HIF-1α participates in the regulation of S100A16-HRD1-GSK3ß/CK1α pathway in renal hypoxia injury.

S100 calcium-binding protein 16 (S100A16) is implicated in both chronic kidney disease (CKD) and acute kidney injury (AKI). Previous research has shown that S100A16 contributes to AKI by facilitating the ubiquitylation and degradation of glycogen synthase kinase 3ß (GSK3ß) and casein kinase 1α (CK1α) through the activation of HMG-CoA reductase degradation protein 1 (HRD1). However, the mechanisms governing S100A16-induced HRD1 activation and the upregulation of S100A16 expression in renal injury are not fully understood. In this study, we observed elevated expression of Hypoxia-inducible Factor 1-alpha (HIF-1α) in the kidneys of mice subjected to ischemia-reperfusion injury (IRI). S100A16 deletion attenuated the increased HIF-1α expression induced by IRI. Using a S100A16 knockout rat renal tubular epithelial cell line (NRK-52E cells), we found that S100A16 knockout effectively mitigated apoptosis during hypoxic reoxygenation (H/R) and cell injury induced by TGF-ß1. Our results revealed that H/R injuries increased both protein and mRNA levels of HIF-1α and HRD1 in renal tubular cells. S100A16 knockout reversed the expressions of HIF-1α and HRD1 under H/R conditions. Conversely, S100A16 overexpression in NRK-52E cells elevated HIF-1α and HRD1 levels. HIF-1α overexpression increased HRD1 and ß-catenin while decreasing GSK-3ß. HIF-1α inhibition restored HRD1 and ß-catenin upregulation and GSK-3ß downregulation by cellular H/R injury. Notably, Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated HIF-1α binding signals on the HRD1 promoter, and luciferase reporter gene assays confirmed HIF-1α's transcriptional regulation of HRD1. Additionally, we identified Transcription Factor AP-2 Beta (TFAP2B) as the upregulator of S100A16. ChIP and luciferase reporter assays confirmed TFAP2B as a transcription factor for S100A16. In summary, this study identifies TFAP2B as the transcription factor for S100A16 and demonstrates HIF-1α regulation of HRD1 transcription within the S100A16-HRD1-GSK3ß/CK1α pathway during renal hypoxia injury. These findings provide crucial insights into the molecular mechanisms of kidney injury, offering potential avenues for therapeutic intervention.

Nanofluidic logic with mechano-ionic memristive switches.

Neuromorphic systems are typically based on nanoscale electronic devices, but nature relies on ions for energy-efficient information processing. Nanofluidic memristive devices could thus potentially be used to construct electrolytic computers that mimic the brain down to its basic principles of operation. Here we report a nanofluidic device that is designed for circuit-scale in-memory processing. The device, which is fabricated using a scalable process, combines single-digit nanometric confinement and large entrance asymmetry and operates on the second timescale with a conductance ratio in the range of 9 to 60. In operando optical microscopy shows that the memory capabilities are due to the reversible formation of liquid blisters that modulate the conductance of the device. We use these mechano-ionic memristive switches to assemble logic circuits composed of two interactive devices and an ohmic resistor.

Evaluation of Blue Honeysuckle Berries (Lonicera caerulea L.) Dried at Different Temperatures: Basic Quality, Sensory Attributes, Bioactive Compounds, and In Vitro Antioxidant Activity.

This study aims to comprehensively investigate the effects of hot-air dehydration on the quality of blue honeysuckle berries (Lonicera caerulea L.). The results demonstrated that drying with hot air at 40-65 °C for 7-72 h resulted in blue honeysuckle berries with a moisture content of 0.21-1.10 g H2O/g dry weight. Generally, low to medium temperatures (40-55 °C) showed a better effect on the quality than high temperatures (60-65 °C). Specifically, drying at 40 °C exclusively resulted in better retention of cuticular wax, the best sensory appearance, and the highest total phenolic content. Drying at 45 °C and 50 °C resulted in the highest antioxidant capacity and the optimal sensory flavor. Drying at 55 °C led to the highest soluble solid/acid ratio, ascorbic acid concentration, total flavonoid, and total anthocyanin. The work introduces an innovative raw berry product and provides a comprehensive practical and theoretical framework for convective dehydration of blue honeysuckle berries.

