P2X7 receptor antagonists modulate experimental autoimmune neuritis via regulation of NLRP3 inflammasome activation and Th17 and Th1 cell differentiation.

BACKGROUND: Guillain-Barré syndrome (GBS), a post-infectious, immune-mediated, acute demyelinating disease of the peripheral nerves and nerve roots, represents the most prevalent and severe acute paralyzing neuropathy. Purinergic P2X7 receptors (P2X7R) play a crucial role in central nervous system inflammation. However, little is known about their role in the immune-inflammatory response within the peripheral nervous system. METHODS: Initially, we assessed the expression of purinergic P2X7R in the peripheral blood of patients with GBS using flow cytometry and qRT-PCR. Next, we explored the expression of P2 X7R in CD4+ T cells, CD8+ T cells, and macrophages within the sciatic nerves and spleens of rats using immunofluorescence labeling and flow cytometry. The P2X7R antagonist brilliant blue G (BBG) was employed to examine its therapeutic impact on rats with experimental autoimmune neuritis (EAN) induced by immunization with the P0180 - 199 peptide. We analyzed CD4+ T cell differentiation in splenic mononuclear cells using flow cytometry, assessed Th17 cell differentiation in the sciatic nerve through immunofluorescence staining, and examined the expression of pro-inflammatory cytokine mRNA using RT-PCR. Additionally, we performed protein blotting to assess the expression of P2X7R and NLRP3-related inflammatory proteins within the sciatic nerve. Lastly, we utilized flow cytometry and immunofluorescence labeling to examine the expression of NLRP3 on CD4+ T cells in rats with EAN. RESULTS: P2X7R expression was elevated not only in the peripheral blood of patients with GBS but also in rats with EAN. In rats with EAN, inhibiting P2X7R with BBG alleviated neurological symptoms, reduced demyelination, decreased inflammatory cell infiltration of the peripheral nerves, and improved nerve conduction. BBG also limited the production of pro-inflammatory molecules, down-regulated the expression of P2X7R and NLRP3, and suppressed the differentiation of Th1 and Th17 cells, thus protecting against EAN. These effects collectively contribute to modifying the inflammatory environment and enhancing outcomes in EAN rats. CONCLUSIONS: Suppression of P2X7R relieved EAN manifestation by regulating CD4+ T cell differentiation and NLRP3 inflammasome activation. This finding underscores the potential significance of P2X7R as a target for anti-inflammatory treatments, advancing research and management of GBS.

pH and ROS Dual-Sensitive Nanocarriers for the Targeted Co-Delivery and On-Demand Sequential Release of Tofacitinib and Glucosamine for Synergistic Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) progression involves multiple cell types, and sequential drug action on target cells is necessary for RA treatment. Nanocarriers are widely used for RA treatment; however, the targeted delivery and on-demand release of multiple drugs remains challenging. Therefore, in this study, a dual-sensitive polymer is developed using chondroitin sulfate (CS) for the co-delivery of the cartilage repair agent, glucosamine (GlcN), and anti-inflammatory drug, tofacitinib (Tof). In the joint cavity, acidic pH facilitates the cleavage of GlcN from CS polymer to repair the cartilage damage. Subsequently, macrophage uptake via CS-CD44 binding and intracellular reactive oxygen species (ROS) mediate conversion of (methylsulfanyl)propylamine to a hydrophilic segment jointly triggered rapid Tof/GlcN release via micelle disassembly. The combined effects of Tof, GlcN, and ROS depletion promote the M1-to-M2 polarization shift to attenuate inflammation. The synergistic effects of these agents against RA are confirmed in vitro and in vivo. Overall, the dual pH/ROS-sensitive CS nanoplatform simultaneously delivers GlcN and Tof, providing a multifunctional approach for RA treatment with synergistic drug effects.

Metabolism-regulating non-coding RNAs in breast cancer: roles, mechanisms and clinical applications.

