Permanent pacemaker reduction using temporary-permanent pacemaker as a 1-month bridge after transcatheter aortic valve replacement: a prospective, multicentre, single-arm, observational study.

Background: The permanent pacemaker (PPM) implantation and pacemaker dependency rates after transcatheter aortic valve replacement (TAVR) are highly variable as some of the conduction disturbances are reversible. It remains poorly investigated how to optimise temporary pacing in these patients. This study aimed to explore the potential reduction in the PPM implantation rate using temporary-permanent pacemaker (TPPM) as a 1-month bridge. Methods: This is a prospective, multicentre, single-arm, observational study. Consecutive patients undergoing TAVR from March 1, 2022 to March 1, 2023 in 13 tertiary hospitals in China were screened. Patients who developed high-degree atrioventricular block, complete heart block, or first-degree atrioventricular block plus new onset left bundle branch block during the TAVR procedure or within 1 month after TAVR were included to receive TPPM. Patients with pre-existing PPM implantation or indications for PPM implantation before the TAVR procedure were excluded. Patients with TPPM were monitored to determine whether the conduction disturbances persisted or recovered. The primary endpoint was the rate of freedom from indications for PPM implantation 1 month after TAVR. This study is registered with ChiCTR, ChiCTR2200057931. Findings: Of 688 patients who have undergone TAVR, 71 developed conduction disturbance and met the inclusion criteria, 1 patient withdrew due to noncompliance, 70 patients received TPPM and completed follow-up. There were 41 (58.6%) men and 29 (41.4%) women in the study, with a mean age of 74.3 ± 7.3 years. At 1 month follow-up, 75.7% (53/70) of the patients with TPPM did not require PPM implantation. For 688 patients who have undergone TAVR, the rate of PPM implantation at 1 month was 2.47% (17/688, 95% CI 1.55%-3.92%), representing a significant reduction in self-comparison with the rate at 48 h after TPPM (2.47% vs. 8.28% [95% CI 6.45%-10.58%], P < 0.0001). Similar results were obtained in the subgroup analysis of patients with HAVB/CHB. Multivariate analysis revealed the baseline PR interval, difference between the membranous septum length and implantation depth, and timing of postprocedural conduction disturbance occurrence were independent predictors of freedom from indications for PPM implantation at 1 month after TAVR. Interpretation: Using TPPM as a 1-month bridge allows for a buffer period to distinguish whether conduction disturbances are reversible or persistent, resulting in a significant reduction in the PPM implantation rate after TAVR when compared with the current strategy. However, this is an observational study, the results need to be confirmed in a randomized trial. Funding: Beijing Science and Technology Plan 2022 from Beijing Municipal Science & Technology Commission.

Regulating tumor innervation by nanodrugs potentiates cancer immunochemotherapy and relieve chemotherapy-induced neuropathic pain.

Sympathetic nerves play a pivotal role in promoting tumor growth through crosstalk with tumor and stromal cells. Chemotherapy exacerbates the infiltration of sympathetic nerves into tumors, thereby providing a rationale for inhibiting sympathetic innervation to enhance chemotherapy. Here, we discovered that doxorubicin increases the density and activity of sympathetic nerves in breast cancer mainly by upregulating the expression of nerve growth factors (NGFs) in cancer cells. To address this, we developed a combination therapy by co-encapsulating small interfering RNA (siRNA) and doxorubicin within breast cancer-targeted poly (lactic-co-glycolic acid) (PLGA) nanoparticles, aiming to suppress NGF expression post-chemotherapy. Incorporating NGF blockade into the nanoplatform for chemotherapy effectively mitigated the chemotherapy-induced proliferation of sympathetic nerves. This not only bolstered the tumoricidal activity of chemotherapy, but also amplified its stimulatory impact on the antitumor immune response by increasing the infiltration of immunostimulatory cells into tumors while concurrently reducing the frequency of immunosuppressive cells. Consequently, the combined nanodrug approach, when coupled with anti-PD-L1 treatment, exhibited a remarkable suppression of primary and deeply metastatic tumors with minimal systematic toxicity. Importantly, the nanoplatform relieved chemotherapy-induced peripheral neuropathic pain (CIPNP) by diminishing the expression of pain mediator NGFs. In summary, this research underscores the significant potential of NGF knockdown in enhancing immunochemotherapy outcomes and presents a nanoplatform for the highly efficient and low-toxicity treatment of breast cancer.

