A PTER-dependent pathway of taurine metabolism linked to energy balance.

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in biosynthesis of taurine from cysteine as well as the downstream derivatization of taurine into secondary taurine metabolites4,5. One such taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by diverse physiologic perturbations that alter taurine and/or acetate flux, including endurance exercise7, nutritional taurine supplementation8, and alcohol consumption6,9. While taurine N-acetyltransferase activity has been previously detected in mammalian cells6,7, the molecular identity of this enzyme, and the physiologic relevance of N-acetyltaurine, have remained unknown. Here we show that the orphan body mass index-associated enzyme PTER (phosphotriesterase-related)10 is the principal mammalian taurine N-acetyltransferase/hydrolase. In vitro, recombinant PTER catalyzes bidirectional taurine N-acetylation with free acetate as well as the reverse N-acetyltaurine hydrolysis reaction. Genetic ablation of PTER in mice results in complete loss of tissue taurine N-acetyltransferase/hydrolysis activities and systemic elevation of N-acetyltaurine levels. Upon stimuli that increase taurine levels, PTER-KO mice exhibit lower body weight, reduced adiposity, and improved glucose homeostasis. These phenotypes are recapitulated by administration of N-acetyltaurine to wild-type mice. Lastly, the anorexigenic and anti-obesity effects of N-acetyltaurine require functional GFRAL receptors. Together, these data uncover enzymatic control of a previously enigmatic pathway of secondary taurine metabolism linked to energy balance.

Development of a multiparametric model for predicting the response to neoadjuvant chemotherapy in breast cancer.

Background: Choosing the appropriate treatment early and predicting the efficacy of neoadjuvant chemotherapy (NAC) for locally advanced breast cancer patients are of particular importance for clinicians. Developing and validating a multiparametric model for predicting NAC would be very meaningful for clinical practice. Methods: This study included 91 patients with locally advanced breast cancer treated from 2016 to 2020. The correlation between multiparametric characteristics and the efficacy of NAC was examined. The data were randomly divided into training and validation sets. A least absolute shrinkage and selection operator (LASSO) regression analysis was used for the variable screening. A multivariable logistic regression analysis was used to construct the model. Calibration and decision curves were used to assess the performance of the established model. Results: Lymph node metastasis, the first standard apparent diffusion coefficient (ADC) at the baseline, the change in the standard ADC at the first follow-up, the change in tumor volume at the first follow-up, and the clinical stage of the tumor at the baseline were selected for inclusion in the model. In the receiver operating characteristic (ROC) analysis, the areas under the curve (AUCs) were 0.984 [95% confidence interval (CI): 0.958-1] and 0.815 (95% CI: 0.509-1) for the primary and validation cohorts, respectively. The utility of the established model was confirmed by calibration and decision curves, and a nomogram was obtained. Conclusions: A multiparametric model based on clinical-pathological-magnetic resonance imaging (MRI) features was established to predict the effect of NAC in patients with locally advanced breast cancer.

Role of Huangqin Decoction in Intestinal Homeostasis and Colon Carcinogenesis Based on "SREBP1 Cholesterol Metabolism Treg Cell Differentiation".

Objective: To explore the role of Huangqin Decoction in intestinal homeostasis maintenance and colon carcinogenesis based on "sterol regulatory element binding protein-1c (SREBP-1)-cholesterol metabolism regulatory T cell (Treg) differentiation." Methods: It was decided to utilize a total of 50 healthy Wistar rats for the study, 20 of which were chosen at random to serve as controls, and 30 of which were used to create an intestinal homeostasis imbalance model. It was determined whether or not the modeling was successful by killing 10 rats from each of the two groups. The remaining 10 rats in the normal group were then employed as the control group for the experiment. The random number table method was used to split the rats into two groups: the Huangqin Decoction (n = 10) and the Natural Recovery (n = 10) groups. For seven days, participants in the Huangqin Decoction group received the herb, whereas those in the natural healing group received normal saline. The relative density of SREBP1, the levels of cholesterol ester (CE), free cholesterol (FC), total cholesterol (TC), and Treg cells were detected and compared. Results: When compared to the control group, the relative density of SREBP1 increased significantly before administration in the Huangqin Decoction group and the natural recovery group, but decreased significantly after administration, with statistical significance (P < 0.05) in the Huangqin Decoction group and the natural recovery group; the Huangqin Decoction group and natural recovery group had significantly higher levels of CE, FC, and TC than the control group before to administration, and these levels increased significantly after administration. CE, FC, and TC levels in Huangqin Decoction and natural recovery groups were much lower than those in natural recovery groups, and the difference was statistically significant (P < 0.05), according to the results; Prior to administration, Treg cell levels in Huangqin Decoction group and the natural recovery group were significantly higher, and Treg cell levels in the Huangqin Decoction group and natural recovery group were significantly lower after administration; the decrease in the Huangqin Decoction group was significantly greater than that in natural recovery group. P < 0.05 indicated that the difference was significant. Conclusion: Using Huangqin Decoction, one may efficiently regulate SREBP1, cholesterol metabolism, and Treg cell development, all of which play an important role in maintaining intestinal stability and minimizing the incidence of colon cancer.

