Notch1 regulates hepatic thrombopoietin production.

ABSTRACT: Notch signaling regulates cell-fate decisions in several developmental processes and cell functions. However, the role of Notch in hepatic thrombopoietin (TPO) production remains unclear. We noted thrombocytopenia in mice with hepatic Notch1 deficiency and so investigated TPO production and other features of platelets in these mice. We found that the liver ultrastructure and hepatocyte function were comparable between control and Notch1-deficient mice. However, the Notch1-deficient mice had significantly lower plasma TPO and hepatic TPO messenger RNA levels, concomitant with lower numbers of platelets and impaired megakaryocyte differentiation and maturation, which were rescued by addition of exogenous TPO. Additionally, JAK2/STAT3 phosphorylation was significantly inhibited in Notch1-deficient hepatocytes, consistent with the RNA-sequencing analysis. JAK2/STAT3 phosphorylation and TPO production was also impaired in cultured Notch1-deficient hepatocytes after treatment with desialylated platelets. Consistently, hepatocyte-specific Notch1 deletion inhibited JAK2/STAT3 phosphorylation and hepatic TPO production induced by administration of desialylated platelets in vivo. Interestingly, Notch1 deficiency downregulated the expression of HES5 but not HES1. Moreover, desialylated platelets promoted the binding of HES5 to JAK2/STAT3, leading to JAK2/STAT3 phosphorylation and pathway activation in hepatocytes. Hepatocyte Ashwell-Morell receptor (AMR), a heterodimer of asialoglycoprotein receptor 1 [ASGR1] and ASGR2, physically associates with Notch1, and inhibition of AMR impaired Notch1 signaling activation and hepatic TPO production. Furthermore, blockage of Delta-like 4 on desialylated platelets inhibited hepatocyte Notch1 activation and HES5 expression, JAK2/STAT3 phosphorylation, and subsequent TPO production. In conclusion, our study identifies a novel regulatory role of Notch1 in hepatic TPO production, indicating that it might be a target for modulating TPO level.

Cholesterol inhibits human voltage-gated proton channel hHv1.

Although human sperm is morphologically mature in the epididymis, it cannot fertilize eggs before capacitation. Cholesterol efflux from the sperm plasma membrane is a key molecular event essential for cytoplasmic alkalinization and hyperactivation, but the underlying mechanism remains unclear. The human voltage-gated proton (hHv1) channel functions as an acid extruder to regulate intracellular pHs of many cell types, including sperm. Aside from voltage and pH, Hv channels are also regulated by distinct ligands, such as Zn2+ and albumin. In the present work, we identified cholesterol as an inhibitory ligand of the hHv1 channel and further investigated the underlying mechanism using the single-molecule fluorescence resonance energy transfer (smFRET) approach. Our results indicated that cholesterol inhibits the hHv1 channel by stabilizing the voltage-sensing S4 segment at resting conformations, a similar mechanism also utilized by Zn2+. Our results suggested that the S4 segment is the central gating machinery in the hHv1 channel, on which voltage and distinct ligands are converged to regulate channel function. Identification of membrane cholesterol as an inhibitory ligand provides a mechanism by which the hHv1 channel regulates fertilization by linking the cholesterol efflux with cytoplasmic alkalinization, a change that triggers calcium influx through the CatSper channel. These events finally lead to hyperactivation, a remarkable change in the mobility pattern indicating fertilization competence of human sperm.

Celastrol inhibits platelet function and thrombus formation.

INTRODUCTION: Celastrol is an active pentacyclic triterpenoid extracted from Tripterygium wilfordii and has anti-inflammatory and anti-tumor properties. Whether Celastrol modulates platelet function remains unknown. Our study investigated its role in platelet function and thrombosis. METHODS: Human platelets were isolated and incubated with Celastrol (0, 1, 3 and 5 µM) at 37 °C for 1 h to measure platelet aggregation, granules release, spreading, thrombin-induced clot retraction and intracellular calcium mobilization. Additionally, Celastrol (2 mg/kg) was intraperitoneally administrated into mice to evaluate hemostasis and thrombosis in vivo. RESULTS: Celastrol treatment significantly decreased platelet aggregation and secretion of dense or alpha granules induced by collagen-related peptide (CRP) or thrombin in a dose-dependent manner. Additionally, Celastrol-treated platelets showed a dramatically reduced spreading activity and decreased clot retraction. Moreover, Celastrol administration prolonged tail bleeding time and inhibited formation of arterial/venous thrombosis. Furthermore, Celastrol significantly reduced calcium mobilization. CONCLUSION: Celastrol inhibits platelet function and venous/arterial thrombosis, implying that it might be utilized for treating thrombotic diseases.