Isthmin-1 promotes growth and progression of colorectal cancer through the interaction with EGFR and YBX-1.

While previous studies have indicated the involvement of Isthmin 1 (ISM1), a secreted protein, in cancer development, the precise mechanisms have remained elusive. In this study, we unveiled that ISM1 is significantly overexpressed in both the blood and tissue samples of colorectal cancer (CRC) patients, correlating with their poor prognosis. Functional experiments demonstrated that enforced ISM1 expression significantly enhances CRC proliferation, migration, invasion and tumor growth. Notably, our investigation reveals an interaction of ISM1 with epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase (RTK) family of CRC cells. The binding of ISM1 triggered EGFR activation and initiate downstream signaling pathways. Meanwhile, intracellular ISM1 interacted with Y-box binding protein 1 (YBX1), enhancing its transcriptional regulation on EGFR. Furthermore, our research uncovered the regulation of ISM1 expression by the hypoxia-inducible transcription factor HIF-1α in CRC cells. Mechanistically, we identified HIF-1α as a direct regulator of ISM1, binding to a hypoxia response element on its promoter. This novel mechanism illuminated potential therapeutic targets, offering insights into restraining HIF-1α/ISM1/EGFR-driven CRC progression and metastasis.

Identifying a panel of nine genes as novel specific model in endometriosis noninvasive diagnosis.

OBJECTIVE: To study biomarkers to develop a novel diagnosis model for endometriosis and validate it using clinical samples. DESIGN: We used publicly available data sets and weighted gene coexpression network analysis to identify differentially expressed genes. Ten machine learning algorithms were used to develop an integrative model for predicting endometriosis. The accuracy and robustness of the model were validated using data sets and clinical samples. SETTING: Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China. PATIENT(S): The study included clinical patients between the ages of 20 and 40 years who required laparoscopic surgery and who had not undergone hormone therapy within the previous 3 months. All the healthy individuals had given birth to a child at least once in their lives. Patients with inflammatory conditions, malignant diseases, immune diseases, myoma, or adenomyosis were excluded. Paraffin blocks of the samples were collected (case, n = 5; control, n = 5). Blood samples of 58 individuals were collected (case, n = 28; control, n = 30). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The areas under the receiver operator characteristic curve of our diagnostic model were measured for data sets and clinical samples. Multiplex immunohistochemical staining and real-time quantitative polymerase chain reaction assays were used for the validation of the model from tissue slides and peripheral blood samples. RESULT(S): A nine-gene panel endometriosis messenger RNA score (EMScore), was constructed to distinguish the patients with endometriosis from healthy individuals using algorithms. The EMScore accurately predicted endometriosis, and the areas under the receiver operator characteristic curve of our diagnostic model were 0.920, and 0.942 for tissue and blood samples, respectively. Moreover, the EMScore outperformed other acknowledged signatures for predicting endometriosis across seven clinical cohorts. Overall, the EMScore constitutes a sensitive and specific noninvasive diagnostic method for endometriosis. CONCLUSION(S): We developed the EMScore, a novel model that can aid in the diagnosis of endometriosis using peripheral blood samples. This study will contribute to the development of improved clinical noninvasive and sensitive diagnostic tools for endometriosis. These nine genes might be potential target molecules for treating endometriosis.

Nature-Inspired Stalactite Nanopores for Biosensing and Energy Harvesting.