Immune microenvironment and clinical feature analyses based on a prognostic model in lymph node-positive breast cancer.

Background: If lymph node metastasis occurs in breast cancer patients, the disease can progress rapidly. Based on the infiltrative immune cells of breast cancer patients with lymph node positivity, we constructed the LNPRS for selecting prognostic predictors. Methods: The LNPRS was established and the predictive value of the LNPRS was verified by independent testing cohorts. A nomogram was also established to confirm the therapeutic guidance significance of the LNPRS. The correlation of the LNPRS with tumor mutation burden, immune microenvironment score, immune checkpoints, the proportion of tumor-infiltrating immune cells, and GSEA and GSVA enrichment pathways were also evaluated. Results: In the training cohort, the overall survival of breast cancer patients who had high LNPRS was shorter than that of patients who had low LNPRS (7.98 years versus 20.42 years, P-value< 8.16E-11). The AUC values for 5-, 10-, and 15-years were 0.787, 0.739, and 0.800, respectively. The ability to predict prognosis for the LNPRS was also tested in 3 independent testing cohorts. Furthermore, the predictive value of the LNPRS for chemotherapy and immunotherapy was also proven. The GSEA and GSVA showed that the LNPRS was closely related to the activation of T and B lymphocytes and IFN-γ secretion. Moreover, breast cancer patients with low LNPRS had higher TME scores than those with high LNPRS. Conclusion: We can conclude that the LNPRS is a robust prognostic biomarker in breast cancer patients with positive lymph nodes and may be helpful for patients to make a clinical decision.

Multifunctional Mesoporous Hollow Cobalt Sulfide Nanoreactors for Synergistic Chemodynamic/Photodynamic/Photothermal Therapy with Enhanced Efficacy.

The unique tumor microenvironment (TME) characteristic of severe hypoxia, overexpressed intracellular glutathione (GSH), and elevated hydrogen peroxide (H2O2) concentration limit the anticancer effect by monotherapy. In this report, glucose oxidase (GOx)-encapsulated mesoporous hollow Co9S8 nanoreactors are constructed with the coverage of polyphenol diblock polymers containing poly(oligo(ethylene glycol) methacrylate) and dopamine moieties containing methacrylate polymeric block, which are termed as GOx@PCoS. After intravenous injection, tumor accumulation, and cellular uptake, GOx@PCoS deplete GSH by Co3+ ions. GOx inside the nanoreactors produce H2O2 via oxidation of glucose to enhance •OH-based chemodynamic therapy (CDT) through the Fenton-like reaction under the catalysis of Co2+. Moreover, Co3+ ions possess catalase activity to catalyze production of O2 from H2O2 to relieve tumor hypoxia. Upon 808 nm laser irradiation, GOx@PCoS exhibit photothermal and photodynamic effects with a high photothermal conversion efficiency (45.06%) and generation capacity of the toxic superoxide anion (•O2-) for photothermal therapy (PTT) and photodynamic therapy (PDT). The synergetic antitumor effects can be realized by GSH depletion, starvation, and combined CDT, PTT, and PDT with enhanced efficacy. Notably, GOx@PCoS can also be used as a magnetic resonance imaging (MRI) contrast agent to monitor the antitumor performance. Thus, GOx@PCoS show great potentials to effectively modulate TME and perform synergistic multimodal therapy.