Metal-based nanoparticles in antibacterial application in biomedical field: Current development and potential mechanisms.

The rise in drug resistance in pathogenic bacteria greatly endangers public health in the post-antibiotic era, and drug-resistant bacteria currently pose a great challenge not only to the community but also to clinical procedures, including surgery, stent implantation, organ transplantation, and other medical procedures involving any open wound and compromised human immunity. Biofilm-associated drug failure, as well as rapid resistance to last-resort antibiotics, necessitates the search for novel treatments against bacterial infection. In recent years, the flourishing development of nanotechnology has provided new insights for exploiting promising alternative therapeutics for drug-resistant bacteria. Metallic agents have been applied in antibacterial usage for several centuries, and the functional modification of metal-based biomaterials using nanotechnology has now attracted great interest in the antibacterial field, not only for their intrinsic antibacterial nature but also for their ready on-demand functionalization and enhanced interaction with bacteria, rendering them with good potential in further translation. However, the possible toxicity of MNPs to the host cells and tissue still hinders its application, and current knowledge on their interaction with cellular pathways is not enough. This review will focus on recent advances in developing metallic nanoparticles (MNPs), including silver, gold, copper, and other metallic nanoparticles, for antibacterial applications, and their potential mechanisms of interaction with pathogenic bacteria as well as hosts.

A novel image deep learning-based sub-centimeter pulmonary nodule management algorithm to expedite resection of the malignant and avoid over-diagnosis of the benign.

OBJECTIVES: With the popularization of chest computed tomography (CT) screening, there are more sub-centimeter (≤ 1 cm) pulmonary nodules (SCPNs) requiring further diagnostic workup. This area represents an important opportunity to optimize the SCPN management algorithm avoiding "one-size fits all" approach. One critical problem is how to learn the discriminative multi-view characteristics and the unique context of each SCPN. METHODS: Here, we propose a multi-view coupled self-attention module (MVCS) to capture the global spatial context of the CT image through modeling the association order of space and dimension. Compared with existing self-attention methods, MVCS uses less memory consumption and computational complexity, unearths dimension correlations that previous methods have not found, and is easy to integrate with other frameworks. RESULTS: In total, a public dataset LUNA16 from LIDC-IDRI, 1319 SCPNs from 1069 patients presenting to a major referral center, and 160 SCPNs from 137 patients from three other major centers were analyzed to pre-train, train, and validate the model. Experimental results showed that performance outperforms the state-of-the-art models in terms of accuracy and stability and is comparable to that of human experts in classifying precancerous lesions and invasive adenocarcinoma. We also provide a fusion MVCS network (MVCSN) by combining the CT image with the clinical characteristics and radiographic features of patients. CONCLUSION: This tool may ultimately aid in expediting resection of the malignant SCPNs and avoid over-diagnosis of the benign ones, resulting in improved management outcomes. CLINICAL RELEVANCE STATEMENT: In the diagnosis of sub-centimeter lung adenocarcinoma, fusion MVCSN can help doctors improve work efficiency and guide their treatment decisions to a certain extent. KEY POINTS: • Advances in computed tomography (CT) not only increase the number of nodules detected, but also the nodules that are identified are smaller, such as sub-centimeter pulmonary nodules (SCPNs). • We propose a multi-view coupled self-attention module (MVCS), which could model spatial and dimensional correlations sequentially for learning global spatial contexts, which is better than other attention mechanisms. • MVCS uses fewer huge memory consumption and computational complexity than the existing self-attention methods when dealing with 3D medical image data. Additionally, it reaches promising accuracy for SCPNs' malignancy evaluation and has lower training cost than other models.

A long chain-induced depletion effect for abnormal grafting in the preparation of bimodal bidisperse polymer-grafted nanoparticles.