Nature provides a wide range of self-assembled structures from the nanoscale to the macroscale. Under the right thermodynamic conditions and with the appropriate material supply, structures like stalactites, icicles, and corals can grow. However, the natural growth process is time-consuming. This work demonstrates a fast, nature-inspired method for growing stalactite nanopores using heterogeneous atomic deposition of hafnium dioxide at the orifice of templated silicon nitride apertures. The stalactite nanostructures combine the benefits of reduced sensing region typically for 2-dimensional material nanopores with the asymmetric geometry of capillaries, resulting in ionic selectivity, stability, and scalability. The proposed growing method provides an adaptable nanopore platform for basic and applied nanofluidic research, including biosensing, energy science, and filtration technologies.

High durability and stability of 2D nanofluidic devices for long-term single-molecule sensing.

Nanopores in two-dimensional (2D) membranes hold immense potential in single-molecule sensing, osmotic power generation, and information storage. Recent advances in 2D nanopores, especially on single-layer MoS2, focus on the scalable growth and manufacturing of nanopore devices. However, there still remains a bottleneck in controlling the nanopore stability in atomically thin membranes. Here, we evaluate the major factors responsible for the instability of the monolayer MoS2 nanopores. We identify chemical oxidation and delamination of monolayers from their underlying substrates as the major reasons for the instability of MoS2 nanopores. Surface modification of the substrate and reducing the oxygen from the measurement solution improves nanopore stability and dramatically increases their shelf-life. Understanding nanopore growth and stability can provide insights into controlling the pore size, shape and can enable long-term measurements with a high signal-to-noise ratio and engineering durable nanopore devices.

A Disintegrin and Metalloprotease 10 Expressions Modulate Potential Metastatic and Thrombus Formation in Pancreatic Carcinoma.

Background: Clinical investigations repurposing a disintegrin and metalloproteases 10 (ADAM10) as metastatic and thrombus marker have achieved encouraging results, but the mechanism behind this association remains unclear. Methods: This study was carried out in NingXia and Wuhan, China from 2017 to 2021. The effects of ADAM10 expression on the metastatic and thrombus-associated genes: tissue factor (TF), P-selectin glycoprotein ligand-1 (PSGL-1), cathepsin G (CTSG) and mucin 1 (MUC1) were examined by immunofluorescence, qRTPCR and Western blotting analysis. Metastatic and thrombotic behaviors were evaluated using NODSCID mouse model. Results: The ADAM10 expression controlled the migration and invasion of pancreatic carcinoma cell-1(PANC-1), and significantly regulated the metastatic and thrombus-associated genes (P<0.05). ADAM10 and MUC1 were regulated and aberrantly expressed by a dependent mechanism. Moreover, ADAM10 expression induced the progression of adenocarcinoma cells and thrombus formation in vivo. Conclusion: Regulation of ADAM10 expression in cancer cells might effectively pave the way for a more potent anti-metastatic and anti-thrombotic approach and could regulate the invasion and migration of cancer cells.

Development of rapamycin-encapsulated exosome-mimetic nanoparticles-in-PLGA microspheres for treatment of hemangiomas.

We have previously developed several kinds of rapamycin-encapsulated nanoparticles to achieve sustained release of rapamycin to treat hemangioma. However, lack of intrinsic targeting and easy clearance by the immune system are major hurdles that artificial fabricated nanoparticles must overcome. We constructed rapamycin-encapsulated macrophage-derived exosomes mimic nanoparticles-in-microspheres (RNM), to achieve the goal of continuous targeted therapy of hemangiomas. The rapamycin-encapsulated exosome mimic nanoparticles (RN) were firstly prepared by the extrusion-based method from the U937 cells (the human macrophage cell line). After then, RN was encapsulated with PLGA (poly(lactic-co-glycolic acid)) microspheres to obtain RNM. The release profile, targeting activity, and biological activity of RN and RNM were investigated on hemangioma stem cells (HemSCs). RN has a size of 100 nm in diameter, with a rapamycin encapsulation efficacy (EE) of 83%. The prepared microspheres RNM have a particle size of ~30 µm), and the drug EE of RNM is 34%. The sustained release of RNM can remarkably be achieved for 40 days. As expected, RN and RNM showed effective inhibition of cellular proliferation, significant cellular apoptosis, and remarkable repressed expression of angiogenesis factors in HemSCs. Our results showed that RNM is an effective approach for prolonged and effective delivery of rapamycin to hemangiomas.