Protein-Delivering Nanocomplexes with Fenton Reaction-Triggered Cargo Release to Boost Cancer Immunotherapy.

Immunotherapeutic efficacy of tumors based on immune checkpoint blockade (ICB) therapy is frequently limited by an immunosuppressive tumor microenvironment and cross-reactivity with normal tissues. Herein, we develop reactive oxygen species (ROS)-responsive nanocomplexes with the function of ROS production for delivery and triggered release of anti-mouse programmed death ligand 1 antibody (αPDL1) and glucose oxidase (GOx). GOx and αPDL1 were complexed with oligomerized (-)-epigallocatechin-3-O-gallate (OEGCG), which was followed by chelation with Fe3+ and coverage of the ROS-responsive block copolymer, POEGMA-b-PTKDOPA, consisting of poly(oligo(ethylene glycol)methacrylate) (POEGMA) and the block with thioketal bond-linked dopamine moieties (PTKDOPA) as the side chains. After intravenous injection, the nanocomplexes show prolonged circulation in the bloodstream with a half-life of 8.72 h and efficient tumor accumulation. At the tumor sites, GOx inside the nanocomplexes can produce H2O2 via oxidation of glucose for Fenton reaction to generate hydroxyl radicals (•OH) which further trigger the release of the protein cargos through ROS-responsive cleavage of thioketal bonds. The released GOx improves the production efficiency of •OH to kill cancer cells for release of tumor-associated antigens via chemodynamic therapy (CDT). The enhanced immunogenic cell death (ICD) can activate the immunosuppressive tumor microenvironment and improve the immunotherapy effect of the released αPDL1, which significantly suppresses primary and metastatic tumors. Thus, the nanocomplexes with Fenton reaction-triggered protein release show great potentials to improve the immunotherapeutic efficacy of ICB via combination with CDT.

Predicting pathologic response to neoadjuvant chemotherapy in patients with locally advanced breast cancer using multiparametric MRI.

BACKGROUND: This study aims to observe and analyze the effect of diffusion weighted magnetic resonance imaging (MRI) on the patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy. METHODS: Fifty patients (mean age, 48.7 years) with stage II-III breast cancer who underwent neoadjuvant chemotherapy and preoperative MRI between 2016 and 2020 were retrospectively evaluated. The associations between preoperative breast MRI findings/clinicopathological features and outcomes of neoadjuvant chemotherapy were assessed. RESULTS: Clinical stage at baseline (OR: 0.104, 95% confidence interval (CI) 0.021-0.516, P = 0.006) and standard apparent diffusion coefficient (ADC) change (OR: 9.865, 95% CI 1.024-95.021, P = 0.048) were significant predictive factors of the effects of neoadjuvant chemotherapy. The percentage increase of standard ADC value in pathologic complete response (pCR) group was larger than that in non-pCR group at first time point (P < 0.05). A correlation was observed between the change in standard ADC values and tumor diameter at first follow-up (r: 0.438, P < 0.05). CONCLUSIONS: Our findings support that change in standard ADC values and clinical stage at baseline can predict the effects of neoadjuvant chemotherapy for patients with breast cancer in early stage.

Hypoxia-Responsive Polyprodrug Nanocarriers for Near-Infrared Light-Boosted Photodynamic Chemotherapy.