One of the challenging problems in the research field of polymer nanocomposites is how to prepare nanocomposites with high grafting density and strong ability of dispersion at the same time. For nanocomposites composed of bimodal bidisperse polymer chains and nanoparticles, the above requirements can be met by rationally adjusting the ratio of long and short polymer chains. In this study, the process of grafting bimodal bidisperse polymer chains onto the surface of nanoparticles in a grafting-to manner was investigated via computer simulation and theoretical methods. Three grafting strategies were designed: first short then long (SL) system, both short and long (Both) system and first long then short (LS) system. An abnormal phenomenon for the Both system was found by analyzing the grafting density of long and short polymer chains on the surface of nanoparticles. We speculate that the reason for this anomalous phenomenon is the "depletion effect" brought about by the long chains in the Both system. We employ the Polymer Reference Interaction Site Model (PRISM) theory to investigate this anomaly in-depth. By comparing the radial distribution function (RDF) predicted by the PRISM theory with the RDF results obtained by the molecular dynamics (MD) simulation, we found that with the increase of the number of long chains in the system, the grafting density of short polymer chains on the nanoparticle surface showed an obvious upward trend. The "depletion effect" brought by long chains was the main reason for higher short chains' grafting density of the Both system compared to the SL system. Our findings provide effective guidance for the design of nanoparticle-grafted bimodal bidisperse polymer chains and provide a theoretical basis for experimentation and production of polymer nanocomposites with better performance.

Vertical-MXene based micro-supercapacitors with thickness-independent capacitance.

MXenes have shown great potential as an emerging two-dimensional (2D) material for micro-supercapacitors (MSCs) due to their high conductivity, rich surface chemistry, and high capacity. However, MXene sheets inherently tend to lay flat on the substrate during film formation to assemble into compact stacked structures, which hinders ion accessibility and prolongs ion transport paths, leading to highly dependent electrochemical properties on the thickness of the film. Here, we demonstrate a vertically aligned Ti3C2Tx MXene based micro-supercapacitor with an excellent electrochemical performance by a liquid nitrogen-assisted freeze-drying method. The vertical arrangement of the 2D MXene sheets allows for directional ion transport, enabling the vertical-MXene based MSCs to exhibit thickness-independent electrochemical properties even in thick films. In addition, the MSCs displayed a high areal capacitance of 87 mF cm-2 at 10 mV s-1 along with an excellent stability of ∼87.4% after 10 000 charge-discharge cycles. Furthermore, the vertical-MXene approach proposed here is scalable and can be extended to other systems involving directional transport.

Transient Receptor Potential (TRP) Channels in Pain, Neuropsychiatric Disorders, and Epilepsy.

Pharmacomodulation of membrane channels is an essential topic in the study of physiological conditions and disease status. Transient receptor potential (TRP) channels are one such family of nonselective cation channels that have an important influence. In mammals, TRP channels consist of seven subfamilies with a total of twenty-eight members. Evidence shows that TRP channels mediate cation transduction in neuronal signaling, but the full implication and potential therapeutic applications of this are not entirely clear. In this review, we aim to highlight several TRP channels which have been shown to mediate pain sensation, neuropsychiatric disorders, and epilepsy. Recent findings suggest that TRPM (melastatin), TRPV (vanilloid), and TRPC (canonical) are of particular relevance to these phenomena. The research reviewed in this paper validates these TRP channels as potential targets of future clinical treatment and offers patients hope for more effective care.

Clinicopathological features and resistance mechanisms in HIP1-ALK-rearranged lung cancer: A multicenter study.