Breast cancer is one of the most common malignancies that pose a serious threat to women's health. Reprogramming of energy metabolism is a major feature of the malignant transformation of breast cancer. Compared to normal cells, tumor cells reprogram metabolic processes more efficiently, converting nutrient supplies into glucose, amino acid and lipid required for malignant proliferation and progression. Non-coding RNAs(ncRNAs) are a class of functional RNA molecules that are not translated into proteins but regulate the expression of target genes. NcRNAs have been demonstrated to be involved in various aspects of energy metabolism, including glycolysis, glutaminolysis, and fatty acid synthesis. This review focuses on the metabolic regulatory mechanisms and clinical applications of metabolism-regulating ncRNAs involved in breast cancer. We summarize the vital roles played by metabolism-regulating ncRNAs for endocrine therapy, targeted therapy, chemotherapy, immunotherapy, and radiotherapy resistance in breast cancer, as well as their potential as therapeutic targets and biomarkers. Difficulties and perspectives of current targeted metabolism and non-coding RNA therapeutic strategies are discussed.

Simultaneous separation and determination of thallium in water samples by high-performance liquid chromatography with inductively coupled plasma mass spectrometry.

An analytical method for separation and determination of thallium species in water using high-performance liquid chromatography with inductively coupled plasma mass spectrometry was developed. The composition and concentration of mobile phase, injection volume, and pH value were optimized respectively with an anion or cation exchange column. The results showed that Tl(I) and Tl(III) were effectively separated using anion exchange column Hamilton PRP-X100, with the mobile phase consisting of 200 mmol/L ammonium acetate and 10 mmol/L diethylenetriaminepentaacetic acid (pH = 4.2). When using a Dionex cation exchange guard column, CS12A, 15 mmol/L HNO3 , and 3 mmol/L diethylenetriaminepentaacetic acid as the mobile phase, Tl(I) and Tl(III) could be effectively separated. The detection limits of the methods were 3-6 and 9-12 ng/L, respectively. In a solution containing Fe ions and oxalic acid, a significant quantity of Tl(I) was oxidized. Fe ions and oxalic acid in the water samples did not interfere with high-performance liquid chromatography-inductively coupled plasma mass spectrometry measurement results.

OAMDP, a novel podophyllotoxin derivative, induces apoptosis, cell cycle arrest and autophagy in hepatoma HepG2 cells.

4ß-(1,3,4-oxadiazole-2-amino-5-methyl)-4-deoxypodophyllotoxin (OAMDP), a novel podophyllotoxin derivative, has demonstrated potent anti-tumor activity with significant cytotoxic effect. Here, we report the anti-proliferative effect of OAMDP, for which OAMDP could suppress the proliferation of HepG2 cells (human hepatoma cell line) in a dose- and time-dependent manner. After treating with OAMDP, cell apoptosis was confirmed by Annexin V-FITC/PI double staining assay. Furthermore, flow cytometry analysis revealed the loss of mitochondrial membrane potential and the increase of intracellular reactive oxygen species in HepG2 cells. OAMDP increased apoptotic cell population with induction of Bax, cytochrome c (cyt-c), caspase-9, caspase-3, PARP1 and the reduction of Bcl-2 and p-Akt protein expressions. The MAPK family, JNK, ERK, p38, p-JNK, p-ERK, p-p38, were also regulated by OAMDP in HepG2 cells. Moreover, cell cycle analysis showed that OAMDP induced S or G2/M phase arrest through modulation of cycle regulatory proteins. In addition, MDC staining and LC3 protein expression indicated that autophagy was induced by OAMDP in HepG2 cells. To sum up, our results suggested that OAMDP, with the ability to induce autophagy, causing cell cycle arrest and apoptosis, has potential to become a novel anti-tumor agent.

Full-Duplex Cooperative Sensing for Spectrum-Heterogeneous Cognitive Radio Networks.

