Simultaneous profiling of spatial gene expression and chromatin accessibility during mouse brain development.

The brain is a complex tissue whose function relies on coordinated anatomical and molecular features. However, the molecular annotation of the spatial organization of the brain is currently insufficient. Here, we describe microfluidic indexing-based spatial assay for transposase-accessible chromatin and RNA-sequencing (MISAR-seq), a method for spatially resolved joint profiling of chromatin accessibility and gene expression. By applying MISAR-seq to the developing mouse brain, we study tissue organization and spatiotemporal regulatory logics during mouse brain development.

Recent Progresses in the Multimodality Imaging Assessment of Myocardial Fibrosis.

Myocardial fibrosis, a common pathophysiological consequence of various cardiovascular diseases, is characterized by fibroblast activation and excessive deposition of extracellular matrix (ECM) collagen. Accumulating evidence indicates that myocardial fibrosis contributes to ventricular stiffness, systolic and diastolic dysfunction, and ultimately leads to the development of heart failure (HF). Early detection and targeted treatment of myocardial fibrosis is critical to reverse ventricular remodeling and improve clinical outcomes in patients with cardiovascular diseases. However, despite considerable progresses made in understanding molecular mechanisms of myocardial fibrosis, non-invasive imaging to assess myocardial fibrosis and guide clinical treatment is still not widely available, limiting the development of innovative treatment strategies. This review summarizes recent progresses of imaging modalities for detecting myocardial fibrosis, with a focus on nuclear medicine, echocardiography and cardiac magnetic resonance (CMR).

ChlOR, a GMC family oxidoreductase that evolved independently from the actinomycete, confers resistance to amphenicol antibiotics.

Overuse of the amphenicol antibiotics chloramphenicol (CHL) and thiamphenicol (TAP) poses a great threat to ecosystem safety and human health. The strain, Nocardioides sp. LMS-CY, Nocardioides sp. QY071 and Nocardioides sp. L-11A, classified as a gram-positive actinomycete, harbours a complete CHL metabolic pathway. However, the metabolic genes (clusters) involved in the entire pathway in gram-positive actinomycetes are still limited. Here, chlORLMS , chlORQY071 and chlORL-11A completely from the actinomycete Nocardioides spp. were found to act on the C1 -OH of the CHL/TAP side chain, directly converting CHL/TAP to 4-nitrobenzaldehyde (PNBD)/4-methylsulfonyl benzaldehyde (PMBD) and transforming PNBD/PMBD into 4-nitrobenzyl alcohol (PNBM)/4-methylsulfonyl phenyl methanol (PMBM). Furthermore, oxidoreductases can transform PNBM into 4-nitrobenzoate (PNBA). The oxidoreductases ChlORLMS , ChlORQY071 and ChlORL-11A were all classified as cellobiose dehydrogenases from the glucose methanol choline (GMC) family. Based on the Swiss-Prot database, ChlORQY071 exhibited a lower identity (27.12%-35.10% similarity) with the reported oxidoreductases. Enzymatic and molecular docking analyses showed that ChlORQY071 and ChlORL-11A from the two similar genomes were remarkably more effective in metabolizing CHL than ChlORLMS . Overall, the detailed resistance mechanism of CHL/TAP by actinomycete strains isolated from soil and livestock manure will provide insights into the occurrence of CHL/TAP resistance genes in the environment, resistance risk and bioremediation of CHL/TAP-contaminated environments.

A Superefficient Ochratoxin A Hydrolase with Promising Potential for Industrial Applications.