The hypoxia environment inside tumors is tightly associated with tumor growth, metastasis, and drug resistance. However, the heterogonous distribution of hypoxic areas limits the efficacy of hypoxia-activatable drug delivery systems. Herein, we report the hypoxia-activable block copolymer polyprodrugs, which are composed of poly(ethylene glycol) (PEG) and copolymerized segments of ortho-nitrobenzyl-linked camptothecin (CPT) methacrylate and 2-(piperidin-1-yl)ethyl methacrylate (PEMA) monomers. After self-assembly in aqueous solution, indocyanine green (ICG) photosensitizers were encapsulated to formulate ICG-loaded micellar nanoparticles (ICG@CPTNB) for near-infrared (NIR) light-boosted photodynamic therapy (PDT), tumor hypoxia aggravation, and responsive drug activation. Through intravenous injection and prolonged blood circulation, the nanoparticles can accumulate into tumor efficiently. Tumor acidity-triggered charge transition of PEMA units remarkably promotes cellular internalization of the nanoparticles. Upon exposure to NIR laser irradiation, ICG inside the nanoparticles produced reactive oxygen species (ROS) along with local hypothermia. Simultaneously, the oxygen consumption during ROS production aggravated the intratumoral hypoxia, which amplified hypoxia-responsive self-immolative CPT release from the nanoparticles. The combined photodynamic chemotherapy using hypoxia-responsive polyprodrug nanoparticles, ICG@CPTNB, overcomes the limitations of single therapy of hypoxia-activable prodrugs or PDT, which remarkably improves the efficiency of tumor growth suppression.

Hypoxia-responsive block copolymer polyprodrugs for complementary photodynamic-chemotherapy.

The inherent hypoxic microenvironment of solid tumors has an important influence on tumor growth, distant metastasis, and invasiveness. The heterogeneous distribution of hypoxic regions inside tumors limits the therapeutic efficacy of O2-assisted therapeutic strategy (e.g. photodynamic therapy (PDT)). On the other hand, the hypoxia-activable prodrugs cannot work effectively in the regions with enough O2 concentration. To address the issues, we prepare a block copolymer polyprodrug consisting of polyethylene glycol (PEG) and copolymerized segments of nitroimidazole-linked camptothecin (CPT) methacrylate and 5,10,15,20-tetraphenylporphyrin (TPP)-containing methacrylate monomers for complementary photodynamic-chemotherapy. The polyprodrug can self-assemble into polymeric micelles in aqueous solution with suitable size and high stability. After intravenous injection, the polyprodrug micelles show tumor accumulation. Followed by light irradiation (650 nm) at tumor sites, TPP moieties induce singlet oxygen (1O2) production in the oxygen-rich area to exert PDT and cause transformation of the oxygen-rich areas into hypoxia. Simultaneously, in the hypoxic areas, the hypoxia-responsive polyprodrugs can be activated to release free CPT due to the cleavage of nitroimidazole linkages. The polyprodrug micelles with the segments for PDT and hypoxia-activable CPT efficiently suppress the growth of HeLa tumors. The well-defined polyprodrug amphiphiles offer an effective strategy to overcome the disadvantages of single treatment of PDT or hypoxia-responsive prodrugs for complementary photodynamic-chemotherapy of cancers.

Role of neutrophil-to-lymphocyte ratio as a prognostic biomarker in patients with breast cancer receiving neoadjuvant chemotherapy: a meta-analysis.

OBJECTIVE: The neutrophil-to-lymphocyte ratio (NLR) is recognised as a suitable prognostic biomarker in patients with breast cancer. Nevertheless, the efficacy of this biomarker in predicting the pathological complete response (pCR) and survival in patients with breast cancer receiving neoadjuvant chemotherapy (NACT) is still controversial. This meta-analysis aimed to identify the association between baseline NLR and the prognosis of patients with breast cancer treated with NACT. DESIGN: Meta-analysis. DATA SOURCES: Relevant literature published before 1 May 2021 was searched using the Cochrane Library, Embase, PubMed and the Web of Science databases. ELIGIBILITY CRITERIA: All studies involving patients with breast cancer treated with NACT and peripheral blood pretreatment NLR recorded as a dichotomous variable were included. DATA EXTRACTION AND SYNTHESIS: Two researchers independently extracted and evaluated OR/HR and its 95% CIs of survival outcomes and clinicopathological parameters. RESULTS: A total of 19 studies were identified. From each study, the impact of NLR on the pCR, OR and HR, with their 95% CIs were extracted and combined using either a random or fixed-effects model. The results indicate that a higher pCR in patients with a low NLR (OR 1.620, 95% CI 1.209 to 2.169, p＜0.001). In addition, an elevated NLR predicted lower disease-free survival (HR 2.269, 95% CI 1.557 to 3.307, p<0.001) and overall survival (HR 1.691, 95% CI 1.365 to 2.096, p<0.001) in patients with breast cancer treated with NACT. CONCLUSIONS: NLR is a suitable biomarker for predicting pCR and survival in patients with breast cancer receiving NACT.

