The nuclear pore complex (NPC) is the sole and selective gateway for nuclear transport, and its dysfunction has been associated with many diseases. The metazoan NPC subcomplex RanBP2, which consists ...of RanBP2 (Nup358), RanGAP1-SUMO1, and Ubc9, regulates the assembly and function of the NPC. The roles of immune signaling in regulation of NPC remain poorly understood. Here, we show that in human and murine T cells, following T-cell receptor (TCR
)
stimulation, protein kinase C-θ (PKC-θ) directly phosphorylates RanGAP1 to facilitate RanBP2 subcomplex assembly and nuclear import and, thus, the nuclear translocation of AP-1 transcription factor. Mechanistically, TCR stimulation induces the translocation of activated PKC-θ to the NPC, where it interacts with and phosphorylates RanGAP1 on Ser
504
and Ser
506
. RanGAP1 phosphorylation increases its binding affinity for Ubc9, thereby promoting sumoylation of RanGAP1 and, finally, assembly of the RanBP2 subcomplex. Our findings reveal an unexpected role of PKC-θ as a direct regulator of nuclear import and uncover a phosphorylation-dependent sumoylation of RanGAP1, delineating a novel link between TCR signaling and assembly of the RanBP2 NPC subcomplex.
l-arginine (l-Arg) supplementation has been reported to enhance the function of immune cells, including dendritic cells (DCs) and T lymphocytes, in cancer models thereby countering the suppressive ...effects of myeloid-derived suppressor cells (MDSCs). The balance of the active immune cells is one factor that determines the progression of cancers in vivo. Docetaxel (DTX), an immunomodulatory chemotherapeutic agent, is now widely used in several types of malignancies including breast cancer. We hypothesized that the combination of DTX and l-Arg would elicit a more robust antitumor response than either molecule alone. To test this hypothesis we utilized BALB/c mice inoculated with 4T1 mammary carcinoma cells. DTX and l-Arg synergistically limited tumor growth in vivo and moderately increased the life span of tumor bearing mice. The anti-tumor effects were associated with the proliferation of splenic CD8+ CTL and CD4+ Th1 effector cells, as well as increased serum levels of interferon gamma. More importantly, DTX+l-Arg effectively increased anti-tumor immunity within the tumor microenvironment. Furthermore, the combined therapy increased the number of myeloid (mDCs) and plasmacytoid (pDCs) dendritic cells, potent activators of the T cell response, and enhanced expression of the maturation markers CD86 and MHC II (required for antigen presentation). The combination therapy also reduced the proliferation of MDSCs. These data suggest that DTX+l-Arg may be a novel therapeutic strategy for breast cancer patients.
•L-arginine and docetaxel combined therapy enhances the anti-tumor effects in breast cancer mice by improving the immune status.•The anti-tumor effects were associated with improved systemic host immune response and local tumor immunity.•The combined therapy leads to the proliferation of CD8+ and CD4+ Th1 effector T cells and IFN-γ, as well as decreased frequency of MDSCs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
L-Arginine (L-Arg), the substrate for nitric oxide (NO) synthase, has been used to treat malaria to reverse endothelial dysfunction in adults. However, the safety and efficacy of L-Arg remains ...unknown in malaria patients under the age of five, who are at the greatest risk of developing cerebral malaria (CM), a severe malaria complication. Here, we tested effects of L-Arg treatment on the outcomes of CM using a mouse model. Experimental cerebral malaria (ECM) was induced in female C57BL/6 mice infected with Plasmodium berghei ANKA, and L-Arg was administrated either prophylactically or after parasite infection. Surprisingly, both types of L-Arg administration caused a decline in survival time and raised CM clinical scores. L-Arg treatment increased the population of CD4+T-bet+IFN-γ+ Th1 cells and the activated macrophages (F4/80+CD36+) in the spleen. The levels of pro-inflammatory cytokines, IFN-γ and TNF-α, in splenocyte cultures were also increased by L-Arg treatment. The above changes were accompanied with a rise in the number of dendritic cells (DCs) and an increase in their maturation. However, L-Arg did not affect the population of regulatory T cells or the level of IL-10 in the spleen. Taken together, these data suggest that L-Arg may enhance the Th1 immune response, which is essential for a protective response in uncomplicated malaria but could be lethal in CM patients. Therefore, the prophylactic use of L-Arg to treat CM, based on the assumption that restoring the bioavailability of endothelial NO improves the outcome of CM, may need to be reconsidered especially for children.
