Microglial polarization is one of the most promising therapeutic strategies for multiple central nervous system (CNS) disorders. However, safe, effective, and controllable microglial regulation still ...faces formidable challenges. Although some anti‐inflammatory factors promote microglia polarization, their short half‐life, high cost, unpredictable in vivo behavior, and complex delivery operations, hamper their clinical application. Here, inspired by the natural microhemorrhage cleaning mechanism, an MG1 peptide and RVG29 peptide engineered nanoerythrocyte (NEMR) that can reprogram microglia are developed from classical M1 toward alternative M2 by inducing heme oxygenase‐1 (HO‐1), stimulating Notch1/Hes1/Stat3 signaling, and further inhibiting NF‐κB p65 translocation. Moreover, anti‐inflammatory carbon monoxide (CO) and bilirubin produced by endogenous metabolism of heme further reinforces the anti‐inflammatory effect. In middle cerebral artery occlusion and experimental autoimmune encephalomyelitis models, a satisfactory prognosis is achieved, with precise regulation of inflammatory microglia in lesion sites, increased expression of anti‐inflammatory factors, reduced blood–brain barrier permeability, as well as promotion of neurogenesis and functional recovery. Furthermore, NEMR can be integrated with clinical therapeutic agents, which facilitates precise drug delivery to enhance therapeutic effects. Hence, the natural nanoerythrocytes, as a feasible, efficient, safe, and practical tool, provides a new strategy for rebalancing of the immune environment in the CNS disorders.
Microglia are the main regulator of inflammatory response in ischemic stroke and multiple sclerosis. An engineered nanoerythrocyte immunosuppressive platform is developed for precise targeting and efficient reprogramming of M1 microglia. The regulation of microglia function, protection of the blood–brain barrier, and neurons are realized through upregulation of heme oxygenase‐1 and reinforcement by intrinsic metabolism to generate anti‐inflammatory substances CO and bilirubin.
Colorectal cancer (CRC) is the second most common cause of cancer incidence worldwide. Oral drug delivery systems (ODDS) have shown great promise for CRC therapy, but the delivery efficiency is still ...challenged by the dense intestinal mucus barrier and nonspecific interception of abnormally proliferated pathogenic bacteria. Herein, self‐thermophoretic nanoparticles (CTPB) is presented to enhance intestinal mucus penetration and reduce pathogenic bacteria interception in CRC for efficient drug delivery. The nanoplatform introduces hollow mesoporous copper sulfide and is asymmetrically sprayed with titanium dioxide as the self‐thermophoretic matrix. Based on the close relationship between pathogenic bacteria and CRC, the nanoplatform is camouflaged by the biomimetic membrane of Staphylococcus aureus to precisely anchor in the intestinal segment of CRC. After near‐infrared laser irradiation, CTPB can effectively increase the intestinal mucus penetration efficiency by 2.7 folds, and decrease the pathogenic bacterial interception by 3.5 folds via the self‐thermophoretic propulsion force. In orthotopic CRC‐bearing mice, CTPB vastly improved the drug delivery efficiency to CRC after oral administration, thus showing a 99.4% antitumor rate after three weeks of treatment, which provides new insight into oral drug delivery for CRC therapy.
The delivery efficiency of oral nanoparticles is always limited by intestinal mucus and pathogenic bacteria interception. A self‐thermophoretic nanoparticle is developed for colorectal cancer therapy through penetrating intestinal mucus and detaching from pathogenic bacteria. With improved delivery efficiency, the nanoparticles showed a 99.4% antitumor efficiency in vivo, and provides a new strategy for orally targeted therapy of colorectal cancer.
In the plastic extrusion process, most of the equipment is not production record and manufacturing information integrated, some production lines are not even installed sensors to monitor basic ...signals. This will cause the production line not being able to manufacture in optimal mode and cannot troubleshoot when exceptions occur. This research is mainly verified by the pressure instability of the extrusion system, unmelted resin will lead to the extrusion instability. The single-screw extruder is used as the experimental process machine (screw diameter is 25mm, screw diameter ratio is 26D, four temperature zones). Since there are many melt properties that cannot be measured by physical sensors, the melt pressure spectrum as input features, and used a regression model to design a soft sensor. To develop a monitoring system to monitor the melt state of the extrusion process. Thus, the pressure signal is captured on the adapter flow channel. The spectrum of the pressure signal is obtained using FFT after analog signal processing. To apply the spectrum to the analysis extrusion instability, this research extracted the Top-10 frequency components in the spectrum. The machine learning model of soft sensor predicts the perturbation frequency of the pressure and other related numerical results. The model dataset contains process parameters, variables and spectral feature. The models used are random forest classification and regression. According to the model results, the classification prediction accuracy is at least 0.91, the R 2 score based on the proposed dataset can reach 0.97. The classification and regression results of the proposed model are satisfactory.