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) respond well to ALK tyrosine kinase inhibitors (TKIs), and echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged NSCLC accounts for the majority of those patients. However, few studies have evaluated ALK-TKIs treatment for patients with huntingtin-interacting protein 1 (HIP1)-ALK fusions. This retrospective study evaluated the clinicopathological characteristics, genomic features, response to ALK-TKIs, and resistance mechanisms in 11 cases with HIP1-ALK fusions from five Chinese centers. Patients who received crizotinib at the Chinese centers had an objective response rate of 90% [9/10 cases, 95% confident index (CI): 54.1%-99.5%], median progression-free survival of 17.9 months (95% CI: 5.8-NA months), and median overall survival of 58.8 months (95% CI: 24.7-NA months). One patient who received first-line lorlatinib treatment achieved partial response for > 26.5 months. Despite the small sample size, HIP1-ALK (H21:A20) variant was the most common variant (four of 11 cases, 36.4%) and associated with better outcomes. Among the 11 cases, there were eight patients having available specimens for genetic testing before ALK-TKIs treatment and four patients undergoing biopsy after ALK-TKIs failure. The most common coexisting gene was TP53 among 11 patients and two of four patients after crizotinib failure harbored acquired ALK mutations (e.g., L1152V/Q1146K and L1196M). Brigatinib treatment appeared to be effective for a patient who failed crizotinib treatment because of the L1152V/Q1146K mutations, which might be related to increased binding affinity to these mutants. Although HIP1-ALK-rearranged NSCLC appears to initially respond well to ALK-TKIs, crizotinib resistance may be correlated with the AKAP9-BRAF fusion, ALK compound mutations (L1152V/Q1146K), and the ALK L1196M mutation. Larger studies are needed to evaluate the significance of HIP1-ALK-rearranged NSCLC.

Understanding of supramolecular solution polymerization and interfacial polymerization via forming multiple hydrogen bonds: a computer simulation study.

By employing dissipative particle dynamics (DPD) simulations combined with stochastic polymerization models, we have conducted a detailed simulation study of supramolecular solution polymerization as well as interfacial polymerization employing a coarse-grained model which is closer to the real monomer structure. By adding bending angle potentials to coarse-grained models representing supramolecular reactive monomers, we achieved monomer model simulations for different kinds of multiple hydrogen bonds. Our simulation results indicated that for the interfacial polymerization system, the volume of the monomer caused a strong steric hindrance effect, which in turn led to a low average degree of polymerization of the product. Therefore, by appropriately reducing the volume of the reaction monomer (corresponding to different confinement ascribed to the multiple hydrogen bonds), the average polymerization degree, the degree of reaction and the polymerization rate of the monomer can be effectively improved. For the solution polymerization system and the interfacial polymerization system, a certain proportion of rigid monomers and flexible monomers (60% rigid monomers and 40% flexible monomers) are mixed. High molecular weight products can thus be obtained via the polymerization reaction. The simulation strategy proposed in this study can not only provide theoretical guidance for better design of new supramolecular systems, but also provide ideas for the further synthesis of higher molecular weight supramolecular polymers.

Group I Metabotropic Glutamate Receptors and Interacting Partners: An Update.

Group I metabotropic glutamate (mGlu) receptors (mGlu1/5 subtypes) are G protein-coupled receptors and are broadly expressed in the mammalian brain. These receptors play key roles in the modulation of normal glutamatergic transmission and synaptic plasticity, and abnormal mGlu1/5 signaling is linked to the pathogenesis and symptomatology of various mental and neurological disorders. Group I mGlu receptors are noticeably regulated via a mechanism involving dynamic protein-protein interactions. Several synaptic protein kinases were recently found to directly bind to the intracellular domains of mGlu1/5 receptors and phosphorylate the receptors at distinct amino acid residues. A variety of scaffolding and adaptor proteins also interact with mGlu1/5. Constitutive or activity-dependent interactions between mGlu1/5 and their interacting partners modulate trafficking, anchoring, and expression of the receptors. The mGlu1/5-associated proteins also finetune the efficacy of mGlu1/5 postreceptor signaling and mGlu1/5-mediated synaptic plasticity. This review analyzes the data from recent studies and provides an update on the biochemical and physiological properties of a set of proteins or molecules that interact with and thus regulate mGlu1/5 receptors.

[Influencing Factors of Diabetes Mellitus on Abdominal Aortic Aneurysm Diameter and Biochemical Parameters].

