Construction of Negative Electrostatic Pore Environments in a Scalable, Stable and Low-Cost Metal-organic Framework for One-Step Ethylene Purification from Ternary Mixtures.

One-step separation of C2 H4 from ternary C2 mixtures by physisorbents remains a challenge to combine excellent separation performance with high stability, low cost, and easy scalability for industrial applications. Herein, we report a strategy of constructing negative electrostatic pore environments in a stable, low-cost, and easily scaled-up aluminum MOF (MOF-303) for efficient one-step C2 H2 /C2 H6 /C2 H4 separation. This material exhibits not only record high C2 H2 and C2 H6 uptakes, but also top-tier C2 H2 /C2 H4 and C2 H6 /C2 H4 selectivities at ambient conditions. Theoretical calculations combined with in situ infrared spectroscopy indicate that multiple N/O sites on pore channels can build a negative electro-environment to provide stronger interactions with C2 H2 and C2 H6 over C2 H4 . Breakthrough experiments confirm its exceptional separation performance for ternary mixtures, affording one of the highest C2 H4 productivity of 1.35 mmol g-1 . This material is highly stable and can be easily synthesized at kilogram-scale from cheap raw materials using a water-based green synthesis. The benchmark combination of excellent separation properties with high stability and low cost in scalable MOF-303 has unlocked its great potential in this challenging industrial separation.

Proteomics and Biochemical Analyses of Secreted Proteins Revealed a Novel Mechanism by Which ADAM12S Regulates the Migration of Gastric Cancer Cells.

Gastric cancer is one of the cancers with the highest morbidity and mortality. Although several therapeutic approaches have been developed to treat this disease, the overall survival rate is still very low due to metastasis, drug resistance, and so forth. Therefore, it is necessary to discover new regulatory molecules and signaling pathways that modulate the metastasis of gastric cancer cells. A Disintegrin And Metalloprotease 12 (ADAM12) was highly expressed in gastric cancer tissues and presented in the patient urine. However, it is unclear whether and how ADAM12 regulates the migration of gastric cancer cells. In this work, we used the secretome protein enrichment with click sugars (SPECS) method to purify the secreted glycosylated proteins and performed quantitative proteomics to identify the secreted proteins that were differentially regulated by ADAM12S, the short and secreted form of ADAM12. Our proteomic and biochemical analyses revealed that ADAM12S upregulated the cell surface glycoprotein CD146, a cell adhesion molecule and melanoma marker, which was dependent on the catalytic residue of ADAM12S. Furthermore, we discovered that the ADAM12S-enhanced migration of gastric cancer cells was, at least partially, mediated by CD146. This work may help to evaluate whether ADAM12 could be a potential therapeutic target for the treatment of gastric cancer patients.

Caffeine excites medial parabrachial nucleus neurons of mice by blocking adenosine A1 receptor.

Caffeine has been used as a first-line drug for treatment of apnea neonatorum for decades due to its high safety and effectiveness. Studies report that caffeine mainly acts as a blocker of Adenosine Receptors (ARs). However, the mechanism of caffeine in reducing apnea neonatorum in the central nervous system has not been fully explored. Medial parabrachial nucleus (MPB) is part of the respiratory center of the pons that may be related to the activity of caffeine. Previous studies have not explored the effect and mechanism of caffeine on MPB neurons. To elucidate this, the current study used antagonists of A1 and A2a receptors to mimic the effect of caffeine in MPB of mice in vitro using the patch-clamp technique. The firing rates and spontaneous post-synaptic currents were recorded. The findings of the study showed that caffeine excited MPB neurons. Notably, the adenosine A1R antagonist 8-cyclopentyl-1,3-dimethyl-xanthine (CPT) but not the adenosine A2aR antagonist Istradefylline (KW6002) mimicked the exciting effect of caffeine, implying that caffeine excited MPB neurons in mice by blocking A1Rs. Further, the results indicated that caffeine could increase efficiency of synaptic transmission to excite MPB neurons. These findings suggest that A1Rs in MPB may be potential targets for caffeine in reducing apnea neonatorum.