Ultra-Sensitive and Selective Electrochemical Bio-Fluid Biopsy for Oral Cancer Screening.

The early diagnosis of recurrence and metastasis is critically important for decreasing the morbidity and mortality associated with oral cancers. Although liquid biopsy methods hold great promise that provide a successive "time-slice" profile of primary and metastatic oral cancer, the development of non-invasive, rapid, simple, and cost-effective liquid biopsy techniques remains challenging. In this study, an ultrasensitive and selective electrochemical liquid biopsy is developed for oral cancer screening based on tracking trace amounts of cancer biomarker by functionalized asymmetric nano-channels. Detection via antigen-antibody reactions is assayed by evaluating changes in ionic current. Upon the recognition of cancer biomarker antigens in bio-fluids, the inner wall of nano-channel immobilized with the corresponding antibodies undergoes molecular conformation transformation and surface physicochemical changes, which significantly regulate the ion transport through the nano-channel and help achieve sensitivity with a detection limit of 10-12 g mL-1 . Furthermore, owing to the specificity of the monoclonal antibody for the antigen, the nano-channel exhibits high selectivity for the biomarker than for structurally similar biological molecules present in bio-fluids. The effectiveness of this technique is confirmed through the diagnosis of clinical cases of oral squamous cell carcinoma. This study presents a novel diagnostic tool for oral cancer detection in bio-fluids.

Free-Standing Covalent Organic Framework Membrane for High-Efficiency Salinity Gradient Energy Conversion.

Both high ionic conductivity and selectivity of a membrane are required for efficient salinity gradient energy conversion. An efficient method to improve energy conversion is to align ionic transport along the membrane thickness to address low ionic conductivity in traditional membranes used for energy harvesting. We fabricated a free-standing covalent organic framework membrane (TpPa-SO3 H) with excellent stability and mechanical properties. This membrane with one-dimensional nanochannels and high charge density demonstrated high ionic conductivity and selectivity. Its power density reached up to 5.9 W m-2 by mixing artificial seawater and river water. Based on our results, we attribute the high energy conversion to the high ion conductivity through aligned one-dimensional nanochannels and high ion selectivity via the size of the nanochannel at ≈1 nm in the membrane. This study paves the way for designing covalent organic framework membranes for high salinity gradient energy conversion.

Recent progresses in marine microbial-derived antiviral natural products.

Viruses have always been a class of pathogenic microorganisms that threaten the health and safety of human life worldwide. However, for a long time, the treatment of viral infections has been slow to develop, and only a few antiviral drugs have been using clinically. Compared with these from terrestrial environments, marine-derived microorganisms can produce active substances with more novel structures and unique functions. From 2015 to 2019, 89 antiviral compounds of 8 structural classes have been isolated from marine microorganisms, of which 35 exhibit anti-H1N1 activity. This review surveys systematically marine microbial-derived natural products with antiviral activity and illustrates the impact of these compounds on antiviral drug discovery research.

Correction: Bioinspired hydrogel-based nanofluidic ionic diodes: nano-confined network tuning and ion transport regulation.

Correction for 'Bioinspired hydrogel-based nanofluidic ionic diodes: nano-confined network tuning and ion transport regulation' by Congcong Zhu et al., Chem. Commun., 2020, 56, 8123-8126, DOI: 10.1039/D0CC01313G.

Bioinspired nervous signal transmission system based on two-dimensional laminar nanofluidics: From electronics to ionics.