Prognostic Value of Inflammatory Cytokines in Predicting Hospital Readmissions in Heart Failure with Preserved Ejection Fraction.

Purpose: The aim of this study was to explore the relationship between inflammatory cytokines and the risk of heart failure (HF) readmission in patients with heart failure with preserved ejection fraction (HFpEF). Patients and Methods: We enrolled 429 patients with HFpEF admitted to the cardiology department in our hospital from January 2020 to July 2022. The patients were divided into the readmission or non-readmission groups according to whether they were readmitted for heart failure within 1 year of discharge. The clinical features and laboratory date of the subjects were collected and analyzed. Multivariate cox regression analysis was used to identify predictors of HF readmission. In addition, receiver operating characteristic (ROC) curves were used to determine the prognostic value of each factor. Results: The levels of IL-1ß, IL-6, IL-10, IL-17, TNF-α, NT-proBNP, heart rate, total cholesterol and NYHA class were significantly higher in the readmission group than in the non-readmission group (p < 0.05). IL-1ß, IL-6, IL-17, TNF-α, NT-proBNP, heart rate and NYHA class were identified as independent predictors of HF readmission. Conclusion: Inflammatory markers, including IL-1ß, IL-6, IL-17 and TNF-α were related to the HF readmission in patients with HFpEF.

Implantable Neural Microelectrodes: How to Reduce Immune Response.

Implantable neural microelectrodes exhibit the great ability to accurately capture the electrophysiological signals from individual neurons with exceptional submillisecond precision, holding tremendous potential for advancing brain science research, as well as offering promising avenues for neurological disease therapy. Although significant advancements have been made in the channel and density of implantable neural microelectrodes, challenges persist in extending the stable recording duration of these microelectrodes. The enduring stability of implanted electrode signals is primarily influenced by the chronic immune response triggered by the slight movement of the electrode within the neural tissue. The intensity of this immune response increases with a higher bending stiffness of the electrode. This Review thoroughly analyzes the sequential reactions evoked by implanted electrodes in the brain and highlights strategies aimed at mitigating chronic immune responses. Minimizing immune response mainly includes designing the microelectrode structure, selecting flexible materials, surface modification, and controlling drug release. The purpose of this paper is to provide valuable references and ideas for reducing the immune response of implantable neural microelectrodes and stimulate their further exploration in the field of brain science.

Advances in conductive hydrogels for neural recording and stimulation.

The brain-computer interface (BCI) allows the human or animal brain to directly interact with the external environment through the neural interfaces, thus playing the role of monitoring, protecting, improving/restoring, enhancing, and replacing. Recording electrophysiological information such as brain neural signals is of great importance in health monitoring and disease diagnosis. According to the electrode position, it can be divided into non-implantable, semi-implantable, and implantable. Among them, implantable neural electrodes can obtain the highest-quality electrophysiological information, so they have the most promising application. However, due to the chemo-mechanical mismatch between devices and tissues, the adverse foreign body response and performance loss over time seriously restrict the development and application of implantable neural electrodes. Given the challenges, conductive hydrogel-based neural electrodes have recently attracted much attention, owing to many advantages such as good mechanical match with the native tissues, negligible foreign body response, and minimal signal attenuation. This review mainly focuses on the current development of conductive hydrogels as a biocompatible framework for neural tissue and conductivity-supporting substrates for the transmission of electrical signals of neural tissue to speed up electrical regeneration and their applications in neural sensing and recording as well as stimulation.

A metal-organic framework complex for enhancing tumor treatments through synergistic effect of chemotherapy and photodynamic therapy.