Objective To investigate the effect of diabetes mellitus and hypoglycemic treatment on the diameter and biochemical parameters of abdominal aortic aneurysm (AAA).Methods A case-control study was conducted to retrospectively analyze the clinical data of AAA patients in Peking Union Medical College Hospital from 2015 to 2021.The AAA patients were classified into a group with diabetes mellitus (n=53) and a group without diabetes mellitus (n=104),and the biochemical parameters and aneurysm diameter were compared between the two groups.According to the aneurysm diameter,they were further classified into a small and medium abdominal aortic aneurysm group (SMAAA group,n=85) and a large abdominal aortic aneurysm group (LAAA group,n=72),and the biochemical parameters between the two groups were compared.Results Among the 157 cases with AAA,the incidence of hypertension in the group without diabetes mellitus was higher than that in the group with diabetes mellitus (χ2=8.147,P=0.004).The aneurysm diameter,homocysteine,and D-dimer in the group with diabetes mellitus were lower than those in the group without diabetes mellitus (t=-3.148,P=0.002;U=-1.503,P=0.013;U=-3.002,P=0.003).The aneurysm diameter and D-dimer in the SMAAA group were lower than those in the LAAA group (t=-14.406,P<0.001;U=-0.388,P<0.001).Multivariate Logistic regression analysis showed that diabetes mellitus (OR=0.477,95%CI=0.238-0.955,P=0.037) and hypoglycemic treatment (OR=0.477,95%CI=0.238-0.955,P=0.037) did not increase the risk of AAA enlargement.Conclusion Diabetes mellitus and hypoglycemic therapy may affect the growth rate of AAA by lowering D-dimer and inflammatory indexes.

Air-Stable Conductive Polymer Ink for Printed Wearable Micro-Supercapacitors.

Printed electronics are expected to facilitate the widespread distributed wearable electronics in the era of the Internet of things. However, developing cheap and stable electrode inks remains a significant challenge in the printed electronics industry and academic community. Here, overcoming the weak hydrophilicity of polyaniline, a low-cost, easy-fabricating, and air-stable conducting polymer (CP) ink is devised through a facile assemble-disperse strategy delivering a high conductivity in the order of 10-2 S cm-1 along with a remarkable specific capacitance of 386.9 F g-1 at 0.5 A g-1 (dehydrated state). The additive-free CP ink is directly employed to print wearable micro-supercapacitors (MSCs) via the spray-coating method, which deliver a high areal capacitance (96.6 mF cm-2 ) and volumetric capacitance (26.0 F cm-3 ), outperforming most state-of-the-art CP-based supercapacitors. This work paves a new approach for achieving scalable MSCs, thus rendering a cost-effective, environmentally friendly, and pervasive energy solution for next-generation distributed electronics.

GANT61 plays antitumor effects by inducing oxidative stress through the miRNA-1286/RAB31 axis in osteosarcoma.

Osteosarcoma (OS) is a rare malignancy of bone associated with poor clinical outcomes. The antitumor effects of GANT61 on OS is unclear. To investigate antitumor effects and mechanism of GANT61 in OS cells and xenograft model. Effects of GANT61 on cell viability, clone formation, cell cycle, apoptosis, migration, and invasion ability of OS cells were assessed. Reactive oxygen species (ROS) levels measured by dichlorofluorescein fluorescence were used to evaluate oxidative stress. The Xenograft model was constructed to investigate the antitumor effects of GANT61 in vivo. The microRNA (miRNA)-1286 was downregulated, while RAB31 upregulated in OS tissues and cells. GANT61 inhibited viability, migration, and invasion ability of OS cells (SaOS-2 and U2OS), and induced apoptosis and the ROS production, along with miRNA-1286 upregulation and RAB13 downregulation. After knockdown of miRNA-1286, GANT6-induced cell inhibition was attenuated, along with RAB31 upregulation. Inversely, miRNA-1286 overexpression downregulated RAB31. Dual-luciferase reporter assay verified that miR-1286 negatively targeted RAB13. Moreover, the knockdown of RAB31 stimulated apoptosis and ROS production while inhibited viability, migration, and invasion of GANT61-treated cells. In vivo experiments further confirmed that GANT61 inhibited tumor growth and RAB13 expression, but enhanced miRNA-1286. The study demonstrated that GANT61 inhibited cell aggressive phenotype and tumor growth by inducing oxidative stress through the miRNA-1286/RAB31 axis. Our findings provided a potential antitumor agent for the OS clinical treatment.

Manipulating Relative Permittivity for High-Performance Wearable Triboelectric Nanogenerators.

