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Noble metal nanozymes hold promise in cancer therapy due to adjustable enzyme-like activities, unique physicochemical properties, etc. But catalytic activities of monometallic nanozyme are confined. In this study, 2D titanium carbide (Ti 3 C 2 T x )-supported RhRu alloy nanoclusters (RhRu/Ti 3 C 2 T x ) are prepared by a hydrothermal method and utilized for synergistic therapy of chemodynamic therapy (CDT), photodynamic therapy (PDT), and photothermal therapy (PTT) on osteosarcoma. The nanoclusters are small in size (3.6 nm), uniform in distribution, and have excellent catalase (CAT) and peroxidase (POD)-like activities. Density functional theory calculations show that there is a significant electron transfer interaction between RhRu and Ti 3 C 2 T x , which has strong adsorption to H 2 O 2 and is beneficial to enhance the enzyme-like activity. Furthermore, RhRu/Ti 3 C 2 T x nanozyme acts as both PTT agent for converting light into heat, and photosensitizer for catalyzing O 2 to 1 O 2 . With the NIR-reinforced POD- and CAT-like activity, excellent photothermal and photodynamic performance, the synergistic CDT/PDT/PTT effect of RhRu/Ti 3 C 2 T x on osteosarcoma is verified by in vitro and in vivo experiments. This study is expected to provide a new research direction for the treatment of osteosarcoma and other tumors., (© 2023 Wiley-VCH GmbH.)

Prostate cancer (PCa) is one of the most common cancers in men. Patients with recurrent disease initially respond to androgen-deprivation therapy, but the tumor eventually progresses into castration-resistant PCa. Thus, new therapeutic approaches for PCa resistance to current treatments are urgently needed. Here, we report that cardiac glycoside neriifolin suppresses the malignancy of cancer cells via increasing DNA damage and apoptosis through activation of endoplasmic reticulum stress (ERS) in prostate cancers. We found that cardiac glycoside neriifolin markedly inhibited the cell growth and induced apoptosis in prostate cancer cells. Transcriptome sequence analysis revealed that neriifolin significantly induced DNA damage and double strand breaks (DSBs), validated with attenuation expression of genes in DSBs repair and increasing phosphorylated histone H2AX (γ-H2AX) foci formation, a quantitative marker of DSBs. Moreover, we found that neriifolin also activated ERS, evidenced by upregulation and activation of ERS related proteins, including eukaryotic initiation factor 2α (eIF2α), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and C/EBP homologous protein (CHOP) as well as downregulation of CCAATenhancerbinding protein alpha (C/EBP-α), a transcriptional factor that forms heterodimers with CHOP. In addition, neriifolin treatment dramatically inhibited the by tumor growth, which were reversed by CHOP loss or overexpression of C/EBP-α in nude mice. Mechanistically, neriifolin suppressed the tumor growth by increasing DNA damage and apoptosis through CHOP-C/EBP-α signaling axis of ERS in prostate cancers. Taken together, these results suggest that cardiac glycoside neriifolin may be a potential tumor-specific chemotherapeutic agent in prostate cancer treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Protein kinase C epsilon (PKCε) belongs to a family of serine/threonine kinases that control cell proliferation, differentiation and survival. Aberrant PKCε activation and overexpression is a frequent feature of numerous cancers. However, its role in regulation of lipid metabolism in cancer cells remains elusive. Here we report a novel function of PKCε in regulating of prostate cancer cell proliferation by modulation of PKM2-mediated de novo lipogenesis. We show that PKCε promotes de novo lipogenesis and tumor cell proliferation via