As the most seriously controlled mycotoxin produced by Aspergillus spp. and Penicillium spp., ochratoxin A (OTA) results in various toxicological effects and widely contaminates agro-products. Biological detoxification is the highest priority regarding OTA in food and feed industry, but currently available detoxification enzymes have relatively low effectiveness in terms of time and cost. Here we show a superefficient enzyme, ADH3, identified from Stenotrophomonas acidaminiphila that has a strong ability to transform OTA into nontoxic ochratoxin-α by acting as an amidohydrolase. Recombinant ADH3 (1.2 µg/mL) completely degrades 50 µg/L OTA within 90 s, while the other most efficient OTA hydrolases available take several hours. The kinetic constant showed that rADH3 (Kcat/Km) catalytic efficiency was 56.7 to 35,000 times higher than those of previous hydrolases rAfOTase, rOTase, and commercial carboxypeptidase A (CPA). Protein structure-based assay suggested that ADH3 has a preference for hydrophobic residues to form a larger hydrophobic area than other detoxifying enzymes at the cavity of the catalytic sites, and this structure allows OTA easier access to the catalytic sites. In addition, ADH3 shows considerable temperature adaptability to exert hydrolytic function at the temperature down to 0°C or up to 70°C. Collectively, we report a superefficient OTA detoxifying enzyme with promising potential for industrial applications. IMPORTANCE Ochratoxin A (OTA) can result in various toxicological effects and widely contaminates agro-products and feedstuffs. OTA detoxifications by microbial strains and bio-enzymes are significant to food safety. Although previous studies showed OTA could be transformed through several pathways, the ochratoxin-α pathway is recognized as the most effective one. However, the most currently available enzymes are not efficient enough. Here, a superefficient hydrolase, ADH3, which can completely transform 50 µg/L OTA into ochratoxin-α within 90 s was screened and characterized. The hydrolase ADH3 shows considerable temperature adaptability (0 to 70°C) to exert the hydrolytic function. Findings of this study supplied an efficient OTA detoxifying enzyme and predicted the superefficient degradation mechanism, laying a foundation for future industrial applications.

The low-nanomolar 4-nitrobenzoate-responsive repressor PnbX negatively regulates the actinomycete-derived 4-nitrobenzoate-degrading pnb locus.

Nitroaromatic compounds pose severe threats to public health and environmental safety. Nitro group removal via ammonia release is an important strategy for bacterial detoxification of nitroaromatic compounds, such as the conversion of 4-nitrobenzoate (4-NBA) to protocatechuate by the bacterial pnb operon. In contrast to the LysR-family transcriptional regulator PnbR in proteobacteria, the actinomycete-derived pnb locus (4-NBA degradation structural genes) formed an operon with the TetR-family transcriptional regulator gene pnbX, implying that it has a distinct regulatory mechanism. Here, pnbBA from the actinomycete Nocardioides sp. strain LMS-CY was biochemically confirmed to express 4-NBA degradation enzymes, and pnbX was essential for inducible degradation of 4-NBA. Purified PnbX-6His could bind the promoter probe of the pnb locus in vitro, and 4-NBA prevented this binding. 4-NBA could bind PnbX at a 1:1 molar ratio with KD  = 26.7 ± 4.2 nM. Low-nanomolar levels of 4-NBA induced the transcription of the pnb operon in strain LMS-CY. PnbX bound a palindromic sequence motif (5'-TTACGTTACA-N8 -TGTAACGTAA-3') that encompasses the pnb promoter. This study identified a TetR-family repressor for the actinomycete-derived pnb operon that recognizes 10-8  M 4-NBA as its ligand, implying that nitro group removal of nitroaromatic compounds may be especially important for actinomycetes.

Reduction of mitochondria and up regulation of pyruvate dehydrogenase kinase 4 of skeletal muscle in patients with chronic kidney disease.

AIM: Muscle weakness is commonly among chronic kidney disease (CKD) patients. Muscle mitochondrial dysfunction and decreased pyruvate dehydrogenase (PDH) activity occur in CKD animals but have not been confirmed in humans, and changes in pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) expression have not been evaluated in CKD muscle. We presume that the reduction of muscle mitochondria and post-translational modification of PDH may cause muscle weakness in CKD patients. Herein, we explored changes in mitochondrial morphology, PDH expression and activity, and PDK/PDP expression in CKD patient muscle. METHODS: Twenty patients with stage 4-5 CKD (CKD group) and 24 volunteers (control group) were included. Clinical characteristics, biochemical information and handgrip strength (HGS) were determined. Skeletal muscle samples were collected from eight stage 5 CKD patients from CKD group. Other eight non-CKD surgical subjects' muscle samples were collected as control. PDH activity was determined using a PDH enzyme activity assay kit, and real-time PCR and western blotting analyses were performed to measure gene expression and protein levels, respectively. Transmission electron microscopy was used to study mitochondria morphology. RESULTS: CKD patients had lower HGS than non-CKD subjects, and HGS was correlated with gender, age, haemoglobin and albumin. Mitochondria were decreased in end-stage renal disease (ESRD) patients muscle. Mfn-1 expression and phospho-Drp1(S637)/Drp1 ratio were inhibited in the ESRD group, implicating dysfunctional mitochondrial dynamics. Muscle PDH activity and phospho-PDH(S293) were decreased in ESRD patient muscle, while PDK4 protein level was up regulated. CONCLUSION: Decreased mitochondria and PDH deficiency caused by up regulation of PDK 4 contribute to muscle dysfunction, and could be responsible for muscle weakness in CKD patients.