Mammalian nervous systems, as natural ionic circuitries, stand out in environmental perception and sophisticated information transmission, relying on protein ionic channels and additional necessary structures. Prosperously emerged ionic regulated biomimetic nanochannels exhibit great potentialities in various application scenarios, especially signal transduction. Most reported direct current systems possess deficiencies in informational density and variability, which are superiorities of alternating current (AC) systems and necessities in bioinspired nervous signal transmission. Here, inspired by myelinated saltatory conduction, alternating electrostatic potential controlled nanofluidics are constructed with a noncontact application pattern and MXene nanosheets. Under time-variant external stimuli, ions confined in the interlaminar space obtain the capability of carriers for the AC ionic circuit. The transmitted information is accessible from typical sine to a frequency-modulated binary signal. This work demonstrates the potentiality of the bioinspired nervous signal transmission between electronics and ionic nanofluidics, which might push one step forward to the avenue of AC ionics.

Bioinspired hydrogel-based nanofluidic ionic diodes: nano-confined network tuning and ion transport regulation.

Biological ion channel-based mass transport and signal transduction play a crucial role in physiological activities, and biomimetic nanochannels in aqueous solutions for ion transport regulation have been extensively studied. Few studies on non-aqueous systems, gel-based nanochannels, mainly focus on the charged gel network or embedded electrolytes. However, the basic issue of how a nanoscale gel network affects the ion transport in nanochannels has been neglected. Here, we demonstrate a non-aqueous biomimetic nanochannel system by employing the agarose hydrogel in conical nanochannels. To tune the hydrogel network by adjusting the gel concentration, the ion transport behavior in gel-based nanochannels is systemically investigated. The experimental results show that the ion transport behaviors in gel-nanochannels with 2% gel present similar ion selectivity and rectification performance to the aqueous system, indicating fast investigation of gel-based systems with the knowledge of the extensively studied aqueous systems. Furthermore, a gel-based solid-state diode and logic circuits were fabricated.

Biomimetic Nacre-Like Silk-Crosslinked Membranes for Osmotic Energy Harvesting.

As an approach to harvesting sustainable energy from ambient conditions, the osmotic energy between river water and seawater contributes to solving global issues such as the energy shortage and environmental pollution. Current attempts based on a reverse electrodialysis technique are limited mainly due to the economically unviable power density and inadequate mass transportation of membrane materials. Here, we demonstrate a benign strategy for designing a multilayer graphene oxide-silk nanofiber-graphene oxide biomimetic nacre-like sandwich as an osmotic power generator. Enhanced interfacial bonding endows the composite membranes with long-term stability in saline, and meanwhile, the two-dimensional nanofluidic channel configuration also reduces the ion transport resistance and provides large storage spaces for ions. Thus, the output power density of the proposed membrane-based generator achieves a value of up to 5.07 W m-2 by mixing seawater and river water. Furthermore, we experimentally and theoretically demonstrate that the thermal-field drives the increased output power density due to the advances in ionic movement range and activity of electrode reaction, showing the promise of strengthened thermo-osmotic energy conversion.

Rap1 promotes proliferation and migration of vascular smooth muscle cell via the ERK pathway.

BACKGROUND: Rap1 is involved in a multitude of cellular signal transduction pathways, which has extensively been linked to cell proliferation and migration. It has been shown to be important in the regulation of physiological and pathological processes. The present study aims to elucidate its detailed mechanistic in proliferation and migration. MATERIAL/METHODS: Vascular smooth muscle cells (VSMCs) were transfected with pcDNA3.1(empty vector), pcDNA3.1 containing Myc-Tagged-Rap1V12 (Rap1V12) or pcDNA3.1 containing Flag-Tagged-Rap1GAP (Rap1GAP).The cells were presence or absence with 8CPT-2'OMe-cAMP or SDF-1 before transfection. The proliferation and migration were examined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and transwell analysis, respectively. Afterwards, western blot was performed to detect the expression of ERK, phosphorylated-ERK, Rap1, Rap1GAP and Rap1GTP. RESULTS: The results showed that proliferation, migration and the expression of Rap1, Rap1GAP, p-EKR were boosted in treatment of Rap1V12-transfection. However, Rap1GAP presented the opposite effects. Subsequently, VSMCs were pretreatment with stimulators Rap1 guanine exchange factor (Rap1GEF), 8CPT-2'OMe-cAMP and stromal cell-derived factor 1 (SDF-1), then transfected with different vectors and the expression of Rap1, Rap1GAP and p-EKR were obviously decreased. CONCLUSIONS: Taken together, these findings indicated for the first time that Rap1 was essential for the VSMCs in proliferation and migration by ERK signaling pathway.