upregulation of lipogenic enzymes and lipid contents in prostate cancer cells. Mechanistically, PKCε interacts with NABD (1-388) domain of C-terminal deletion on pyruvate kinase isoform M2 (PKM2) and enhances the Tyr105 phosphorylation of PKM2, leading to its nuclear localization. Moreover, forced expression of mutant Tyr105 (Y105F) or PKM2 inhibition suppressed de novo lipogenesis and cell proliferation induced by overexpression of PKCε in prostate cancer cells. In a murine tumor model, inhibitor of PKM2 antagonizes lipogenic enzymes expression and prostate cancer growth induced by overexpression of PKCε in vivo. These data indicate that PKCε is a critical regulator of de novo lipogenesis, which may represent a potential therapeutic target for the treatment of prostate cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The toll-like receptor 4 (TLR4) pathway is involved in seizures. We investigated whether ultrasound-targeted microbubble destruction (UTMD)-mediated delivery of short hairpin RNA (shRNA) targeting the TLR4 gene (shRNA-TLR4) can reduce ischemia-induced seizures in rats with hyperglycemia. A total of 100 male Wistar rats were randomly assigned to five groups: (1) Sham; (2) normal saline (NS); (3) shRNA-TLR4, where rats were injected with shRNA-TLR4; (4) shRNA-TLR4 + US, where rats were injected with shRNA-TLR4 followed by ultrasound (US) irradiation; and (5) shRNA-TLR4 + microbubbles (MBs) + US, where rats were injected with shRNA-TLR4 mixed with MBs followed by US irradiation. Western blot and immunohistochemical staining were used to measure TLR4-positive cells. Half of the rats in the NS group developed tonic-clonic seizures, and TLR4 expression in the CA3 region of the hippocampus was increased in these rats. In addition, the NS group showed an increased number of TLR4-positive cells compared with the Sham group, while there was a decreased number of TLR4-positive cells in the shRNA, shRNA + US, and shRNA + MBs + US groups. Our findings indicate that the TLR4 pathway is involved in the pathogenesis of ischemia-induced seizures in hyperglycemic rats and that UTMD technology may be a promising strategy to treat brain diseases., Competing Interests: Conflict of interest: Authors state no conflict of interest., (© 2022 the author(s), published by De Gruyter.)

T cell receptor-engineered T cells (TCR-Ts) have emerged as potent cancer immunotherapies. While most research focused on classical cytotoxic CD8 + T cells, the application of CD4 + T cells in adoptive T cell therapy has gained much interest recently. However, the cytotoxic mechanisms of CD4 + TCR-Ts have not been fully revealed. In this study, we obtained an MHC class I-restricted MART-1 27-35 -specific TCR sequence based on the single-cell V(D)J sequencing technology, and constructed MART-1 27-35 -specific CD4 + TCR-Ts and CD8 + TCR-Ts. The antitumor effects of CD4 + TCR-Ts were comparable to those of CD8 + TCR-Ts in vitro and in vivo . To delineate the killing mechanisms of cytotoxic CD4 + TCR-Ts, we performed single-cell RNA sequencing and found that classical granule-dependent and independent cytolytic pathways were commonly used in CD4 + and CD8 + TCR-Ts, while high expression of LTA and various costimulatory receptors were unique features for cytotoxic CD4 + TCR-Ts. Further signaling pathway analysis revealed that transcription factors Runx3 and Blimp1/Tbx21 were crucial for the development and killing function of cytotoxic CD4 + T cells. Taken together, we report the antitumor effects and multifaceted killing mechanisms of CD4 + TCR-Ts, and also indicate that MHC class I-restricted CD4 + TCR-Ts could serve as potential adoptive T cell therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liang, Xu, Liu, Li, Wang, Li, Liao, Lu, Li, Mu, Sun and Zhu.)