In a recent article, Yamada et al. proposed to utilize CuI‐CuBr alloys (CuI1‐xBrx) as a hole‐density‐tunable p‐type transparent semiconductor. Employing first‐principles calculations, they attributed ...the acceptor state to Cu vacancies (VCu). Despite the interesting experimental demonstration, it is found that the first‐principles results in the paper are unphysical and misleading due to the adoption of an incorrect level of theory and the lack of a rigorous methodology for computing defect formation energies. Below are the specific concerns.
Copper vacancies (VCu) play a decisive role in the p‐type conductivity of copper halides, but their first‐principles modeling has been problematic in the literature, leading to unphysical results. This article demonstrates that the use of hybrid functionals and the inclusion of spin‐orbit coupling are essential to accurately describing the electronic structures, defect energetics, and band offsets in copper halides.
Delta-secretase cleaves both APP and Tau to mediate the formation of amyloid plaques and neurofibrillary tangle in Alzheimer's disease (AD). However, how aging contributes to an increase in ...delta-secretase expression and AD pathologies remains unclear. Here we show that a CCAAT-enhancer-binding protein (C/EBPβ), an inflammation-regulated transcription factor, acts as a key age-dependent effector elevating both delta-secretase (AEP) and inflammatory cytokines expression in mediating pathogenesis in AD mouse models. We find that C/EBPβ regulates delta-secretase transcription and protein levels in an age-dependent manner. Overexpression of C/EBPβ in young 3xTg mice increases delta-secretase and accelerates the pathological features including cognitive dysfunctions, which is abolished by inactive AEP C189S. Conversely, depletion of C/EBPβ from old 3xTg or 5XFAD mice diminishes delta-secretase and reduces AD pathologies, leading to amelioration of cognitive impairment in these AD mouse models. Thus, our findings support that C/EBPβ plays a pivotal role in AD pathogenesis via increasing delta-secretase expression.
BDNF/TrkB neurotrophic signaling regulates neuronal development, differentiation, and survival, and deficient BDNF/TrkB activity underlies neurodegeneration in Alzheimer’s disease (AD). However, ...exactly how BDNF/TrkB participates in AD pathology remains unclear. Here, we show that deprivation of BDNF/TrkB increases inflammatory cytokines and activates the JAK2/STAT3 pathway, resulting in the upregulation of transcription factor C/EBPβ. This, in turn, results in increased expression of δ-secretase, leading to both APP and Tau fragmentation by δ-secretase and neuronal loss, which can be blocked by expression of STAT3 Y705F, knockdown of C/EBPβ, or the δ-secretase enzymatic-dead C189S mutant. Inhibition of this pathological cascade can also rescue impaired synaptic plasticity and cognitive dysfunctions. Importantly, reduction in BDNF/TrkB neurotrophic signaling is inversely coupled with an increase in JAK2/STAT3, C/EBPβ, and δ-secretase escalation in human AD brains. Therefore, our findings provide a mechanistic link between BDNF/TrkB reduction, C/EBPβ upregulation, δ-secretase activity, and Aβ and Tau alterations in murine brains.
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•Deprivation of BDNF increases inflammatory cytokines•Deprivation of BDNF upregulates C/EBPβ by JAK2/STAT3 pathway•BDNF knockout increases expression of AEP by C/EBPβ•Inhibition of JAK2/STAT3/C/EBPβ/AEP prevents BDNF-depletion-mediated pathology
Deficient BDNF/TrkB activity underlies AD pathogenesis. Wang et al. report that deprivation of BDNF/TrkB increases inflammatory cytokines and activates the JAK2/STAT3 pathway, resulting in the upregulation of C/EBPβ/AEP signaling. Reduction of BDNF is inversely coupled with the aforementioned pathway in AD brains. Inhibition of JAK2/STAT3/C/EBPβ/AEP prevents BDNF-depletion-mediated pathology.
Background/Aims: Adipocyte-derived exosomes (ADEs) stimulate the activation of macrophages and contribute to the development of insulin resistance. Sonic Hedgehog (Shh) is an exosome-carrying protein ...and stimulates macrophages to secrete inflammatory cytokines. However, the impact of ADEs carrying Shh on the pro-inflammatory activation of macrophages and consequently, adipocyte insulin resistance is unclear. Methods: 3T3-L1 adipocytes were cultured with high glucose and insulin to imitate the pathogeny of insulin resistance. ADEs were isolated from conditioned media of 3T3-L1 adipocytes via differential ultracentrifugation. We explored the role of ADEs carrying Shh in the polarization of macrophages by flow cytometry. Western blot and electrophoretic mobility shift assay (EMSA) were performed to determine the activation of Shh-mediated signalling pathways. The effects of ADE-treated macrophages on adipocyte insulin signalling were studied by Western blot. Results: We found that circulating Shh-positive exosomes were increased in type 2 diabetes patients. High glucose and insulin increased the secretion of Shh-positive ADEs. The ADEs carrying Shh induced pro-inflammatory or M1 polarization of bone marrow-derived macrophages (BMDM) and RAW 264.7 macrophages. Inhibitors of Ptch and PI3K blocked the M1 polarization induced by ADEs, which suggests that ADEs carrying Shh mediated M1 macrophage polarization through the Ptch/PI3K signalling pathway. ADE-treated RAW 264.7 macrophages were subsequently used to assess the effect on insulin signalling in adipocytes. Using a co-culture assay, we showed that both ADE-treated macrophages and exosomes from these macrophages could decrease the expression of insulin-resistant substrate-1 (IRS-1) and hormone-sensitive lipase (HSL) in adipocytes. Inhibitors of Ptch and PI3K blocked the down-regulation of IRS-1 and HSL induced by ADE-treated macrophages. Conclusion: Together, these data indicate that ADEs carrying Shh induce the M1 polarization of macrophages, which contributes to insulin resistance in adipocytes through the Ptch/PI3K pathway.