Acid-responsive endosomolytic polymeric nanoparticles with amplification of intracellular oxidative stress for prodrug delivery and activation.

Prodrug strategy especially in the field of chemotherapy of cancers possesses significant advantages reducing the side toxicity of anticancer drugs. However, high-efficiency delivery and in situ activation of prodrugs for tumor growth suppression are still a great challenge. Herein, we report rationally engineered pH-responsive endosomolytic polymeric micelles for the delivery of an oxidation-activable prodrug into the cytoplasm of cancer cells and amplification of intracellular oxidative stress for further prodrug activation. The prepared block copolymers consist of a poly(ethylene glycol) (PEG) block and a segment grafted by endosomolytic moieties and acetal linkage-connected cinnamaldehyde groups. The amphiphilic diblock copolymers can self-assemble to form micelles in water for loading the oxidation-activable phenylboronic pinacol ester-caged camptothecin prodrug (ProCPT). The obtained micelles can release free cinnamaldehyde under acidic conditions in tumor tissues and endo/lysosomes followed by efficient endosomal escape, which further induces enhancement of intracellular reactive oxygen species (ROS) to activate the prodrugs. Simultaneously, intracellular glutathione (GSH) can be reduced by quinone methide that was produced during prodrug activation. The ProCPT-loaded micelles can finally achieve efficient tumor accumulation and retention as well as effective tumor growth inhibition. More importantly, hematological and pathological analysis of toxicity reveals that the ProCPT-loaded micelles do not cause obvious toxic side effects toward important organs of mice. A positive immunomodulatory microenvironment in tumor tissue and serum can be detected after treatment with ProCPT-loaded micelles. Therefore, the endosomolytic ProCPT-loaded micelles exert synergistic therapeutic effects toward tumors through amplification of intracellular oxidative stress and activation of the prodrugs.

Pretreatment systemic inflammation response index is predictive of pathological complete response in patients with breast cancer receiving neoadjuvant chemotherapy.

BACKGROUND: Inflammation plays an important role in tumor proliferation, metastasis, and resistance to chemotherapy. The systemic inflammation response index (SIRI), has been reported to be closely related to prognosis in many tumors, such as breast and gastric cancers. However, the predictive value of pretreatment SIRI on pathological complete response (pCR) rates in patients with breast cancer treated with neoadjuvant chemotherapy (NAC) is unknown. This study examined the correlation between SIRI and pCR in patients with breast cancer receiving NAC and identified convenient and accurate predictive indicators for pCR. METHODS: We retrospectively analyzed the clinicopathological parameters and pretreatment peripheral blood characteristics of the 241 patients with breast cancer who received NAC between June 2015 and June 2020. Receiver operating characteristic (ROC) curves were used to determine the optimal cutoff of SIRI. ROC curves were also plotted to verify the accuracy of inflammatory markers for pCR prediction. The chi-squared test was used to explore the relationships of SIRI with pCR and other clinicopathological parameters. Multivariate analyses were performed using a logistic regression model. RESULTS: Among the 241 patients, 48 (19.92%) achieved pCR. pCR was significantly related to SIRI, the neutrophil-lymphocyte ratio (NLR), the lymphocyte-monocyte ratio (LMR), molecular subtypes and other clinicopathological parameters, such as BMI, clinical T and N staging, and histological grade. Multivariate analyses indicated that the clinical T and N staging, SIRI, and NLR were independent prognostic factors for pCR in patients with breast cancer. The area under the ROC curve for SIRI was larger than that for NLR. Compared to patients with SIRI ≥0.72, patients with SIRI < 0.72 had a nearly 5-fold higher chance of obtaining pCR (odds ratio = 4.999, 95% confidence interval = 1.510-16.551, p = 0.000). CONCLUSIONS: Pretreatment SIRI is predictive of pCR in patients with breast cancer receiving NAC, and the index can assist physicians in formulating personalized treatment strategies.

Cisplatin resistance reversal in lung cancer by tumor acidity-activable vesicular nanoreactors via tumor oxidative stress amplification.