Obstetric posterior reversible encephalopathy syndrome (PRES), caused by preeclampsia (PE) or eclampsia, is a clinical imaging syndrome and a critical maternal complication, with vasogenic edema in white matter as a typical imaging characteristic. Serum neurofilament light (NFL) is a marker of neuroaxonal injury. Therefore, we performed this study to explore the diagnostic and prognostic role of NFL in obstetric PRES. We used stored serum samples and clinical data obtained from 2148 PE or eclampsia patients from the Guangzhou Medical Centre for Critical Pregnant Women from January 2015 to January 2020. The serum NFL concentration was measured by Simoa assay. Patients without complete data and MRI examinations were excluded. All patients were grouped into the PRES and non-PRES groups based on the PRES diagnostic criteria. In total, 222 patients met the inclusion criteria and were grouped into the PRES (n = 123) and non-PRES (n = 99) groups. The NFL level was significantly higher in the PRES group than in the non-PRES group (p < 0.0001). The discriminatory accuracy of diagnostic panels (headaches + NFL, NFL) in receiver operating characteristic curve analysis (area under the curve) was 0.9338 and 0.7664. Importantly, the NFL level was significantly correlated with edema severity (Spearman's correlation, p < 0.0001), and a poorer pregnancy outcome was observed in the PRES group. In conclusion, an increased NFL level can add predictive value for diagnosing obstetric PRES, and its level is associated with both clinical severity and pregnancy outcome, suggesting that NFL could serve as a diagnostic and prognostic biomarker for obstetric PRES., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

With increasing industrial activities, mercury has been largely discharged into environment and caused serious environmental problems. The growing level of mercury pollution has become a huge threat to human health due to its significant biotoxicity. Therefore, the simple and fast means for on-site monitoring discharged mercury pollution are highly necessary to protect human beings from its pernicious effects in time. Herein, a "turn off" fluorescent biosensor (mCherry L199C) for sensing Hg 2+ was successfully designed based on direct modification of the chromophore environment of fluorescent protein mCherry. For rapid screening and characterization, the designed variant of mCherry (mCherry L199C) was directly expressed on outer-membrane of  Escherichia coli cells by cell surface display technique. The fluorescent biosensor was characterized to have favorable response to Hg 2+ at micromole level among other metal ions and over a broad pH range. Further, the cells of the fluorescent biosensor were encapsulated in alginate hydrogel to develop the cells-alginate hydrogel-based paper. The cells-alginate hydrogel-based paper could detect mercury pollution in 5 min with simple operation process and inexpensive equipment, and it could keep fluorescence and activity stable at 4 °C for 24 hr, which would be a high-throughput screening tool in preliminarily reporting the presence of mercury pollution in natural setting., (Copyright © 2021. Published by Elsevier B.V.)

Leptin is an adipocytokine that is primarily secreted by white adipose tissue, and it contributes to the pathogenesis of neuropathic pain in collaboration with N-methyl-D-aspartate receptors (NMDARs). Functional NMDARs are a heteromeric complex that primarily comprise two NR1 subunits and two NR2 subunits. NR2A is preferentially located at synaptic sites, and NR2B is enriched at extrasynaptic sites. The roles of synaptic and extrasynaptic NMDARs in the contribution of leptin to neuropathic pain are not clear. The present study examined whether the important role of leptin in neuropathic pain was related to synaptic or extrasynaptic NMDARs. We used a rat model of spared nerve injury (SNI) and demonstrated that the intrathecal administration of the NR2A-selective antagonist NVP-AAM077 and the NR2B-selective antagonist Ro25-6981 prevented and reversed mechanical allodynia following SNI. Administration of exogenous leptin mimicked SNI-induced behavioral allodynia, which was also prevented by NVP-AAM077 and Ro25-6981. Mechanistic studies showed that leptin enhanced NR2B- but not NR2A-mediated currents in spinal lamina II neurons of naïve rats. Leptin also upregulated the expression of NR2B, which was blocked by the NR2B-selective antagonist Ro25-6981, in cultured dorsal root ganglion (DRG) neurons. Leptin enhanced neuronal nitric oxide synthase (nNOS) expression, which was also blocked by Ro25-6981, in cultured DRG cells. However, leptin did not change NR2A expression, and the NR2A-selective antagonist NVP-AAM077 had no effect on leptin-enhanced nNOS expression. Our data suggest an important cellular link between the spinal effects of leptin and the extrasynaptic NMDAR-nNOS-mediated cellular mechanism of neuropathic pain.