Prognostic value of pretreatment platelet counts in lung cancer: a systematic review and meta-analysis.

BACKGROUND: The prognostic value of elevated pretreatment platelet counts remains controversial in lung cancer patients. We performed the present meta-analysis to determine its precise role in these patients. METHODS: We employed a multiple search strategy in the PubMed, EMBASE and Cochrane Library databases to identify eligible studies. Disease-free survival (DFS)/progression-free survival (PFS)/time to progression (TTP) and overall survival (OS) were used as outcomes with hazard ratios (HRs) and 95% confidence intervals (CIs). Heterogeneity among the studies and publication bias were also evaluated. RESULTS: A total of 40 studies including 16,696 lung cancer patients were eligible for the analysis. Overall, the pooled analysis showed that compared with normal platelet counts, elevated pretreatment platelet counts were associated with poorer OS (HR = 1.54, 95% CI: 1.37-1.72, P < 0.001) and poorer DFS/PFS/TTP (HR = 1.62, 95% CI: 1.33-1.98, P < 0.001) in patients with lung cancer. In subgroup analyses, elevated pretreatment platelet counts were also associated with poorer OS and DFS/PFS/TTP in most subgroups. There was no evidence of publication bias. CONCLUSIONS: This meta-analysis revealed that elevated pretreatment platelet counts were an independent predictor of OS and DFS/PFS/TTP in lung cancer patients. Large-scale prospective studies and a validation study are warranted.

The Role of the AIMP1 Pathway in Diabetic Retinopathy: AIMP1-Targeted Intervention Study in Diabetic Retinopathy.

INTRODUCTION: We characterized the role of aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) in retinal inflammation and apoptosis regulation, both in vivo and in vitro. In addition, we used clinical specimens to show the relationship between AIMP1 and the development of diabetic retinopathy (DR). OBJECTIVE: To elucidate the role of AIMP1 in DR. METHODS: A diabetic AIMP1-specific knockout (KO) C57 mouse model was used. Human retinal microvascular endothelial cells (HRMECs) were incubated with normal glucose, high glucose (HG), and HG + AIMP1-small interfering RNA (siRNA). The expression of AIMP1 and relative inflammatory and apoptotic cytokines in diabetic mice retina and HRMECs were measured using Western blotting and polymerase chain reaction. The apoptosis of HRMECs was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The levels of AIMP1 in the vitreous humor and serum were determined using ELISA. Possible correlations between the intravitreal level of AIMP1 and blood glucose, glycosylated hemoglobin HbA1c, intravitreal levels of IL-1ß, and caspase-3 were determined. RESULTS: The expression of inflammatory and apoptotic proteins was inhibited in the AIMP1 KO mice and HRMECs incubated with AIMP1-siRNA. The apoptosis of HRMECs was decreased in the AIMP1-siRNA group. The intravitreal level of AIMP1 in DR patients was significantly higher than that in nondiabetic patients (p < 0.01). There was a positive correlation between intravitreal AIMP1 and HbA1c and intravitreal IL-1ß and caspase-3 (p < 0.05). CONCLUSIONS: HG induced increased expression of AIMP1 in HRMECs and retinas from diabetic C57 mice, thereby increasing the expression of inflammatory and apoptotic cytokines, which promoted DR progression. A decrease in AIMP1 expression prevented the development of DR by inhibiting the activation of inflammatory and apoptotic signaling. Therefore, AIMP1 is an effective interfering target for the prevention and treatment of DR.

Correction to: KIF5B-RET fusion kinase promotes cell growth by multilevel activation of STAT3 in lung cancer.

After the publication of this work [1].

Urine klotho is a potential early biomarker for acute kidney injury and associated with poor renal outcome after cardiac surgery.