In cognitive radio networks (CRNs), spectrum sensing is critical for guaranteeing that the opportunistic spectrum access by secondary users (SUs) will not interrupt legitimate primary users (PUs). The application of full-duplex radio to spectrum sensing enables SU to carry out sensing and transmission simultaneously, improving both spectrum awareness and CRN throughput. However, the issue of spectrum sensing with full-duplex radios deployed in heterogeneous environments, where SUs may observe different spectrum activities, has not been addressed. In this paper, we give a first look into this problem and develop a light-weight cooperative sensing framework called PaCoSIF, which involves only a pairwise SU transmitter (SU-Tx) and its receiver (SU-Rx) in cooperation. A dedicated control channel is not required for pairwise cooperative sensing with instantaneous feedback (PaCoSIF) because sensing results are collected and fused via the reverse channel provided by full-duplex radios. We present a detailed protocol description to illustrate how PaCoSIF works. However, it is a challenge to optimize the sensing performance of PaCoSIF since the two sensors suffer from spectrum heterogeneity and different kinds of interference. Our goal is to minimize the false alarm rate of PaCoSIF given the bound on the missed detection rate by adaptively adjusting the detection threshold of each sensor. We derive an expression for the optimal threshold using the Lagrange method and propose a fast binary-searching algorithm to solve it numerically. Simulations show that, with perfect signal-to-interference-and-noise-ratio (SINR) information, PaCoSIF could decrease the false alarm rate and boost CRN throughput significantly against conventional cooperative sensing when SUs are deployed in spectrum-heterogeneous environments. Finally, the impact of SINR error upon the performance of PaCoSIF is evaluated via extensive simulations.

tsRNA: A Promising Biomarker in Breast Cancer.

tRNA-derived small RNAs (tsRNAs) are a novel class of non-coding small RNAs, generated from specific cleavage sites of tRNA or pre-tRNA. tsRNAs can directly participate in RNA silencing, transcription, translation, and other processes. Their dysregulation is closely related to the occurrence and development of various cancers. Breast cancer is one of the most common and fastest-growing malignant tumors in humans. tsRNAs have been found to be dysregulated in breast cancer, serving as a new target for exploring the pathogenesis of breast cancer. They are also considered new tumor markers, providing a basis for diagnosis and treatment. This article reviews the generation, classification, mechanism of action, function of tsRNAs, and their biological effects and related mechanisms in breast cancer, in the hope of providing a new direction for the diagnosis and treatment of breast cancer.

Veliparib exerts protective effects in intracerebral hemorrhage mice by inhibiting the inflammatory response and accelerating hematoma resolution.

Poly (ADP-ribose) polymerase (PARP) inhibitors have potent anti-inflammatory effects, including the suppression of brain microglial activation. Veliparib, a well-known PARP1/2 inhibitor, exhibits particularly high brain penetration, but its effects on stroke outcome is unknown. Here, the effects of veliparib on the short-term outcome of intracerebral hemorrhage (ICH), the most lethal type of stroke, were investigated. Collagenase-induced mice ICH model was applied, and the T2-weighted magnetic resonance imaging was performed to evaluate lesion volume. Motor function and hematoma volume were also measured. We further performed immunofluorescence, enzyme linked immunosorbent assay, flow cytometry, and blood-brain barrier assessment to explore the potential mechanisms. Our results demonstrated veliparib reduced the ICH lesion volume dose-dependently and at a dosage of 5 mg/kg, veliparib significantly improved mouse motor function and promoted hematoma resolution at days 3 and 7 post-ICH. Veliparib inhibited glial activation and downregulated the production of pro-inflammatory cytokines. Veliparib significantly decreased microglia counts and inhibited peripheral immune cell infiltration into the brain on day 3 after ICH. Veliparib improved blood-brain barrier integrity at day 3 after ICH. These findings demonstrate that veliparib improves ICH outcome by inhibiting inflammatory responses and may represent a promising novel therapy for ICH.

Ascorbic acid potentiates photodynamic inactivation mediated by octyl gallate and blue light for rapid eradication of planktonic bacteria and biofilms.