Drug resistance of cisplatin significantly limits its therapeutic efficacy in clinical applications against different cancers. Herein, we develop a novel strategy to overcome cisplatin drug resistance through sensitizing cisplatin-resistant human lung cancer cells (A549R) under amplified oxidative stress using a vesicular nanoreactor for simultaneous cisplatin delivery and H2O2 generation. We engineer the nanoreactor by the self-assembly of the amphiphilic diblock copolymers to co-deliver glucose oxidase (GOD) and cisplatin (Cis) (Cis/GOD@Bz-V). Cis/GOD@Bz-V was rationally designed to stay impermeable during blood circulation while mild acidity (pH 6.5-6.8) can activate its molecular-weight selective membrane permeability and release cisplatin locally. Diffusion of small molecules such as oxygen and glucose across the membranes can induce the in situ generation of superfluous H2O2 to promote cellular oxidative stress and sensitize A549R cells via activation of pro-apoptotic pathways. Cis/GOD@Bz-V nanoreactors could effectively kill A549R at pH 6.8 in the presence of glucose by the combination of H2O2 generation and cisplatin release. Growth of A549R xenograft tumors can be inhibited efficiently without the obvious toxic side effects via the systemic administration of Cis/GOD@Bz-V. Accordingly, the tumor acidity-activable cisplatin-loaded nanoreactors show great potential to enhance the therapeutic efficacy against cisplatin-resistant cancers.

Ferrocene-containing polymersome nanoreactors for synergistically amplified tumor-specific chemodynamic therapy.

Chemodynamic therapy (CDT) has been proposed to convert tumoral H2O2 into toxic hydroxyl radicals (OH) via Fenton or Fenton-like reactions for antitumor efficacy, which is frequently limited by low H2O2 concentrations or lack of enough metal ions inside tumor tissues. In this report, we present ferrocene-containing responsive polymersome nanoreactors via loading glucose oxidase (GOD) and hypoxia-activable prodrug tirapazamine (TPZ) in the inner aqueous cavities. After intravenous injection, the polymersome nanoreactors with the optimized nanoparticle size of ~100 nm and poly(ethylene glycol) corona facilitate tumor accumulation. The tumor acidic microenvironment can trigger the permeability of the polymersome membranes to activate the nanoreactors and release the loaded TPZ prodrugs. Tumor oxygen and glucose can enter the polymersome nanoreactors and are transformed into H2O2 under the catalysis of GOD, which are further converted into OH via Fenton reaction under catalysis of ferrocene moieties. The oxygen consumption can aggravate tumor hypoxia to activate hypoxia-responsive TPZ prodrugs which can produce benzotriazinyl (BTZ) radicals and OH. All the produced radicals synergistically kill tumor cells via the amplified CDT and suppress the tumor growth efficiently. Thus, the ferrocene-containing responsive polymersome nanoreactors loading GOD and TPZ represent a potent nanoplatform to exert amplified CDT for improved anticancer efficacy.

Glutathione and Reactive Oxygen Species Dual-Responsive Block Copolymer Prodrugs for Boosting Tumor Site-Specific Drug Release and Enhanced Antitumor Efficacy.

A remarkable hallmark of cancer cells is the heterogeneous coexistence of overproduced intracellular glutathione (GSH) and a high level of reactive oxygen species (ROS) compared with those in normal cells, which have been frequently used as the stimuli to trigger drug release from the nanocarriers. Most of the stimuli-responsive delivery vehicles have been designed to respond to only one redox stimulus (e.g., GSH or ROS). Herein, we develop a GSH and ROS dual-responsive amphiphilic diblock copolymer prodrug (BCP) (GR-BCP) consisting of poly(ethylene glycol) (PEG)- and camptothecin (CPT)-conjugated poly(methacrylate) in the side chains via thioether bonds. In comparison, GSH or ROS single-responsive BCPs (G-BCPs or R-BCPs) were prepared, where CPT drugs were linked by disulfide or thioketal bonds, respectively. The three BCPs can form well-defined spherical micellar nanoparticles in an aqueous solution with a diameter of ∼50 nm. Compared with G-BCP and R-BCP, GR-BCP realized the highest cytotoxicity against HeLa cells with the half-inhibitory concentration (IC50) of 6.3 µM, which is much lower than 17.8 µM for G-BCP and 28.9 µM for R-BCP. Moreover, for in vivo antitumor performance, G-BCP, R-BCP, and GR-BCP showed similar efficiencies in blood circulation and tumor accumulation after intravenous injection. However, GR-BCP realized the most efficient tumor suppression with few side effects. Our findings demonstrate that intracellular GSH and ROS dual-responsive BCPs show a more efficient responsive drug release inside tumor cells for boosting the antitumor efficacy as compared with GSH or ROS single-responsive BCPs, which provides novel strategies for designing redox-responsive BCPs.