Chloroquine (CQ), a well-known anti-malarial drug, has long been used for the treatment of autoimmune diseases because of its profound immunomodulatory effects. However, whether this drug modifies ...anti-malaria immune response is still not clear. Here we studied the immunomodulatory role of CQ in a mouse model of malaria. DBA/2 mice were infected with Plasmodium yoelii (Py) parasite (intraperitoneal injection of parasitized erythrocytes) and divided into three groups. Two groups received single dose of CQ (gavage administration) at 6 hours after Py infection (post-6h) and 3 days after Py infection (post-3d), respectively. The third group received saline as control. The course of disease was monitored and the changes of immune response were investigated. It is shown that mice from the post-6h group took longer time to clear the parasites compared with those of the post-3d group. The activation of T helper cells, macrophages, and B cells was significantly suppressed in mice with post-6h CQ treatment as compared with control mice on day 3 and day 5 after infection. In contrast, no such changes were found in mice from the post-3d group. Dendritic cells (DCs) from the post-6h CQ treated mice were less mature as compared with those from control mice as well as those from the post-3d group. Taken together, our data suggest that treatment with CQ early in infection inhibits protective immune response against Py infection possibly via mechanisms involving the modulation of DC’s function. Our finding provided important information for reasonable use of CQ in malaria chemotherapy.
•DNAzyme modified TFBG-SPR biosensor for ultratrace lead ion detection on the basis of “hot spot” effect.•A large dynamic measurement range (10−11 M–10−6 M) and a competitive low limit of detection ...(8.56 pM).•High stability and excellent selectivity towards lead ion over other environmentally related metal ions.•Lead ion detection was successfully validated in clinical human serum samples.
Heavy metal lead ion (Pb2+) detection takes more and more attention due to its synergistic toxicity to human health and undegradability in environment. Currently, there are urgent demands for portable, anti-interference and economical Pb2+ sensors with high sensitivity and selectivity for environmental monitoring as well as modern healthcare in clinic. In this article, via compact and high performed titled fiber Bragg grating (TFBG) surface plasmon resonance (SPR) sensing platform, we present a novel DNAzyme biosensor for ultratrace Pb2+ detection on the basis of “hot spot” effect in near-infrared band. A gold nanoparticle (GNP)-on-Au film construction was built by DNAzyme and its substrate strand. When Pb2+ with high catalytic activity cleave the DNAzyme linked rA (ribonucleotide adenosine) containing substrate strand, making DNA double helix structure transform to a single strand, the GNPs that connected with DNAzyme fall down to the sensor surface. By FDTD simulation, we have demonstrated that the appearing “hot spot” effect due to the narrow gap (<2 nm) will eventually result in enhancement of the spectrum signal response which is directly related to the Pb2+ concentration. In experiments, the proposed fiber biosensor exhibits a competitive low limit of detection ∼ 8.56 pM, excellent selectivity against other environmentally related metal ions and the large dynamic response range from 10−11 M to 10−6 M. More significantly, clinical human serum samples were used to verify the practicability of this TFBG-SPR-DNAzyme-GNPs biosensor showing great potential value in various clinical applications as a high efficiency, portable and easy to miniaturization point-of-care testing technology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•Exo immunization can obtain wonderful immune protection, which obviously improved parasitemia and survival rate in C57BL/6J mice infected with P.bANKA, the potential regulating ...mechanisms partly correlated with downregulating the levels of inflammatory cytokines/adhesion molecular and ameliorating the brain pathology, which is protecting integrity of BBB and inhibiting iRBC sequestration in cerebrovascular, and induced the strong antibody response in Exos immunized C57BL/6J mice infected with P.bANKA.•In this study, I.V. immunization has a better immunization effect compared with S.C. + CpG ODN.
RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. To mitigate the risk of cerebral malaria (CM) among children under the age of 5, it is imperative to develop new vaccines. EVs are potential vaccine candidates as they obtain the ability of brain-targeted delivery and transfer plasmodium antigens and immunomodulators during infections. This study extracted EVs from BALB/c mice infected with Plasmodium yoelii 17XNL (P.y17XNL). C57BL/6J mice were intravenously immunized with EVs (EV-I.V. + CM group) or subcutaneously vaccinated with the combination of EVs and CpG ODN-1826 (EV + CPG ODN-S.C. + CM group) on days 0 and 20, followed by infection with Plasmodium berghei ANKA (P.bANKA) on day 20 post-second immunization. We monitored Parasitemia and survival rate. The integrity of the Blood-brain barrier (BBB) was examined using Evans blue staining.The levels of cytokines and adhesion molecules were evaluated using Luminex, RT-qPCR, and WB. Brain pathology was evaluated by hematoxylin and eosin and immunohistochemical staining. The serum levels of IgG, IgG1, and IgG2a were analyzed by enzyme-linked immunosorbent assay. Compared with those in the P.bANKA-infected group, parasitemia increased slowly, death was delayed (day 10 post-infection), and the survival rate reached 75 %–83.3 % in the EV-I.V. + ECM and EV + CPG ODN-S.C. + ECM groups. Meanwhile, compared with the EV + CPG ODN-S.C. + ECM group, although parasitemia was almost the same, the survival rate increased in the EV-I.V. + ECM group.Additionally, EVs immunization markedly downregulated inflammatory responses in the spleen and brain and ameliorated brain pathological changes, including BBB disruption and infected red blood cell (iRBC) sequestration. Furthermore, the EVs immunization group exhibited enhanced antibody responses (upregulation of IgG1 and IgG2a production) compared to the normal control group. EV immunization exerted protective effects, improving the integrity of the BBB, downregulating inflammation response of brain tissue, result in reduces the incidence of CM. The protective effects were determined by immunological pathways and brain targets elicited by EVs. Intravenous immunization exhibited better performance than subcutaneous immunization, which perhaps correlated with EVs, which can naturally cross BBB to play a better role in brain protection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Nonantibody-mediated transfusion-related acute lung injury (TRALI) may account for up to 25% of TRALI cases. This indicates the need for further research to understand the pathophysiological ...mechanisms involved beyond antibody mediation fully. During this research, a TRALI rat model was developed using the trauma-blood loss-massive transfusion method. The severity of pulmonary edema was checked via measurement of lung histopathological changes and the amount of Evans blue dye fluid and bronchoalveolar lavage fluid protein leakage. In addition, potential mechanisms of pathophysiological pathways and inflammation cascades were investigated in TRALI rats in vivo . The findings indicated that TRALI increased inflammatory cytokines and triggered elevated levels of high-mobility group box 1 (HMGB1)/receptor-interacting protein kinase 3 (RIP3), apoptosis protein, and mRNAs in the TM (TRALI model) group as opposed to the normal control. Furthermore, TRALI activated the toll-like receptor 4/nuclear factor kappa B and mitogen-activated protein kinase signaling pathways, which partially regulated the inflammatory response in the TRALI rats. A significant increase was observed in the inflammatory mediators HMGB1 and RIP3 during the early stages of TRALI, suggesting that these mediators could be used as diagnostic markers for TRALI. In addition, HMGB1 and RIP3 promoted the inflammatory response by stimulating the toll-like receptor 44/nuclear factor kappa B and mitogen-activated protein kinase signaling pathways in the lung tissue of rats. Identifying efficient agents from inflammatory mediators such as alarmin can be an innovative scheme for diagnosing and preventing TRALI. These findings give HMGB1 and RIP3 a strong theoretical and experimental foundation for clinical use.
Due to the large-dynamic range and reversible conductivity modulation capability, polyaniline (PANI) shows promising prospects for diverse applications, such as supercapacitors, rechargeable ...batteries, and electrochromic materials. However, online characterization of the optical properties of the conductive polymer in the infrared band throughout the synthesis and redox state changing processes poses a challenge. Here, we propose and demonstrate an analysis and sensing platform for real-time evaluation of both thickness and the complex refractive index of PANI nanofilm, and employed for ammonia gas concentration sensing. The coupled optical probing mode of tilted fiber Bragg grating (TFBG) as a robust and portable permittivity perception tool is utilized for online perceiving the large-dynamic-range conductivity change of PANI nanofilm. By reproducing the spectral evolution of the probing cladding mode resonance, we introduce a simulation method for analyzing the optical properties of polymer nanofilms within the infrared band. For ammonia gas detection, the sensing platform exhibited continuous and reliable detection within a concentration range of 25–500 ppm, with an optimal film thickness of 156 nm. A good linear response was observed with a sensitivity of up to 5.2 × 10−3 dB/ppm, and a linearity (R2 = 0.9876) with a detection limit of 10 ppm. Our proposed low-cost and large dynamic range conductivity-modulated PANI-TFBG platform for optical properties online analysis and sensing shows potential in environmental monitoring, healthcare, and the biochemical field.