Porphyrin-based metal-organic frameworks (PMOFs) are a kind of crystal hybrid material with broad application prospects in energy, catalysis, biomedicine, and other fields. In this study, the La-TCPP PMOF nanocrystal was constructed using a porphyrin ligand and La ion. This material can produce a high loading rate on doxorubicin (DOX) owing to its special porous structure. The high loading rate of drug molecules and the reactive oxygen species (ROS) of the porphyrin ligand enable La-TCPP@DOX nanocrystal to produce a powerful killing effect on cancer cells under the synergistic attack of chemotherapy (CT) and photodynamic therapy (PDT). Finally, by modifying the targeted aptamer, the actual therapeutic effect of this special La-TCPP@DOX@Apt material on tumors was confirmed by applying the established mouse tumor model. The composite nanomaterial not only avoids the side effects caused by high concentrations of chemotherapeutic drugs, but also overcomes the limitation of PDT owing to insufficient light penetration and can inhibit and kill solid tumors under the condition of synergistic attack. This study is a complement to PMOF crystal materials, and its tumor-killing ability was achieved by loading drugs and introducing targeting molecules, which proves that the synergistic attack can more effectively inhibit and treat solid tumors. These studies have a reference and guiding significance for the treatment of cancer patients.

Research development of porphyrin-based metal-organic frameworks: targeting modalities and cancer therapeutic applications.

Porphyrins are naturally occurring organic molecules that have attracted widespread attention for their potential in the field of biomedical research. Porphyrin-based metal-organic frameworks (MOFs) that utilize porphyrin molecules as organic ligands have gained attention from researchers due to their excellent results as photosensitizers in tumor photodynamic therapy (PDT). Additionally, MOFs hold significant promise and potential for other tumor therapeutic approaches due to their tunable size and pore size, excellent porosity, and ultra-high specific surface area. Active delivery of nanomaterials via targeted molecules for tumor therapy has demonstrated greater accumulation, lower drug doses, higher therapeutic efficacy, and reduced side effects relative to passive targeting through the enhanced permeation and retention effect (EPR). This paper presents a comprehensive review of the targeting methods employed by porphyrin-based MOFs in tumor targeting therapy over the past few years. It further discusses the applications of porphyrin-based MOFs for targeted cancer therapy through various therapeutic methods. The objective of this paper is to provide a valuable reference and source of ideas for targeted therapy using porphyrin-based MOF materials and to inspire further exploration of their potential in the field of cancer therapy.

Fibroadipose vascular anomaly: a clinicopathological study of 75 cases.

AIMS: Fibroadipose vascular anomaly (FAVA) is a complex vascular malformation that is likely to be under-recognised. In this study we aimed to report the pathological features and somatic PIK3CA mutations associated with the most common clinicopathological features. METHODS AND RESULTS: Cases were identified by reviewing the lesions resected from patients with FAVA registered at our Haemangioma Surgery Centre and unusual intramuscular vascular anomalies in our pathology database. There were 23 males and 52 females, who ranged in age from 1 to 51 years. Most cases occurred in the lower extremities (n = 62). The majority of the lesions were intramuscular, with a few disrupting the overlying fascia and involving subcutaneous fat (19 of 75), and a minority of the cases had cutaneous vascular stains (13 of 75). Histopathologically, the lesion was composed of anomalous vascular components that were intertwined with mature adipocytic and dense fibrous tissues and vascular components with: (a) clusters of thin-walled channels, some with blood-filled nodules and others with thin walls resembling pulmonary alveoli; (b) numerous small vessels (arteries, veins and indeterminate channels) - proliferative small blood vessels were often mixed with adipose tissue; (c) larger abnormal venous channels usually irregularly and sometimes excessively muscularised; (d) lymphoid aggregates or lymphoplasmacytic aggregates were usually observed; and (e) lymphatic malformations were sometimes seen as minor elements. All patients had their lessons subjected to PCR, and 53 patients had somatic PIK3CA mutations (53 of 75). CONCLUSIONS: FAVA is a slow-flow vascular malformation with specific clinicopathological and molecular characteristics. Its recognition is fundamental for its clinical/prognostic implications and for targeted therapy.

Biomimetic Nanovaccines Potentiating Dendritic Cell Internalization via CXCR4-Mediated Macropinocytosis.