As the world marches into the era of the Internet of Things (IoT), the practice of human health care is on the cusp of a revolution, driven by an unprecedented level of personalization enabled by a variety of wearable bioelectronics. A sustainable and wearable energy solution is highly desired , but challenges still remain in its development. Here, we report a high-performance wearable electricity generation approach by manipulating the relative permittivity of a triboelectric nanogenerator (TENG). A compatible active carbon (AC)-doped polyvinylidene fluoride (AC@PVDF) composite film was invented with high relative permittivity and a specific surface area for wearable biomechanical energy harvesting. Compared with the pure PVDF, the 0.8% AC@PVDF film-based TENG obtained an enhancement in voltage, current, and power by 2.5, 3.5, and 9.8 times, respectively. This work reports a stable, cost-effective, and scalable approach to improve the performance of the triboelectric nanogenerator for wearable biomechanical energy harvesting, thus rendering a sustainable and pervasive energy solution for on-body electronics.

Acid-Sensing Ion Channels and Mechanosensation.

Acid-sensing ion channels (ASICs) are mainly proton-gated cation channels that are activated by pH drops and nonproton ligands. They are part of the degenerin/epithelial sodium channel superfamily due to their sodium permeability. Predominantly expressed in the central nervous system, ASICs are involved in synaptic plasticity, learning/memory, and fear conditioning. These channels have also been implicated in multiple disease conditions, including ischemic brain injury, multiple sclerosis, Alzheimer's disease, and drug addiction. Recent research has illustrated the involvement of ASICs in mechanosensation. Mechanosensation is a form of signal transduction in which mechanical forces are converted into neuronal signals. Specific mechanosensitive functions have been elucidated in functional ASIC1a, ASIC1b, ASIC2a, and ASIC3. The implications of mechanosensation in ASICs indicate their subsequent involvement in functions such as maintaining blood pressure, modulating the gastrointestinal function, and bladder micturition, and contributing to nociception. The underlying mechanism of ASIC mechanosensation is the tether-gate model, which uses a gating-spring mechanism to activate ASIC responses. Further understanding of the mechanism of ASICs will help in treatments for ASIC-related pathologies. Along with the well-known chemosensitive functions of ASICs, emerging evidence has revealed that mechanosensitive functions of ASICs are important for maintaining homeostasis and contribute to various disease conditions.

Mesophilic Pyrophosphatase Function at High Temperature: A Molecular Dynamics Simulation Study.

The mesophilic inorganic pyrophosphatase from Escherichia coli (EcPPase) retains function at 353 K, the physiological temperature of hyperthermophilic Thermococcus thioreducens, whereas the homolog protein (TtPPase) from this hyperthermophilic organism cannot function at room temperature. To explain this asymmetric behavior, we examined structural and dynamical properties of the two proteins using molecular dynamics simulations. The global flexibility of TtPPase is significantly higher than its mesophilic homolog at all tested temperature/pressure conditions. However, at 353 K, EcPPase reduces its solvent-exposed surface area and increases subunit compaction while maintaining flexibility in its catalytic pocket. In contrast, TtPPase lacks this adaptability and has increased rigidity and reduced protein/water interactions in its catalytic pocket at room temperature, providing a plausible explanation for its inactivity near room temperature.

Carbon Nanolights in Piezopolymers are Self-Organizing Toward Color Tunable Luminous Hybrids for Kinetic Energy Harvesting.

Herein, an all-solid-state sequential self-organization and self-assembly process is reported for the in situ construction of a color tunable luminous inorganic/polymer hybrid with high direct piezoresponse. The primary inorganic self-organization in solid polymer and the subsequent polymer self-assembly are achieved at high pressure with the first utilization of piezo-copolymer (PVDF-TrFE) as the host matrix of guest carbon quantum dots (CQDs). This process induces the spontaneous formation of a highly ordered, microscale, polygonal, and hierarchically structured CQDs/PVDF-TrFE hybrid with multicolor photoluminescence, consisting of very thermodynamic stable polar crystalline nanowire arrays. The electrical polarization-free CQDs/PVDF-TrFE hybrids can efficiently harvest the environmental available kinetic mechanical energy with a new large-scale group-cooperation mechanism. The open-circuit voltage and short-circuit current outputs reach up to 29.6 V cm-2 and 550 nA cm-2 , respectively. The CQDs/PVDF-TrFE-based hybrid nanogenerator demonstrates drastically improved durable and reliable features during the real-time demonstration of powering commercial light emitting diodes. No attenuation/fluctuation of the electrical signals is observed for ≈10 000 continuous working cycles. This study may offer a new design concept for progressively but spontaneously constructing novel multiple self-adaptive complex inorganic/polymer hybrids that promise applications in the next generation of self-powered autonomous optoelectronic devices.