Blockade of adenosine A2A receptor alleviates cognitive dysfunction after chronic exposure to intermittent hypoxia in mice.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is widely known for its multiple systems damage, especially neurocognitive deficits in children. Since their discovery, adenosine A2A receptors (A2ARs) have been considered as key elements in signaling pathways mediating neurodegenerative diseases such as Huntington's and Alzheimer's, as well as cognitive function regulation. Herein, we investigated A2AR role in cognitive impairment induced by chronic intermittent hypoxia (CIH). Mice were exposed to CIH 7 h every day for 4 weeks, and intraperitoneally injected with A2AR agonist CGS21680 or A2AR antagonist SCH58261 half an hour before IH exposure daily. The 8-arm radial arm maze was utilized to assess spatial memory after CIH exposures.To validate findings using pharmacology, the impact of intermittent hypoxia was investigated in A2AR knockout mice. CIH-induced memory dysfunction was manifested by increased error rates in the radial arm maze test. The behavioral changes were associated with hippocampal pathology, neuronal apoptosis, and synaptic plasticity impairment. The stimulation of adenosine A2AR exacerbated memory impairment with more serious neuropathological damage, attenuated long-term potentiation (LTP), syntaxin down-regulation, and increased BDNF protein. Moreover, apoptosis-promoting protein cleaved caspase-3 was upregulated while anti-apoptotic protein Bcl-2 was downregulated. Consistent with these findings, A2AR inhibition with SCH58261 and A2AR deletion exhibited the opposite result. Overall, these findings suggest that A2AR plays a critical role in CIH-induced impairment of learning and memory by accelerating hippocampal neuronal apoptosis and reducing synaptic plasticity. Blockade of adenosine A2A receptor alleviates cognitive dysfunction after chronic exposure to intermittent hypoxia in mice.

Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development.

Therapeutic strategies are urgently needed for patients with acute myeloid leukemia (AML). Leukocyte immunoglobulin-like receptor B4 (LILRB4), which suppresses T-cell activation and supports tissue infiltration of AML cells, represents an attractive drug target for anti-AML therapeutics. Here, we report the identification and development of an LILRB4-specific humanized mAb that blocks LILRB4 activation. This mAb, h128-3, showed potent activity in blocking the development of monocytic AML in various models including patient-derived xenograft mice and syngeneic immunocompetent AML mice. MAb h128-3 enhanced the anti-AML efficacy of chemotherapy treatment by stimulating mobilization of leukemia cells. Mechanistic studies revealed four concordant modes of action for the anti-AML activity of h128-3: (i) reversal of T-cell suppression, (ii) inhibition of monocytic AML cell tissue infiltration, (iii) antibody-dependent cellular cytotoxicity, and (iv) antibody-dependent cellular phagocytosis. Therefore, targeting LILRB4 with antibody represents an effective therapeutic strategy for treating monocytic AML.

Activation of adenosine A2a receptor accelerates and A2a receptor antagonist reduces intermittent hypoxia induced PC12 cell injury via PKC-KATP pathway.

Obstructive sleep apnea hypopnea syndrome (OSAHS) is associated with multiple system diseases. Neurocognitive dysfunction resulting from central nervous system complications has been reported, especially in children with OSAHS. Chronic intermittent hypoxia is accepted to be the major pathophysiological mechanism of OSAHS. Adenosine plays an important role in cellular function via interactions with its receptors. A2a receptor has been recognized as a factor involved in neuroprotection. However, the role of adenosine A2a receptor in intermittent hypoxia induced cellular injury is not completely understood. In this study, we aim to investigate the underlying mechanisms of A2a receptor mediated cellular damage caused by intermittent hypoxia in PC12 cells. We found that activated A2a receptor by CGS21680 decreased cellular viability, increased PKC as well as ATP-sensitive potassium channel (KATP) subunits expression Kir6.2 and SUR1. Inhibition of A2a receptor by SCH58261 increased cellular viability, suppressed PKC and SUR1 expression level, ultimately showing a protective role in PC12 cells. Moreover, we observed that CHE, which is an antagonist of PKC, downregulated Kir6.2 and SUR1 expression and increased cellular viability. Additionally, we found that A2a receptor activation induced cell injury was associated with increased Cleaved-Caspase 3 expression, which can be decreased by inhibition of A2a receptor or PKC. In conclusion, our findings indicate that A2a receptor induced KATP expression by PKC activation and plays a role in accelerating PC12 cells injury induced by intermittent hypoxia exposure via A2a-PKC-KATP signal pathway mediated apoptosis.

LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration.

Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.

Xianyu decoction attenuates the inflammatory response of human lung bronchial epithelial cell.

BACKGROUND: Xianyu decoction (XD), a Chinese experience recipe, shows inhibitory effects on lung cancer. However, the potential functions of XD on pneumonia were unknown. This study aimed to investigate the effect of XD on inflammatory response of childhood pneumonia. METHODS: Human lung bronchial epithelial cell line BEAS-2B was cultured in different doses of LPS with or without XD treatment. The expression of miR-15a and IKBKB were altered by transfection assay. RT-PCR and western blot were used to evaluate the effects of XD and miR-15a mimic/inhibitor on the expression levels of miR-15a, IKBKB, p65 and IκBα. ELISA was used to determine the levels of CRP, IL-6 and IL-8. RESULTS: High expression of miR-15a was observed in serum and cell model of pneumonia. miR-15a promoted the expression of inflammatory cytokines IL-6, IL-8, CRP and IKBKB in vitro. XD treatment downregulated the level of miR-15a in pneumonia children. In addition, XD reduced the expression of inflammatory cytokines and the phosphorylation levels of p65 and IκBα by inhibition of miR-15a and IKBKB expression in LPS-stimulated BEAS-2B cells. CONCLUSION: XD downregulated the level of miR-15a in serum of pneumonia children. Additionally, XD inhibited inflammatory response in LPS-stimulated BEAS-2B cells possibly by blocking IKBKB/NF-κB signal pathway which was regulated by miR-15a.

Activating adenosine A1 receptor accelerates PC12 cell injury via ADORA1/PKC/KATP pathway after intermittent hypoxia exposure.

Obstructive sleep apnea hypopnea syndrome (OSAHS) is associated with the neurocognitive deficits as a result of the neuronal cell injury. Previous studies have shown that adenosine A1 receptor (ADORA1) played an important role against hypoxia exposure, such as controlling the metabolic recovery in rat hippocampal slices and increasing the resistance in the combined effects of hypoxia and hypercapnia. However, little is known about whether ADORA1 takes part in the course of neuronal cell injury after intermittent hypoxia exposure which was the main pathological characteristic of OSAHS. The present study is performed to explore the underlying mechanism of neuronal cell injury which was induced by intermittent hypoxia exposure in PC12 cells. In our research, we find that the stimulation of the ADORA1 by CCPA accelerated the injury of PC12 cells as well as upregulated the expression of PKC, inwardly rectifying potassium channel 6.2(Kir6.2) and sulfonylurea receptor 1(SUR1) while inhibition of the ADORA1 by DPCPX alleviated the injury of PC12 cells as well as downregulated the expression of PKC, Kir6.2, and SUR1. Moreover, inhibition of the PKC by CHE, also mitigated the injury of PC12 cells, suppressed the Kir6.2 and SUR1 expressions induced by PKC. Taken together, our findings indicate that ADORA1 accelerated PC12 cells injury after intermittent hypoxia exposure via ADORA1/PKC/KATP signaling pathway.

[A comparative study on efficiency of different therapeutics methods used for obstructive sleep apnea hypopnea syndrome in children].