Although targeted delivery of nanoparticulate vaccines to dendritic cells (DCs) holds tremendous potential, it still faces insufficient internalization and endosome degradation via the receptor-mediated endocytosis pathway. Inspired by the advantages of CXC-chemokine receptor type 4 (CXCR4)-mediated macropinocytosis in the internalization of DCs, a multifunctional vaccine is constructed based on a reactive oxygen species (ROS)-responsive nanoparticulate core and macropinocytosis-inducing peptide-fused cancer membrane shell, allowing the direct cytosolic delivery of cancer membrane-associated antigen and a stimulator of interferon genes (STING) agonist, cGAMP for highly efficient cancer immunotherapy. The biomimetic nanovaccines show a dramatically enhanced cellular uptake by DCs via CXCR4-mediated macropinocytosis. Such a direct delivery process promotes cytosolic release of cGAMP in response to ROS, and together promoted DC maturation and T cell priming by activating the STING pathway. Consequently, the biomimetic nanovaccines not only result in a great tumor rejection in prophylactic B16-F10 melanoma murine model, but also markedly suppress the growth of established melanoma tumors when combined with anti-PD-1 checkpoint blockade. This study advances the design of biomimetic nanovaccines and provides a promising strategy for macropinocytosis-mediated cancer vaccination.

Granulocyte-macrophage colony stimulating factor enhances efficacy of nimustine rendezvousing with temozolomide plus irradiation in patients with glioblastoma.

BACKGROUND: Glioblastoma is the most common and most aggressive type of primary brain tumor. OBJECTIVE: The aim of this study was to investigate the efficacy and safety of intranasal granulocyte-macrophage colony stimulating factor (GM-CSF) administration combined with chemoradiotherapy in patients with glioblastoma who underwent surgery. METHODS: Ninety-two patients were randomly divided into two groups: a control group (n= 46), who received radiotherapy with adjuvant local delivery of nimustine hydrochloride (ACNU) and systemic administration of temozolomide, and an intervention group (n= 46), who received intranasal GM-CSF prior to each cycle of adjuvant chemotherapy in addition to the treatment of the control group. Karnofsky performance status (KPS) scores, progression-free survival (PFS), overall survival (OS), and adverse effects were calculated and compared between the two groups. RESULTS: Compared with the control group, the intervention group had longer PFS (7.8 vs. 6.9 months, P= 0.016) and OS (19.2 vs. 17.1 months, P= 0.045, without adjustment for interim analyses). The KPS scores were also higher in the intervention group than in the control group after 6 months (84.35 ± 8.86 vs. 80.65 ± 7.72; t= 4.552, P= 0.036). Furthermore, the patients in the intervention group had lower incidence of neutropenia and thrombocytopenia (8.7% vs. 29.5%, P= 0.012; 8.7% vs. 18.2%, P= 0.186). Other adverse events were similar in both groups, and most adverse events were grade I/II and resolved spontaneously. CONCLUSION: Intranasal GM-CSF enhances the efficacy of the local ACNU administration combined with oral temozolomide chemotherapy. The survival and performance status were significantly improved in patients with glioblastoma after surgery. Additionally, the GM-CSF therapy was able to reduce the occurrence of chemotherapy-related neutropenia and thrombocytopenia.

Lanthanide-based MOFs: synthesis approaches and applications in cancer diagnosis and therapy.

Metal-organic frameworks (MOFs) have attracted considerable attention as emerging nanomaterials. Based on their tunable size, high porosity, and large specific surface area, MOFs have a wide range of applications in the fields of chemistry, energy, and biomedicine. However, the MOF materials obtained from lanthanides with a unique electronic configuration as inorganic building units have unique properties such as optics, magnetism, and radioactivity. In this study, various synthetic methods for preparing MOF materials using lanthanides as inorganic building units are described. Combined with the characteristics of lanthanides, their application prospects of lanthanide-based MOFs in tumor diagnosis and treatment are emphasized. The authors hope to provide methodological reference for the construction of MOF materials of rare-earth elements, and to provide ideas and inspiration for their practical applications in the field of biomedicine.

Recent progress on adsorption of cadmium ions from water systems using metal-organic frameworks (MOFs) as an efficient class of porous materials.