Background: Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical-imaging syndrome as well as a critical maternal complication. The precise pathophysiological mechanism remains controversial, mostly due to the lack of a reliable experimental animal model. Because women with eclampsia almost always present with RPLS as a complication, we hypothesize that seizures induced by preeclampsia may lead to RPLS in rats., Methods: Pregnant Sprague-Dawley rats received pentylenetetrazol (PTZ, 40 mg/kg, intraperitoneal injection) after lipopolysaccharide (LPS, 1 µg/kg, tail vein injection) to induce eclampsia-like seizures. An anatomical view and brain water content were used to ascertain the success of the model. Moreover, blood pressure, serum biochemical indicators, serum and cerebrospinal fluid (CSF) inflammatory factors, neuroinflammation markers (Iba-1 for microglia and GFAP for astrocytes by immunofluorescence) and blood brain barrier (BBB) injury markers (VE-cadherin and ZO-1 protein by Western blotting) were measured to determine the possible mechanism., Results: The rat cerebral cortex was congested and oedematous, and water contents were significantly higher following LPS and PTZ treatments. Additionally, the BP, serum and CSF inflammatory factors and neuroinflammation markers were significantly elevated, while the expression levels of VE-cadherin and ZO-1 protein were significantly decreased by LPS and PTZ treatments., Conclusions: Excess inflammation may account for the phenotypes observed in this possible eclamptic RPLS rat model induced by LPS and PTZ, providing a better understanding of mechanism of RPLS. Specifically, excess inflammation leads to BBB dysfunction and subsequently results in fluid leakage that causes lesions and increases the entrance of inflammatory factors into the brain, thus increasing the neuronal excitability that triggers seizures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The pandemic of the coronavirus disease (COVID-19) poses a huge challenge all countries, since no one is well prepared for it. To be better prepared for future pandemics, we evaluated association between the internet search data with reported COVID-19 cases to verify whether it could become an early indicator for emerging epidemic. After the keyword filtering and Index composition, we found that there were close correlations between Composite Index and suspected cases for COVID-19 (r = 0.921, P  < 0.05). The Search Index was applied for the Autoregressive Integrated Moving Average with Exogenous Variables (ARIMAX) model to quantify the relationship. Compared with the model based on surveillance data only, the ARIMAX model had smaller Akaike Information Criterion (AIC = 403.51) and the most accurate predictive values. Overall, the Internet search data could serve as a convenient indicator for predicting the epidemic and to monitor its trends., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

Purpose: Posterior reversible encephalopathy syndrome (PRES), defined by its clinical and imaging manifestations, is a critical maternal complication. The specific pathophysiological mechanism of PRES has not been fully elucidated and remains controversial. Recently, several case studies reported that hypomagnesemia is present in the acute phase of PRES regardless of its etiology. Moreover, magnesium sulfate is a conventional treatment for preeclampsia (PE) and eclampsia; therefore, we hypothesized that hypomagnesemia might play an important role in the cascades involved in PRES in PE or eclampsia., Method: We consecutively collected PE and eclampsia patients who were examined via magnetic resonance imaging (MRI) and tested for magnesium levels between January 2013 and January 2017. All patients were grouped into PRES and non-PRES groups based on MRI results. Demographic data, magnesium levels and imaging features were collected retrospectively., Results: A total of 72 patients met the inclusion criteria; these participants were sorted into PRES (n = 38) and non-PRES (n = 34) groups. Twenty-four patients (63%) in the PRES group and 2 patients (6%) in the non-PRES group presented hypomagnesemia. Moreover, magnesium levels were significantly lower in the PRES group during both the acute phase (p < 0.001) and the post-phase (p = 0.04) than in the non-PRES group. However, there was no correlation between magnesium levels and