Enhanced rapamycin delivery to hemangiomas by lipid polymer nanoparticles coupled with anti-VEGFR antibody.

The most common tumors in children are infantile hemangiomas which could cause morbidity and severe complications. The development of novel alternative drugs to treat infantile hemangiomas is necessary, since Hemangeol is the only US Food and Drug Administration-approved drug for infantile hemangiomas. However, Hemangeol has several disadvantages, including a high frequency of administration and adverse effects. Rapamycin is a well­established antiangiogenic drug, and we have previously developed rapamycin lipid polymer nanoparticles (R­PLNPs) as a local sustained­release drug delivery system to achieve controlled rapamycin release and to decrease the frequency of administration and side effects of rapamycin. To improve the targeting of R­PLNPs to infantile hemangiomas in the present study, R­PLNPs were modified to include an antibody against vascular endothelial growth factor receptor (VEGF). The characteristics, and the anti­hemangioma activity of the resulting R­PLNPs coupled with the anti­VEGFR2 antibody (named R­PLNPs­V) were examined in vitro and in vivo. R­PLNPs­V possessed a small size (115 nm) and sustained drug release for 6 days. The anti­VEGFR2 antibody promoted the targeting and cytotoxic effect of R­PLNPs­V to human hemangioma endothelial cells and human umbilical vein endothelial cells. Using a subcutaneous infantile hemangioma xenograft in mice, the in vivo therapeutic effect (evaluated with hemangioma weight, volume, and microvessel density) of R­PLNPs­V was demonstrated to be superior compared with rapamycin alone and other non­targeted nanoparticles, without any total body weight loss. In summary, R­PLNPs­V could facilitate targeted delivery and sustained release of rapamycin to infantile hemangiomas, and thus may represent a promising candidate treatment for infantile hemangiomas.

Inhibition of hemangioma growth using polymer-lipid hybrid nanoparticles for delivery of rapamycin.

Although infantile hemangiomas is benign, its rapid growth may induce serious complications. However, only one drug Hemangeol™ has been approved by US Food and Drug Administration (FDA) to treat infantile hemangiomas. Thus it is necessary to develop novel alternative drugs to treat infantile hemangiomas. Rapamycin is a well-know potent antiangiogenic agent, whereas the daily oral administration of rapamycin exerts undesired metabolic effects due to its inhibition of mechanistic target of rapamycin (mTOR) which is critical in cell metabolism. We hereby developed rapamycin-loaded polymer-lipid hybrid nanoparticles (Rapamycin-PLNPs) as a local controlled release system to realize local and sustained release of rapamycin, aiming to reduce the side effects and frequency of administration of rapamycin. Rapamycin-PLNPs are of a small size (129.1nm), desired drug encapsulation efficiency (63.7%), and sustained drug release for 5 days. Rapamycin-PLNPs were shown to be able to effectively bind to hemangioma endothelia cells (HemECs), induce significant proliferation inhibition and reduce expression of angiogenesis factors in HemECs. The therapeutic effect of Rapamycin-PLNPs against infantile hemangioma in vivo was superior to rapamycin, as reflected by reduced hemangioma volume, weight and microvessel density. Taken together, Rapamycin-PLNPs represent a very promising local approach in the treatment of infantile hemangiomas.