Acid-sensing ion channel 1a is involved in ischaemia/reperfusion induced kidney injury by increasing renal epithelia cell apoptosis.

Acidic microenvironment is commonly observed in ischaemic tissue. In the kidney, extracellular pH dropped from 7.4 to 6.5 within 10 minutes initiation of ischaemia. Acid-sensing ion channels (ASICs) can be activated by pH drops from 7.4 to 7.0 or lower and permeates to Ca2+ entrance. Thus, activation of ASIC1a can mediate the intracellular Ca2+ accumulation and play crucial roles in apoptosis of cells. However, the role of ASICs in renal ischaemic injury is unclear. The aim of the present study was to test the hypothesis that ischaemia increases renal epithelia cell apoptosis through ASIC1a-mediated calcium entry. The results show that ASIC1a distributed in the proximal tubule with higher level in the renal tubule ischaemic injury both in vivo and in vitro. In vivo, Injection of ASIC1a inhibitor PcTx-1 previous to ischaemia/reperfusion (I/R) operation attenuated renal ischaemic injury. In vitro, HK-2 cells were pre-treated with PcTx-1 before hypoxia, the intracellular concentration of Ca2+ , mitochondrial transmembrane potential (∆ψm) and apoptosis was measured. Blocking ASIC1a attenuated I/R induced Ca2+ overflow, loss of ∆ψm and apoptosis in HK-2 cells. The results revealed that ASIC1a localized in the proximal tubular and contributed to I/R induced kidney injury. Consequently, targeting the ASIC1a may prove to be a novel strategy for AKI patients.

Coupling Between Interleukin-1R1 and Necrosome Complex Involves in Hemin-Induced Neuronal Necroptosis After Intracranial Hemorrhage.

Background and Purpose- Accumulated evidence suggests that hemin-a breakdown product of hemoglobin-plays a pivotal role in the inflammatory injuries that result after hemorrhagic stroke through the Toll Like Receptor 2-Toll Like Receptor 4 signal pathway. However, the mechanism of how hemin triggers neuronal necroptosis directly after intracranial hemorrhage (ICH) is still an area of active research. As animal model and preclinical studies have shown, the recombinant interleukin-1 receptor antagonist (IL-1RA) improves clinical outcomes after stroke. As such, we have chosen to investigate the mechanism of how IL-1RA exerts protective effect in hemin-induced neuronal necroptosis after ICH. Methods- Our ICH model was induced by hemin injection in C57BL/6 mice and IL-1R1-/- mice. In addition, we used primary cultured neurons to assess hemin-induced cell death. Co-immunoprecipitation, immunoblot, immunofluorescent staining, neurological deficit scores, and brain water content were used to study the mechanisms of IL-1R1 modulation in neuronal necroptosis both in vitro and in vivo. Results- Free hemin could mediate neuronal necroptosis directly by assembling necrosome complex and then to trigger cell death. This phenomenon was driven by IL-1R1 as IL-1R1 can form a complex with necrosome. After treatment with IL-1RA, both the expression and translocation of the necrosome decreased while disruption of the interaction between IL-1R1 and RIP1/RIP3 (receptor interacting protein 1/3) increased neuron survival. In addition, the IL-1R1-deficient mice demonstrated lower levels of necrosome components, including RIP1, RIP3, and MLKL (mixed lineage kinase domain-like protein), compared with control groups after hemin treatment. In addition, the neurological deficit scores, brain water content, and inflammatory response were all also reduced in the IL-1R1-deficient mice. Conclusions- Functional inhibition of the interaction between IL-1R1 and the necrosome complex improves neuron survival and promotes the recovery of neurological function in experimental ICH. Targeting IL-1R1/RIP1/RIP3 assembly could be a promising therapeutic strategy for patients with ICH.