•A polymer-optic fiber platform for analysis of optical properties of PANI and sensing Ammonia gas is demonstrated.•TFBG is utilized for assessing complex refractive index or thickness for PANI.•The detection limit of ammonia is 10 ppm with a sensitivity of 5.2 × 10−3 dB/ppm.•Using this simulation-assist method, interfacial reaction processes could be further evaluated using TFBG as a “witness sample".
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To investigate the performance characteristics of polymers with different functional groups in drilling fluid matrix (clay suspension), two anionic acrylamide-based polymers with molecular weights of ...approximately 1 million and the same monomer ratio, namelypoly(acrylamidoacrylate) (P(AM-AA)) and poly(acrylamidoallyl sulfonate) (P(AM-SAS)), were synthesized using a water-dispersion polymerization method. Using polyacrylamide (PAM) with the same molecular weight as a reference, thermogravimetric analysis, scanning electron microscopy, zeta potential analysis, particle size distribution test, and drilling fluid performance test were conducted to assess the thermal stability of the polymers as well as the microstructures and properties of the corresponding drilling fluids. The results demonstrated that both P(AM-AA) and P(AM-SAS) exhibited significant intercalation effects on clay in drilling fluids, leading to an increase in the zeta potential of clay particles and the formation of a bimodal particle size distribution. These polymers also effectively reduced filtration loss and altered the rheological properties of the drilling fluids. However, the influence of polymers on temperature and salt resistance did not conform to the traditional understanding that sulfonic acid groups offer better hydration and salt resistance compared to carboxyl groups. The performance characteristics of the polymers were influenced not only by their own structure, but also by the clay content, salt content, temperature in the drilling fluids. Specifically, in freshwater drilling fluids, P(AM-AA) exhibited a slightly lower but comparable reduction in filter loss compared to P(AM-SAS). Furthermore, P(AM-AA) was less affected by clay content than P(AM-SAS) and showed stronger filter loss reduction in brine drilling fluids with NaCl content ≤3 wt%, while exhibiting less sensitivity to variations in NaCl content. Conversely, P(AM-SAS) demonstrated stronger filter loss reduction and lower sensitivity to NaCl content in brine drilling fluids with NaCl content >3 wt%. The influence of high-temperature aging (120-180 °C) on filter loss reduction function was similar for both P(AM-AA) and P(AM-SAS). The rheology of the formulated drilling fluid was less sensitive to clay content when utilizing P(AM-AA) compared to P(AM-SAS). Moreover, the apparent viscosity of the drilling fluid with P(AM-AA) was more impacted by NaCl when the NaCl content was below 5 wt%, showing greater sensitivity than P(AM-SAS). However, there was no significant difference in rheological stability between P(AM-AA) and P(AM-SAS) under high-temperature aging conditions.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
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•A “on–off” DNAzyme coordination structure based TFBG-SPR biosensor is established for ultrasensitive lead ion detection.•“On”—DNAzyme is modified on the sensor and its cleavage ...substrate hybridizes with the DNA-AuNP conjugates.•“Off”—the DNA-AuNP conjugates fall off the sensor via the catalytic cracking characteristic of lead ion.•A wide lead ion detection range of 10 orders of magnitude and ultra-low limit of detection (3 fM) are achieved.•Biological sample recovery tests successfully validate the effectiveness of biosensor for Pb2+ detection in clinical settings.
Ultra-trace lead ion detection has significant implications in various domains, notably in point-of-care testing, environmental monitoring, and cancer-targeted therapies and diagnostics. The demand for rapid and precise lead-ion detection in clinical settings necessitates innovative approaches. In this study, a lead-ion biosensor was designed using DNAzyme-based tilted fiber Bragg grating surface plasmon resonance (TFBG-SPR). The lead ions specifically cleave toward DNAzyme’s ribonucleotide adenosine (rA)-containing substrate strand, and a high sensitivity “on–off” sensing structure on the TFBG-SPR surface was established by using the DNA-conjugated AuNPs as a signal amplification element. This “on–off”-type lead ion biosensor has a competitive limit of detection of 3 fM and a wide dynamic measurement range up to ten orders, meeting stringent requirements for ultra-trace, label-free and online clinical detection. Owing to the unique catalytic effect of DNAzyme binding to lead ions, high selectivity was demonstrated. Moreover, to validate its practicality in clinical diagnosis, we successfully achieved spiked-recovery results with 100.39 % average recovery rate and a swift 17-minute analysis time within the colorectal cancer patient samples. By combining DNA biomolecular, TFBG-SPR probe and “on–off” AuNPs-DNA structure, the fM level detection of lead ion in fiber highlighted its potential in vivo and in vitro complex application scenarios.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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