This study reported for the first time that Ascorbic acid (AA) could appreciably boost the efficiency of Octyl gallate (OG)-mediated photodynamic inactivation (PDI) on Escherichia coli and Staphylococcus aureus in planktonic and biofilm states. The combination of OG (0.075 mM) and AA (200 mM) with 420 nm blue light (212 mW/cm2) led to a >6 Log killing within only 5 min for E. coli and S. aureus and rapid eradication of biofilms. The mechanism of action appears to be the generation of highly toxic hydroxyl radicals (•OH) via photochemical pathways. OG was exposed to BL irradiation to generate various reactive oxygen radicals (ROS) and the addition of AA could transform singlet oxygen (1O2) into hydrogen peroxide (H2O2), which could further react with AA to generate enormous •OH. These ROS jeopardized bacteria and biofilms by nonspecifically attacking various biomacromolecules. Overall, this PDI strategy provides a powerful microbiological decontamination modality to guarantee safe food products.

A comprehensive evaluation of circ_0065214/ miR-188-3p/GPNMB axis in breast cancer.

CircRNAs are involved in multiple aspects during carcinogenesis, including tumorigenesis, vascularization, apoptosis and others. Exploring the role of circRNAs in breast cancer (BC) enables us to understand the development mechanism of BC more comprehensively. Here, we screened out and verified an up-regulated circRNA in BC from GEO data. Quantitative Real-time PCR (qRT-PCR) showed that circ_0065214 had a high expression level in BC patients. Besides, circ_0065214 had good diagnostic value in BC serum, and the area under the diagnostic curve, sensitivity and specificity were 0.78, 0.63 and 0.85, respectively. The combined application of circ_0065214 with CEA and CA-153 can further improve the diagnostic efficiency. The knockdown of circ_0065214 in vivo and in vitro inhibited the proliferation, migration and invasion of BC, but promoted autophagy. At last, dual-luciferase reporter assay and rescue assays revealed that circ_0065214 acted as a decoy to adsorb miR-188-3p, and then relieved the repressive effect of miR-188-3p on its target GPNMB. Our results demonstrated that circ_0065214 regulated the expression of GPNMB by competitively binding to miR-188-3p, thus promoting the proliferation, migration and invasion of breast cancer cells and inhibiting autophagy. These findings provided an original therapeutic strategy for BC.

Resistance of an intertidal oyster(Saccostrea mordax)to marine heatwaves and the implication for reef building.

Marine heatwaves (MHWs) have a significant impact on intertidal bivalves and the ecosystems they sustain, causing the destruction of organisms' original habitats. Saccostrea mordax mainly inhabits the intertidal zone around the equator, exhibiting potential tolerance to high temperatures and maybe a species suitable for habitat restoration. However, an understanding about the tolerance mechanism of S. mordax to high temperatures is unclear. It is also unknown the extent to which S. mordax can tolerate repeated heatwaves of increasing intensity and frequency. Here, we simulated the effects of two scenarios of MHWs and measured the physiological and biochemical responses and gene expression spectrum of S. mordax. The predicted responses varied greatly across heatwaves, and no heatwave had a significant impact on the survival of S. mordax. Specifically, there were no statistically significant changes apparent in the standard metabolic rate and the activities of enzymes of the oyster during repeated heatwaves. S. mordax exposed to high-intensity heatwaves enhanced their standard metabolic rate to fuel essential physiological maintenance and increasing activity of SOD and expression of HSP70/90. These strategies are presumably at the expense of functions related to immunity and growth, as best exemplified by significant depressions in activities of enzymes (NaK, CaMg, T-ATP, and AKP) and expression levels of genes (Rab, eEF-2, HMGR, Rac1, SGK, Rab8, etc.). The performance status of S. mordax tends to improve by implementing a suite of less energy-costly compensatory mechanisms at various levels of biological organization when re-exposed to heatwaves. The adaptive abilities shown by S. mordax indicate that they can play a crucial role in the restoration of oyster reefs in tropical seas.