BACKGROUND: Current paradigms of detecting acute kidney injury (AKI) are insensitive and non-specific. Klotho is a pleiotropic protein that is predominantly expressed in renal tubules. In this study, we evaluated the diagnostic and prognostic roles of urine Klotho for AKI following cardiac surgery. METHODS: We conducted a prospective study involving 91 patients undergoing cardiac surgery. AKI was defined according to the AKIN definition. The renal outcomes within 7 days after operation were evaluated. Perioperative levels of urine Klotho and urine neutrophil gelatinase-associated lipocalin (NGAL) were measured by using ELISA. RESULTS: Of 91 participants, 33 patients (36.26%) developed AKI. Of these AKI patients, 21 (63.64%), 8 (24.24%), and 4 (12.12%) were staged 1, 2, and 3, respectively. Serum creatinine in AKI patients began to slightly increase at first postoperative time and reached the AKI diagnostic value 1 day after operation. Postoperative urine Klotho peaked at the first postoperative time (0 h after admission to the intensive care unit (ICU)) in patients with AKI, and was higher than that in non-AKI patients up to day 3. The AUC of detecting AKI for urine Klotho was higher than urine NGAL at the first postoperative time and 4 h after admission to the ICU. In a multivariate model, increased first postoperative urine Klotho may be an independent predictor for AKI occurrence following cardiac surgery. The concentrations of first postoperative urine Klotho were higher in AKI stage 2 and 3 than those in stage 1 (p < 0.05), and were higher in patients with incomplete recovery of renal function than those with complete recovery (p < 0.05). CONCLUSIONS: Urine Klotho may serve as an early biomarker for AKI and subsequent poor short-term renal outcome in patients undergoing cardiac surgery.

Long Noncoding RNA EGFR-AS1 Promotes Cell Proliferation by Increasing EGFR mRNA Stability in Gastric Cancer.

BACKGROUND/AIMS: LncRNA EGFR-AS1 is an antisense transcript of EGFR, which plays a key role in gastric cancer progression. This study was aimed to explore the effects of lncRNA EGFR-AS1 on GC and the underling mechanisms. METHODS: The silencing of EGFR-AS1 expression was performed by using EGFR-AS1 shRNA lentivirus in MGC803 and SGC-7901 GC cell. The levels of lncRNA EGFR-AS1 and EGFR were detected by qPCR and western blot. Cell proliferation was assessed by CCK-8, EdU, and colony formation assays. The EGFR mRNA stability was explored by using RNA synthesis inhibitor α-amanitin. RESULTS: In our study, EGFR-AS1 significantly up-regulated in GC tissues and correlated with tumor size. And the expression of EGFR-AS1 positively correlated with EGFR in tissues. Moreover, knock-down of EGFR-AS1 inhibited the proliferation of GC cells via suppressing EGFR-dependent PI3K/AKT pathway in vitro and in vivo. Mechanismly, depletion of EGFR-AS1 was found to decrease EGFR expression by reduction of EGFR mRNA stability. CONCLUSION: Our findings suggested that EGFR-AS1 might have an oncogenic effect on GC and serve as a potential target of GC.

Klotho Reduces Necroptosis by Targeting Oxidative Stress Involved in Renal Ischemic-Reperfusion Injury.

BACKGROUND/AIMS: Klotho is a multifunctional protein expressed predominantly in kidney tubular epithelium. Here, we investigated the protective effects of Klotho on necroptosis in renal ischemic-reperfusion injury (IRI) and the role of oxidative stress in this process. METHODS: Mice were subjected to bilateral renal pedicle clamping. Mouse renal tubular epithelial (TCMK-1) cells were exposed to hypoxia/reoxygenation (H/R) or H2O2. Kidney samples from acute kidney injury (AKI) patients and controls were examined by immunofluorescence. Klotho protein and N-acetyl-L-cysteine (NAC) were used to define their roles in mediating necroptosis. Necroptosis was assessed by TUNEL staining, immunoblotting, and real-time PCR. Oxidative stress was studied via ELISA, immunoblotting, colorimetric, and thiobarbituric acid reactive substances assays. RESULTS: Renal IRI induced Klotho deficiency in the serum and kidney, but an increase in the urine. The levels of the necroptotic markers receptor-interacting protein kinase (RIP) 1, RIP3, IL-1ß, and TUNEL-positive cells increased after IRI; all increases were ameliorated by Klotho. In TCMK-1 cells, Klotho and NAC attenuated the elevation in RIP1, RIP3, and LDH release induced by H/R or H2O2. Moreover, Klotho decreased the levels of oxidative stress biomarkers and elevated superoxide dismutase 2 expression in both in vivo and in vitro experiments. Studies in human samples further confirmed the Klotho deficiency and increased formation of RIP3 puncta in AKI kidneys. CONCLUSION: Klotho protects tubular epithelial cells from IRI and its anti-necroptotic role may be associated with oxidative stress inhibition.