Length effect of stimuli-responsive block copolymer prodrug filomicelles on drug delivery efficiency.

Filomicelles possess some unique properties for improved in vivo drug delivery efficiency relative to commonly used spherical nanocarriers, which have attracted great interests. However, the length effect of the block copolymer prodrug-based filomicelles with a comparable cross-section diameter on the drug delivery efficiency and antitumor efficacy still need to be systematically studied. In this report, we prepare three optimized nanoparticles with a comparable cross-section diameter of ~40 nm, including long filomicelles (LFMs) with the length of ~2.5 µm, short filomicelles (SFMs) with the length of ~180 nm, and spherical micelles (SMs) with a diameter of ~40 nm. All of them are self-assembled from the pH and oxidation dual-responsive block copolymer prodrug, PEG-b-P(CPTKMA-co-PEMA), consisting of poly(ethylene glycol) (PEG) and a copolymerized block of thioketal-linked camptothecin methacrylate (CPTKMA) and 2-(pentamethyleneimino) ethyl methacrylate (PEMA). At pH 6.5, the nanoparticles are positively charged due to the protonation of PPEMA segments. Among them, SFMs are demonstrated to be internalized into cells most efficiently at pH 6.5 due to larger interaction areas with cell membranes relative to SMs. Moreover, SFMs show prolonged blood circulation similar to SMs as well as deepest tumor penetration and best antitumor efficacy among the three nanoparticles. LFMs show worst in vivo performance because their too long structure limits the cellular uptake and tumor accumulation. Therefore, the responsive polymer prodrug filomicelles with an optimized length show great potentials to overcome the physiological barriers and improve the drug delivery efficiency.

Endothelial Cdk5 deficit leads to the development of spontaneous epilepsy through CXCL1/CXCR2-mediated reactive astrogliosis.

Blood-brain barrier (BBB) dysfunction has been suggested to play an important role in epilepsy. However, the mechanism mediating the transition from cerebrovascular damage to epilepsy remains unknown. Here, we report that endothelial cyclin-dependent kinase 5 (CDK5) is a central regulator of neuronal excitability. Endothelial-specific Cdk5 knockout led to spontaneous seizures in mice. Knockout mice showed increased endothelial chemokine (C-X-C motif) ligand 1 (Cxcl1) expression, decreased astrocytic glutamate reuptake through the glutamate transporter 1 (GLT1), and increased glutamate synaptic function. Ceftriaxone restored astrocytic GLT1 function and inhibited seizures in endothelial Cdk5-deficient mice, and these effects were also reversed after silencing Cxcl1 in endothelial cells and its receptor chemokine (C-X-C motif) receptor 2 (Cxcr2) in astrocytes, respectively, in the CA1 by AAV transfection. These results reveal a previously unknown link between cerebrovascular factors and epileptogenesis and provide a rationale for targeting endothelial signaling as a potential treatment for epilepsy.

The synergistic effect of Au-COF nanosheets and artificial peroxidase Au@ZIF-8(NiPd) rhombic dodecahedra for signal amplification for biomarker detection.