Vector gap solitons of spin-orbit-coupled Bose-Einstein condensate in honeycomb optical lattices.

The combination of the two hot topics of spin-orbit coupling and honeycomb lattices leads to the appearance of fascinating issues. In this paper, we investigate the existence and stability of vector gap solitons of spin-orbit-coupled Bose-Einstein condensates loaded in honeycomb optical lattices. The existence and stability of vector gap solitons are highly sensitive to the properties of interspin and intraspin atomic interaction. We numerically obtain the parametric dependence of the existence of vector gap solitons both in the semi-infinite gap and in the first gap. Since only dynamically stable localized modes in nonlinear systems are likely to be generated and observed in experiments, we examine the stability of the vector gap solitons by using the direct evolution dynamics, and obtain the phase diagram of stable and unstable vector gap solitons on the parameter plane of interspin and intraspin atomic interactions.

Ultraefficient OG-Mediated Photodynamic Inactivation Mechanism for Ablation of Bacteria and Biofilms in Water Augmented by Potassium Iodide under Blue Light Irradiation.

While photodynamic inactivation (PDI) has emerged as a novel sterilization strategy for drinking water treatment that recently attracted tremendous attention, its efficiency needs to be further improved. In this study, we aimed to clarify the ultraefficient mechanism by which potassium iodide (KI) potentiates octyl gallate (OG)-mediated PDI against bacteria and biofilms in water. When OG (0.15 mM) and bacteria were exposed to blue light (BL, 420 nm, 210 mW/cm2), complete sterilization (>7.5 Log cfu/mL of killing) was achieved by the addition of KI (250 mM) within only 5 min (63.9 J/cm2). In addition, at lower doses of OG (0.1 mM) with KI (100 mM), the biofilm was completely eradicated within 10 min (127.8 J/cm2). The KI-potentiated mechanism involves in situ rapid photogeneration of a multitude of reactive oxygen species, especially hydroxyl radicals (•OH), reactive iodine species, and new photocytocidal substances (quinone) by multiple photochemical pathways, which led to the destruction of cell membranes and membrane proteins, the cleavage of genomic DNA and extracellular DNA within biofilms, and the degradation of QS signaling molecules. This multitarget synergistic strategy provided new insights into the development of an environmentally friendly, safe, and ultraefficient photodynamic drinking water sterilization technology.

Coupling water cycle processes with water demand routes of vegetation using a cascade causal modeling approach in arid inland basins.

Vegetation degradation is the key cause of land desertification in arid areas. Water stress is one of the most critical factors leading to vegetation degradation. The water needed for vegetation growth is inseparable from the water cycle processes. It is a new scope to reveal the vegetation water demand mechanisms from the water cycle processes. Water cycle processes in arid inland basins can be conceptually separated as RFA (runoff formation area) and RCA (runoff consumption area). In this study, both the water demand mechanisms of natural vegetation and farmland were discovered by creatively constructing the vegetation water demand route model. The TRB (Tarim River Basin), a typical arid inland basin system that RFA is separated from RCA, is considered as the study area. The tendency and relevance of water cycle factors and NDVI were detected. The dominant factors of vegetation growth were identified. According to the interaction causality of water cycle factors and vegetation, the PLS-SEM (partial least squares structural equation models) were constructed in RFA and RCA. Results displayed that SMroot (root-zone soil moisture), groundwater and precipitation were the dominant water sources for natural vegetation in RFA. The water demand for natural vegetation in RCA mainly came from SMroot and that for farmland mainly came from SMsurf (surface soil moisture). New findings showed that blue and green water circulations were more active in RFA than in RCA. Natural vegetation had better adaptability and resilience to water shortages compared with farmland. The higher effect of vegetation on AET (actual evapotranspiration) denoted the better growth status. It is contributed to the rational utilization of water resources in arid basins.