Serum Romo1 is significantly associated with disease severity in patients with obstructive sleep apnea syndrome.

PURPOSE: We aim to evaluate reactive oxygen species modulator 1 (Romo1) levels in obstructive sleep apnea syndrome (OSAS) and analyze its possible relationships to OSAS severity, reactive oxygen species (ROS), and C-reactive protein (CRP). Additionally, we also investigated the effects of nasal continuous positive airway pressure (nCPAP) on serum Romo1. METHODS: One hundred and five patients diagnosed with OSAS were classified into the OSAS group, and 41 subjects without OSAS were recruited for the control group. The OSAS group was further divided into mild, moderate, and severe OSAS subgroups. Fifteen patients with moderate and severe OSAS were treated with nCPAP. Serum levels of Romo1, ROS, and CRP were also measured. RESULTS: Serum Romo1, ROS, and CRP were the lowest in normal subjects and increased across OSAS severities (P < 0.05). Univariate analysis showed that serum Romo1 was positively correlated with apnea-hypopnea index (AHI), oxygen desaturation index (ODI), time spent below 90% oxygen saturation (Ts90%), arousal index, ROS, and CRP, and was negatively correlated with minimal oxygen saturation (miniSaO2) (all P < 0.05). Multiple linear regression analysis showed that serum Romo1 level was significantly associated with AHI and ODI, after adjusting for age, gender, BMI, and CRP. After 6 months of nCPAP therapy, serum Romo1, ROS, and CRP were significantly decreased (P < 0.05). CONCLUSIONS: The increase of serum Romo1 in OSAS patients was positively correlated with disease severity. Serum Romo1 may be an important parameter for monitoring the severity of OSAS and treatment efficiency.

Autophagy protects renal tubular cells against ischemia / reperfusion injury in a time-dependent manner.

BACKGROUND/AIMS: Autophagy is a dynamic catabolic process that maintains cellular homeostasis. Whether it plays a role in promoting cell survival or cell death in the process of renal ischemia/reperfusion (I/R) remains controversial, partly because renal autophagy is usually examined at a certain time point. Therefore, monitoring of the whole time course of autophagy and apoptosis may help better understand the role of autophagy in renal I/R. METHODS: Autophagy and apoptosis were detected after mice were subjected to bilateral renal ischemia followed by 0-h to 7-day reperfusion, exposure of TCMK-1 cells to 24-h hypoxia, and 2 to 24-h reoxygenation. The effect of autophagy on apoptosis was assessed in the presence of autophagy inhibitor 3-methyladenine (3-MA) and autophagy activator rapamycin. RESULTS: Earlier than apoptosis, autophagy increased from 2-h reperfusion, reached the maximum at day 2, and then began declining from day 3 when renal damage had nearly recovered to normal. Exposure to 24-h hypoxia induced autophagy markedly, but it decreased drastically after 4 and 8-h reoxygenation, which was accompanied with increased cell apoptosis. Inhibition of autophagy with 3-MA increased the apoptosis of renal tubular cells during I/R in vivo and hypoxia/reoxygenation (H/R) in vitro. In contrast, activation of autophagy by rapamycin significantly alleviated renal tissue damage and tubular cell apoptosis in the two models. CONCLUSION: Autophagy was induced in a time-dependent manner and occurred earlier than the onset of cell apoptosis as an early response that played a renoprotective role during renal I/R and cell H/R. Up-regulation of autophagy may prove to be a potential strategy for the treatment of acute kidney injury.

ObRb downregulation increases breast cancer cell sensitivity to tamoxifen.