edema severity during the acute phase., Conclusions: These results demonstrate that hypomagnesemia frequently occurs in the acute phase of obstetric PRES and suggest a potential relationship between them. Such a connection would support the application of magnesium sulfate in PE and eclampsia patients to prevent PRES. However, additional randomized trials are needed., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Glioblastoma multiforme (GBM) is the most prevalent and lethal malignant intracranial tumor in the brain, with very poor prognosis and survival. The epidermal growth factor receptor variant III (EGFRvIII) contributes to increased oncogenicity that does not occur through binding EGFR ligands and instead occurs through constitutive activation, which enhances glioma tumorigenicity and resistance to targeted therapy. Aptamers are nucleic acids with high affinity and specificity to targets selected by systematic evolution of ligands by exponential enrichment (SELEX), and are usually developed as antagonists of disease-associated factors. Herein, we generated a DNA aptamer U2, targeting U87-EGFRvIII cells, and demonstrated that U2 alters the U87-EGFRvIII cell growth, radiosensitivity, and radiotherapy of glioblastoma cells. We detected U2 and U87-EGFRvIII cells by flow cytometry and confocal microscopy to explore the binding ability of U2 to U87-EGFRvIII cells. Then, we found that aptamer U2 inhibits the proliferation, migration, invasion, and downstream signaling of U87-EGFRvIII cells. Moreover, the U2 aptamer can increase the radiosensitivity of U87-EGFRvIII in vitro and has a better antitumor effect on 188 Re-U2 in vivo. Therefore, the results revealed the promising potential of the U2 aptamer to be a new type of drug candidate and aptamer-targeted drug delivery system for glioblastoma therapy., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The neuroprotective effects of kallidinogenase against acute cerebral infarction have been demonstrated, and the use of microbubbles has been suggested as a therapeutic mechanism for drug delivery. This study was designed to investigate the optimal parameters for preparing kallidinogenase-loaded microbubbles (KLMs) and to evaluate the effects of KLM-targeted therapy on neurogenesis and angiogenesis following experimental acute cerebral infarction in rats., Materials and Methods: KLMs were prepared by mechanical shaking. Male Wistar rats were randomly divided into an ultrasound-mediated KLM-treated group and 4 control groups. Treatments were administered via daily tail vein injection on 6 consecutive days, starting at 24 hours after middle cerebral artery occlusion (MCAO). The ultrasound-treated groups were subjected to a 2-MHz pulse of ultrasonic irradiation on the lateral skull of the ischemic side for 10 minutes during injection. Cell proliferation was examined using a 5-bromo-2-deoxyuridine assay. Infarct volume and neurological function were evaluated on days 3 and 7 after MCAO., Results: The ultrasound-mediated KLM and kallidinogenase treatments significantly increased the numbers of doublecortin-immunoreactive cells in the subventricular zone (SVZ) and laminin + cells in the peri-infarction region on day 7 after MCAO, compared with the other 3 groups (all P <.05). The neurological function scores of the ultrasound-mediated KLM-treated group were significantly better than those of rats treated with kallidinogenase alone or with the other treatments (all P <.05)., Conclusions: Treatment with the ultrasound-mediated KLMs promoted the proliferation of SVZ neuroblasts and vascular regeneration, which contributed to functional improvement after stroke. These findings provide a novel therapy for ischemic stroke., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Endotoxin tolerance is induced by exposure to a repeated LPS challenge. Stress can exacerbate LPS-induced inflammation in the mouse hippocampus. However, the effects of stress on endotoxin tolerance have not been elucidated. The present experiments were designed to assess whether tolerance could be induced in the hippocampus by intraperitoneal injection of LPS at a dose of 250μg/kg for 7days, to investigate the effects of chronic unpredictable stress (CUS) on LPS-induced tolerance, and to assess underlying mechanisms in male Kunming mice. The levels of IL-1β in the hippocampus increased to a plateau after 