Here, a new type of signal amplification strategy is proposed employing Au nanoparticle (AuNP)-functionalized covalent organic framework (Au-COF) nanosheets and AuNP functionalized ZIF-8(NiPd) (Au@ZIF-8(NiPd)) rhombic dodecahedra nanocomposites for sandwich electrochemical sensor construction. The peroxidase mimics Au@ZIF-8(NiPd) took the place of natural enzymes in enzyme-assisted amplification strategies, both acting as catalysts for H2O2 reduction for signal amplification, and serving as ideal nanocarriers for signal probe anchoring. The cancer biomarker thrombin (TB) was selected as the target. Thrombin binding aptamers (TBA 2) were fixed on Au@ZIF-8(NiPd), and the obtained TBA 2-Au@ZIF-8(NiPd) bioconjugates were employed as tracer labels, and TB was sandwiched between the tracer labels and capture probe TBA 1 which were immobilized on the Au-COF nanosheet modified electrode. Au-COFs with a high specific area, super electroconductivity, and uniformly distributed AuNPs were utilized as the electrode substrate to fix TBA 1. Exploiting the sandwich method, the proposed TB aptasensor exhibited a wide linear range of 0.1 pM to 20 nM with a low detection limit of 15 fM (S/N = 3). The ingenious sensing strategy enriched the application diversity of the artificial enzyme and showed promise in research and development of point-of-care diagnostics.

ROS-Responsive Polymeric Nanocarriers with Photoinduced Exposure of Cell-Penetrating Moieties for Specific Intracellular Drug Delivery.

In situ modulation of the surface properties on the micellar drug delivery nanocarriers offers an efficient method to improve the drug delivery efficiency into cells while maintaining stealth and stability during blood circulation. Light has been demonstrated to be a temporally and spatially controllable tool to improve cellular internalization of nanoparticles. Herein, we develop reactive oxygen species (ROS)-responsive mixed polymeric micelles with photoinduced exposure of cell-penetrating moieties via photodynamic ROS production, which can facilitate cellular internalization of paclitaxel (PTX) and chlorin e6 (Ce6)-coloaded micelles for the synergistic effect of photodynamic and chemotherapy. The thioketal-bond-linked block polymers poly(ε-caprolactone)-TL-poly(N,N-dimethylacrylamide) (PCL-TL-PDMA) with a long PDMA block are used to self-assemble into mixed micelles with PCL-b-poly(2-guanidinoethyl methacrylate) (PCL-PGEMA) consisting of a short PGEMA block, which are further used to coencapsulate PTX and Ce6. After intravenous injection, prolonged blood circulation of the micelles guarantees high tumor accumulation. Upon irradiation by 660 nm light, ROS production of the micelles by Ce6 induces cleavage of PDMA to expose PGEMA shells for significantly improved cellular internalization. The combination of photodynamic therapy and chemotherapy inside the tumor cells achieves improved antitumor efficacy. The design of ROS-responsive mixed polymeric nanocarriers represents a novel and efficient approach to realize both long blood circulation and high-efficiency cellular internalization for combined photodynamic and chemotherapy under light irradiation.

OsBBX14 promotes photomorphogenesis in rice by activating OsHY5L1 expression under blue light conditions.

In rice, OsBBX14, a B-box (BBX) transcription factor, reportedly delays heading. Here, we revealed that OsBBX14 positively regulates rice photomorphogenesis. The OsBBX14-overexpressing (OsBBX14-OX) seedlings were hypersensitive to light, especially blue light, and exhibited dwarfism, while the OsBBX14 knock-out plants (osbbx14) were taller than wild-type plants under blue light. Histological analyses indicated that the observed dwarfism was mainly due to decreased cell length. Additionally, OsBBX14 abundance (mRNA and protein levels) was influenced by different light wavelengths in a time-dependent manner. The expression levels of HY5Ls (LONG HYPOCOTYL 5 LIKE) and ELIPs (EARLY LIGHT-INDUCIBLE PROTEIN) genes, whose Arabidopsis thaliana homologs function as positive regulators in the light signaling pathway, were significantly upregulated in OsBBX14-OX lines. In contrast, the expression of genes related to cell wall organization and dwarfism was downregulated in OsBBX14-OX lines. Chromatin immunoprecipitation (ChIP) assays confirmed that OsBBX14 binds to the T/G-box of HY5L1 (LONG HYPOCOTYL 5 LIKE 1) promoter. LUC complementation imaging (LCI) results suggested that OsBBX14 had physical interaction with OsCRY2 protein. Collectively, in response to blue light, OsBBX14 promotes photomorphogenesis, probably by directly or indirectly regulating the expression of HY5L1 or other genes related to cell wall organization and dwarfism.