OBJECTIVE: To evaluate effectiveness therapeutic regimens for obstructive sleep apnea hypopnea syndrome (OSAHS) children at an acceptable cost. METHOD: This study was performed at Yuying Children's Hospital of Wenzhou Medical University from Mar. 2008 to Dec. 2010. Prospective random number table method was used for the analysis; 60 children with mild OSAHS were divided into Mild OSAHS Montelukast Treatment (MM) group and Mild OSAHS Adenotonsillectomy Treatment (MAT) group. 32 children in MM group were treated with leukotriene receptor antagonists (LTRAs), while 28 children in MAT group were treated with adenotonsillectomy. Also, 58 children with moderate and severe OSAHS were divided into severe OSAHS Montelukast Treatment (SM) group and severe OSAHS Adenotonsillectomy Treatmen (SAT) group. Twenty-two children in SM group were treated with LTRAs, while 36 children in SAT group were treated with adenotonsillectomy. All selected children were evaluated by polysomnography (PSG) and Obstructive Sleep Apnea-18 (OSA-18) items before and after a six-month treatment. Both records were taken and analyzed, surgical complications and the reason for non-remission after operation were also analyzed. Two therapies were compared based on economic consideration and therapeutic effect. Result (1) PSG: A significant change of a significant change of Apnea Hypopnea Index (AHI) was observed in MM group after the treatment (before receiving the treatment 4.56 ± 1. 26, and after receiving the treatment 3. 48 ± 1. 52, t =3. 50, P <0. 05). But for oxygen desaturation Index (ODI) (MM group 2. 18 ± 2. 19, and MAT group 1. 80 ± 2. 34) and Lowest Oxygen satuation (LSaO2) (MM group 91. 66 ± 2. 34, and MAT group 92. 79 ± 2. 18), there was no significant difference in MM group and MAT group after the treatment (ODI, t =0. 65, and LSaO2 t = - 1. 93, P >0. 05). (2) OSA-18 scores: Significant differences were found in sleeping disorder (before 14. 81 ± 6. 28, and after 10. 56 ± 3. 57), the degree of familial stress (before 13. 56 ± 3. 54, and after 8. 97 ± 2. 96), and OSA-18 total scores (before 52. 66 ± 1. 11, and after 42. 56 6. 48) in MM group after the treatment (sleeping disorder Z - 3. 14, the degree of familial stress Z = -4. 50, and OSA-18 total scores Z= -4. 01, P <0. 05). (3) In addition to the cost of drugs, groups with surgical treatment had a larger economic burden than those with LTRAs treatment. (4) Treatment was totally effective for 28 children (88%) in MM group, and 28 children (100%) in MAT group. Meanwhile, treatment also achieved an obvious effect on 2 children (9%) in SM group, and in 35 children (97%) in SAT group. In MAT group, 3 children improved (11%). And in SAT group, 7 children improved (19%), but treatment was found to be ineffective in 1 case (3%). Among those effective and ineffective cases in groups with surgical treatment, there were 9 children with nasal diseases. CONCLUSION: (1) Surgical treatment is recommended as the first choice for children with moderate and severe OSAHS. And for those who also suffer from nasal diseases, treatment combining drugs with surgery is necessary. (2) LTRAs therapy has a good effect for mild OSAHS. Surgery is also recommended when drugs could not achieve any obvious improvement in clinical symptoms of children with mild OSAHS.

Multiple system morbidities associated with children with snore symptom.

OBJECTIVE: To exam the relationship between snoring and morbidities of multiple systems in children. STUDY DESIGN: Children with snoring were enrolled and divided into primary snorer (PS) group and obstructive sleep apnea hypopnea syndrome (OSAHS) group based on polysomnography. The healthy children served as the control group. The growth parameters, maxillofacial malformations, blood chemistry, electrocardiogram, and echocardiogram were recorded and intelligence testing was performed in the enrolled children who were ≥6 years old. RESULTS: The weight and height were similar in the control group (n = 60) and the PS group (n = 63), but lower in the OSAHS group (n = 89; P < 0.001). Occurrence of adenoidal face and dental malocclusion in the OSAHS and the PS group was significantly higher than that in the control group (P < 0.001). Compared with the control group, the OSAHS group had a lower serum high-density lipoprotein cholesterol level, higher low-density lipoprotein cholesterol level; and a possible higher pulmonary artery pressure based on the echocardiogram (P < 0.001). All the above parameters in the PS group were similar to those in the control group. Full-scale IQ and performance IQ of the OSAHS group was lower (P < 0.001), attention deficits were significantly higher in the OSAHS group (P < 0.001), but were similar in the PS group when compared to the control group. CONCLUSIONS: OSAHS in children is associated with delayed growth, maxillofacial malformations, impaired cognitive functions, abnormalities in lipid metabolism, and changes in pulmonary artery pressures. PS children also have higher incidence of maxillofacial malformations but have a normal growth and normal cognitive functions.