4days of LPS injection. When the CUS protocol was performed with concurrent LPS injections for 7days, body weight decreased, and IL-1β expression in the hippocampus increased simultaneously. The expression of TLR4-MyD88-NF-κB signaling molecules and their negative regulators (PI3K, Akt) were also analyzed on day 7 after the last injection. The mRNA expression of TLR4 and MyD88 and the protein levels of TLR4 and NF-κBp65 were significantly increased, but the protein levels of PI3K and p-Akt were significantly decreased in the hippocampus of the mice. In conclusion, our findings show that endotoxin tolerance in the hippocampus was induced after four days of peripheral LPS challenge at a dose of 250μg/kg per day, and CUS abrogated this effect. CUS abolished endotoxin tolerance by reducing PI3K-mediated inhibition of TLR4-MyD88-NF-κB signaling pathways., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A highly efficient and environmentally-friendly oxidation process is always desirable for air purification. This study reported a novel carbon quantum dots (CQDs)/ZnFe 2 O 4 composite photocatalyst for the first time through a facile hydrothermal process. The CQDs/ZnFe 2 O 4 (15 vol %) composite demonstrates stronger transient photocurrent response, approximately 8 times higher than that of ZnFe 2 O 4 , indicating superior transfer efficiency of photogenerated electrons and separation efficiency of photogenerated electron-hole pairs. Compared with pristine ZnFe 2 O 4 nanoparticles, CQDs/ZnFe 2 O 4 displayed enhanced photocatalytic activities on gaseous NO x removal and high selectivity for nitrate formation under visible light (λ > 420 nm) irradiation. Electron spin resonance analysis and a series of radical-trapping experiments showed that the reactive species contributing to NO elimination were ·O 2 - and ·OH radicals. The possible mechanisms were proposed regarding how CQDs improve the photocatalytic performance of ZnFe 2 O 4 . The CQDs are believed to act as an electron reservoir and transporter as well as a powerful energy-transfer component during the photocatalysis processes over CQDs/ZnFe 2 O 4 samples. Furthermore, the toxicity assessment authenticated good biocompatibility and low cytotoxity of CQDs/ZnFe 2 O 4 . The results of this study indicate that CQDs/ZnFe 2 O 4 is a promising photocatalyst for air purification.

Purpose: Post-stroke seizures are considered as a major cause of epilepsy in adults. The pathophysiologic mechanisms resulting in post-stroke seizures are not fully understood. The present study attempted to reveal a new mechanism underlying neuronal hyperexcitability responsible to the seizure development after ischemic stroke., Methods: Transient global ischemia was produced in adult Wistar rats using the 4-vessel occlusion (4-VO) method. The spontaneous behavioral seizures were defined by the Racine scale III-V. The neuronal death in the brain was determined by hematoxylin-eosin staining. The expression levels of A-type potassium channels were analyzed by immunohistochemical staining and western blotting., Results: We found that the incidence of spontaneous behavioral seizures increased according to the severity of ischemia with 0% after 15-min ischemia and ∼50% after 25-min ischemia. All behavioral seizures occurred with 48h after ischemia. Morphological analysis indicated that brain damage was not correlated with behavioral seizures. Immunohistochemical staining showed that the expression levels of the A-type potassium channel subunit Kv4.2 was significantly reduced in ischemic brains with behavioral seizures, but not in ischemic brains without seizures. In addition, rats failing to develop spontaneous behavioral seizures within 2days after ischemia were more sensitive to bicuculline-induced seizures at 2 months after ischemia than control rats. Meanwhile, Kv4.2 expression was decreased in brain at 2 months after ischemia., Conclusion: Our results demonstrated the reduction of Kv4.2 expression might contribute to the development of post-ischemic seizures and long-term increased seizure susceptibility after ischemia. The mechanisms underlying post-stroke seizures and epilepsy is unknown so far. The down-regulation of IA channels may explained the abnormal neuronal hyperexcitability responsible for the seizure development after ischemic stroke., (Copyright © 2016 Elsevier B.V. All rights reserved.)