circ-231, eIF4A3 and STAU1 to secondary structure of 5' UTR. Results: RNA immunoprecipitation assays showed that circ-231 interacted with eIF4A3 in HEK293T and ESCC. Further study confirmed that circ-231 orchestrated with eIF4A3 to control protein expression of TPI1 and PRDX6, but not for mRNA transcripts. The in-depth mechanism study uncovered that both circ-231 and eIF4A3 were involved in unwinding of secondary structure in 5' UTR of TPI1 and PRDX6. More importantly, circ-231 promoted the interaction between eIF4A3 and STAU1. Intriguingly, both circ-231 and eIF4A3 were dependent on STAU1 binding to secondary structure in 5' UTR. Biological function assays revealed that circ-231 promoted the migration and proliferation of ESCC via TPI1 and PRDX6. In ESCC, the up-regulated expression of circ-231 was observed and patients with ESCC characterized by higher expression of circ-231 have concurrent lymph node metastasis, compared with control. Conclusions: Our data unravels the detailed mechanism by which STAU1 binds to secondary structure in 5' UTR of mRNAs and recruits eIF4A3 through interacting with circ-231 and thereby eIF4A3 is implicated in unwinding of secondary structure, which is common to HEK293T and ESCC. However, importantly, our data reveals that circ-231 promotes migration and proliferation of ESCC and the up-regulated circ-231 greatly correlates with tumor lymph node metastasis, insinuating that circ-231 could be a therapeutic target and an indicator of risk of lymph node metastasis for patients with ESCC.