Leptin is a potent adipokine that plays an important role in the progression of breast cancer and interferes with the action of tamoxifen. We investigated the molecular mechanism underlying the effect of leptin on tamoxifen resistance in breast cancer cells that express leptin receptor (ObRb), and evaluated the impact of ObRb suppression on tamoxifen treatment in MCF-7 and tamoxifen-resistant (TAM-R) cells. Leptin-induced signaling pathway activation was examined by qRT-PCR and Western blotting. Chromatin immunoprecipitation assays were performed to further examine the binding of estrogen receptor (ER) α on the promoter of cyclin D1 (CCND1) gene. The effects of combined ObRb knockdown and tamoxifen treatment were evaluated in MCF-7 and TAM-R cells. We found that the enhanced proliferation effects induced by leptin were related to extracellular-signal-regulated kinase (ERK) 1/2 and signal transducers and activators of transcription (STAT) 3 signaling pathway activation and CCND1 upregulation. Leptin enhanced CCND1 gene transcription by inducing the binding of ERα to the promoter of CCND1 gene. ObRb knockdown significantly enhanced the inhibitory effects of tamoxifen on TAM-R cell proliferation and survival. This study suggested that long-term endocrine therapy facilitates leptin and ObRb overexpression in breast cancer cells, which attenuates the inhibitory effect of tamoxifen by activating both the ERK1/2 and STAT3 signaling pathways and upregulating CCND1 gene expression. Combination therapy involving ObRb knockdown and tamoxifen treatment may be an alternative therapeutic option for tamoxifen-resistant breast cancer.

KIF5B-RET fusion kinase promotes cell growth by multilevel activation of STAT3 in lung cancer.

BACKGROUND: Lung cancer in nonsmokers tends to be driven by a single somatic mutation or a gene fusion. KIF5B-RET fusion is an oncogene identified in non-small cell lung cancers. In this study, we verified the oncogenic activity of KIF5B-RET fusion and investigated how KIF5B-RET activates the specific signaling pathways for cellular transformation. We aimed to provide a basis for the further development of the therapy for KIF5B-RET positive lung cancer patients. METHODS: RT-PCR was used to screen for KIF5B-RET fusions in Chinese lung cancer patients. To verify the oncogenic activity of KIF5B-RET kinase in lung cancer cells, we manipulated its expression genetically followed by colony formation and tumor formation assays. The mechanism by which KIF5B-RET kinase induces proliferation was investigated by western blot, coimmunoprecipitation, and administration of RET, MAPK and STAT3 inhibitors. RESULTS: Our study identified a KIF5B-RET fusion in Chinese NSCLC patients and demonstrated that KIF5B-RET transfected cells showed a significantly increased proliferation rate and colony-forming ability. Furthermore, we found that KIF5B-RET fusion kinase induced multilevel activation of STAT3 at both Tyr705 and Ser727, and KIF5B-RET-STAT3 signaling related inhibitors repressed the proliferation and tumorigenicity of lung cancer cells significantly. CONCLUSIONS: Our data suggest that KIF5B-RET promotes the cell growth and tumorigenicity of non-small cell lung cancers through multilevel activation of STAT3 signaling, providing possible strategies for the treatment of KIF5B-RET positive lung cancers.

Enhanced local Foxp3 expression in lung tissue attenuates airway inflammation in a mouse model of asthma.

OBJECTIVE: Bronchial asthma is a chronic inflammatory disease of the airway mediated by a Th2 immune response. A great deal of data has demonstrated that regulatory T cells (Tregs) have the ability to suppress Th2 immune responses and the transcription factor fork-head box protein 3 (Foxp3) is indispensable for the development of CD4 + CD25 + Tregs. In this study, we hypothesized that enhanced local Foxp3 expression in lung tissue could suppress Th2-mediated allergic asthma. METHODS: Foxp3/PMX retroviruses containing the mouse Foxp3 gene were constructed and administered into asthmatic mice through intra-tracheal instillation before ovalbumin challenging. Foxp3 expression, airway hyper-responsiveness (AHR), bronchoalveolar lavage fluid (BALF) and tissue inflammatory cell and cytokine profiles were characterized. RESULTS: Foxp3 mRNA and protein were increased in the lung tissue of asthmatic mice. Enhanced expression of Foxp3 locally in the lung tissue reduced the airway AHR, inflammatory cell infiltration and mucus production. It also attenuated Th2 and Th17 immune responses as evidenced by reduced IL-4, IL-13 and IL-17 levels. CONCLUSIONS: This study demonstrates that enhanced Foxp3 expression in the airway by intra-tracheally instilled Foxp3/PMX retroviruses alleviates allergic airway inflammation by reducing the Th2 immune response.

P2X7 receptor deficiency attenuates cisplatin-induced kidney injury via inhibiting NLRP3 inflammasome activation.