DJ‐1, also known as Parkinson's disease protein 7 (Park7), is a multifunctional protein that regulates oxidative stress and mitochondrial function. Dysfunction of DJ‐1 is implicated in the ...pathogenesis of Parkinson's disease (PD). Hyperhomocysteinemia is associated with an increased risk of PD. Here we show that homocysteine thiolactone (HTL), a reactive thioester of homocysteine (Hcy), covalently modifies DJ‐1 on the lysine 182 (K182) residue in an age‐dependent manner. The N‐homocysteinylation (N‐hcy) of DJ‐1 abolishes its neuroprotective effect against oxidative stress and mitochondrial dysfunction, exacerbating cell toxicity. Blocking the N‐hcy of DJ‐1 restores its protective effect. These results indicate that the N‐hcy of DJ‐1 abolishes its neuroprotective effect and promotes the progression of PD. Inhibiting the N‐hcy of DJ‐1 may exert neuroprotective effect against PD.
N‐homocysteinylation of DJ‐1 by HTL promotes neurodegeneration.
Synaptic loss is an early pathological event in Alzheimer’s disease (AD), but its underlying molecular mechanisms remain largely unknown. Recently, microRNAs (miRNAs) have emerged as important ...modulators of synaptic function and memory.
We used miRNA array and quantitative polymerase chain reaction to examine the alteration of miRNAs in AD mice and patients as well as the Morris water maze to evaluate learning and memory in the mice. We also used adeno-associated virus or lentivirus to introduce tyrosine-protein phosphatase non-receptor type 1 (PTPN1) expression of silencing RNAs. Long-term potentiation and Golgi staining were used to evaluate the synaptic function and structure. We designed a peptide to interrupt miR-124/PTPN1 interaction.
Here we report that neuronal miR-124 is dramatically increased in the hippocampus of Tg2576 mice, a recognized AD mouse model. Similar changes were observed in specific brain regions of affected AD individuals. We further identified PTPN1 as a direct target of miR-124. Overexpression of miR-124 or knockdown of PTPN1 recapitulated AD-like phenotypes in mice, including deficits in synaptic transmission and plasticity as well as memory by impairing the glutamate receptor 2 membrane insertion. Most importantly, rebuilding the miR-124/PTPN1 pathway by suppression of miR-124, overexpression of PTPN1, or application of a peptide that disrupts the miR-124/PTPN1 interaction could restore synaptic failure and memory deficits.
Taken together, these results identified the miR-124/PTPN1 pathway as a critical mediator of synaptic dysfunction and memory loss in AD, and the miR-124/PTPN1 pathway could be considered as a promising novel therapeutic target for AD patients.
δ-Secretase, an age-dependent asparagine protease, cleaves both amyloid precursor protein (APP) and Tau and is required for amyloid plaque and neurofibrillary tangle pathologies in Alzheimer's ...disease (AD). However, whether δ-secretase activation is sufficient to trigger AD pathogenesis remains unknown. Here we show that the fragments of δ-secretase-cleavage, APP (586-695) and Tau(1-368), additively drive AD pathogenesis and cognitive dysfunctions. Tau(1-368) strongly augments BACE1 expression and Aβ generation in the presence of APP. The Tau(1-368) fragment is more robust than full-length Tau in binding active STAT1, a BACE1 transcription factor, and promotes its nuclear translocation, upregulating BACE1 and Aβ production. Notably, Aβ-activated SGK1 or JAK2 kinase phosphorylates STAT1 and induces its association with Tau(1-368). Inhibition of these kinases diminishes stimulatory effect of Tau(1-368). Knockout of STAT1 abolishes AD pathologies induced by δ-secretase-generated APP and Tau fragments. Thus, we show that Tau may not only be a downstream effector of Aβ in the amyloid hypothesis, but also act as a driving force for Aβ, when cleaved by δ-secretase.
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