Nephrotoxicity is a major constraint of cisplatin application in many solid tumors. Since the lack of preventive strategies, the necessity exists to identify critical molecular targets involved in cisplatin nephrotoxicity. The Purinergic ligand-gcotedion channel 7 receptor (P2X7R) is a ligand-gated ion channel that is predominantly implicated in inflammation and cell death. Our aim is to investigate the role P2X7R in cisplatin-induced acute and chronic kidney injury, as well as the underlying mechanism. In this study, we found that cisplatin can cause an increase in the expression of P2X7R in mouse kidney tissue, and P2X7R knockout can alleviate acute renal function damage caused by cisplatin, as well as the expression of kidney injury molecule 1 (KIM-1) and interleukin-18 (IL-18). Cisplatin can cause an increase in the expression of nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome in mouse kidney tissue. Compared with wild-type mice, P2X7R -/- mice showed decreased expression of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved Caspase-1, and cleaved IL-1ß in kidney tissue after cisplatin administration, and the apoptosis of renal tubular epithelial cells were also decreased. In addition, we also found that NLRP3 knockout can improve cisplatin induced degeneration, detachment, and necrosis of renal tubular epithelial cells. Furthermore, P2X7R -/- mice also showed reduced renal fibrosis and better long-term renal prognosis. In conclusion, our study identified that P2X7R knockout can improve cisplatin induced acute renal injury and chronic renal fibrosis by inhibiting the activation of NLRP3 inflammasome.

Does mangrove leave falling dominate the bury of polycyclic aromatic hydrocarbons in the mangrove of China?

Mangrove wetlands are vital coastal ecosystems that can absorb and accumulate pollutants. Polycyclic aromatic hydrocarbons (PAHs) are persistent organic pollutants that pose potential risks to ecosystems and human health. However, their source and transport fate in mangrove areas are poorly understood. This study investigates 29 PAHs pollution of water and sediment in Zhangjiangkou Mangrove Wetland, the northernmost large-scale mangrove wetland reserve in China. We examine the distribution, source, transport mechanisms and risk assessment of PAHs. The results show that the concentrations of PAHs in mangrove sediment range from 55.62 to 347.36 ng/g (DW), with 5-ring PAHs being the dominant species. While the concentrations of PAHs in surface water range from 10.61 to 46.39 ng/L, with 2-ring PAHs and alkylated PAHs being the dominant species. The PAHs concentrations in surface water and sediment of river are higher than those in mangrove area, indicating that mangrove water could receive PAHs through tidal exchange. Based on diagnostic ratios (DRs), principal component analysis (PCA), and positive matrix factorization (PMF), we infer that the leaf deposition (48.55%) could be an important pathway of PAHs in mangrove sediment except for river water transport (51.45%), while the PAHs in estuary water originate mainly from point sources such as biomass burning (50.96%) and traffic emission (49.04%). The range of toxic equivalents in surface water and sediment was 2.73-16.09 ng TEQ g-1 and 0.03-3.63 ng/L, respectively. Although the ecological risk assessment suggests that the PAHs pollution in surface water and sediment poses a low risk, we recommend more attention to the protection of the mangrove ecosystem. This study reveals that mangrove leaf falling might be a significant mechanism of PAH sequestration in the mangrove system, which deserves more attention in future research.

Distinct anthropogenic signatures: A comparative analysis of polycyclic aromatic hydrocarbons in sediments from two southeastern Chinese bays.

Sansha and Luoyuan Bay are influenced by different industrial structure, but the sources and pollution status of polycyclic aromatic hydrocarbons (PAHs), especially alkylated PAHs, are poorly understood. We studied 25 PAHs in surface sediments from the two bays. The results showed that PAHs concentrations in Sansha and Luoyuan Bay sediment range from 6.54 to 479.28 ng/g and 118.82 to 2984.09 ng/g, respectively. Alkylated PAHs dominated in Sansha (48.86 % of Σ25PAHs), while 3-ring PAHs dominated in Luoyuan (36.32 % of ∑25PAHs). Results of sources analysis indicated oil spills as the main PAHs source in Sansha, and domestic emissions and fossil fuel combustion in Luoyuan. Ecological risk assessment of showed low sediment risk, but in Luoyuan was higher than in Sansha. Compared with Luoyuan Bay, Sansha Bay emits less industrial pollutants, so the pollution is lower than Luoyuan Bay. Increased attention to protecting Luoyuan Bay is recommended.