Various articles have been written about MOFs, which are organic-inorganic polymer structures that are unique in three-dimensional porosity, crystalline structure, and their ability to adsorb cadmium ion pollutants from aqueous solutions. These materials possess active metal sites, highly porous structures, high specific surfaces, high chemical functionality, and porous topologies. It is necessary to study adsorption kinetics, isotherms, and mechanisms in order to better understand the adsorption process. Adsorption kinetics can provide information about the adsorption rate and reaction pathway of adsorbents. Adsorption isotherms analyze the possibility of absorbances based on the Gibbs equation and thermodynamic theories. Moreover, in practical applications, knowledge of the adsorption mechanism is essential for predicting adsorption reactions and designing MOFs structures. In this review, the latest suggested adsorption mechanisms, kinetics, and isotherms of MOFs-based materials for removing cadmium ions are presented. A comparison is then conducted between different MOFs and the mechanisms of cadmium ion removal. We also discuss the future role of MOFs in removing environmental contaminants. Lastly, we discuss the gap in research and limitations of MOFs as adsorbents in actual applications, and probable technology development for the development of cost-efficient and sustainable MOFs for metal ion removal.

Recent Development of Neural Microelectrodes with Dual-Mode Detection.

Neurons communicate through complex chemical and electrophysiological signal patterns to develop a tight information network. A physiological or pathological event cannot be explained by signal communication mode. Therefore, dual-mode electrodes can simultaneously monitor the chemical and electrophysiological signals in the brain. They have been invented as an essential tool for brain science research and brain-computer interface (BCI) to obtain more important information and capture the characteristics of the neural network. Electrochemical sensors are the most popular methods for monitoring neurochemical levels in vivo. They are combined with neural microelectrodes to record neural electrical activity. They simultaneously detect the neurochemical and electrical activity of neurons in vivo using high spatial and temporal resolutions. This paper systematically reviews the latest development of neural microelectrodes depending on electrode materials for simultaneous in vivo electrochemical sensing and electrophysiological signal recording. This includes carbon-based microelectrodes, silicon-based microelectrode arrays (MEAs), and ceramic-based MEAs, focusing on the latest progress since 2018. In addition, the structure and interface design of various types of neural microelectrodes have been comprehensively described and compared. This could be the key to simultaneously detecting electrochemical and electrophysiological signals.

Synthesis of Au@MOF core-shell hybrids for enhanced photodynamic/photothermal therapy.

Photodynamic/photothermal therapy (PDT/PTT) has become a research focus of cancer treatment due to the non-invasiveness, spatio-temporal controllability, and effectiveness of repeated treatment. Here, Au@MOF core-shell hybrids were designed and constructed by the layer-by-layer method, and the thickness of the MOF shell can be adjusted by controlling the coordination reaction between the layers. Au nanorod cores mainly produce the PTT effect due to their strong absorbance at 650 nm. The porphyrin ligand in the MOF shell can convert O2 into 1O2 under light conditions, resulting in a high PDT effect. Moreover, the metal node Fe3O(OAc)6(H2O)3+ cluster of the MOF can catalyze the decomposition of H2O2 into O2 to overcome the hypoxic environment of tumors, which further improves the effect of PDT. The combination of the porphyrin ligand in the MOF structure and Au nanorods has promoted the synergistic effects of PDT/PTT. As expected, the results confirmed that Au@MOF hybrids showed no obvious biotoxicity in both cells and animal experiments, and exhibited good biocompatibility. With the synergistic effects of PDT/PTT, cancer cells could be effectively killed and tumor growth could be inhibited. In addition, the modification of folic acid on the surface of Au@MOF can further enrich the hybrids at the tumor site and enhance the inhibitory effect on tumors. These studies have proved that PDT and PTT can be effectively combined and have greater advantages in enhancing the treatment of tumors.

The modulation effect of charge transfer on photoluminescence in metal-organic frameworks.

Metal-organic framework (MOF) nanomaterials with distinct matrix coordination-induced emission (MCIE) and quenching (MCIQ) effects were designed. The MOF structure can effectively restrict the intramolecular rotation of the organic linkers and enable the excited nanoparticles to exhibit the MCIE effect. However, if the ligand-to-metal charge transfer (LMCT) process occurs in the MOF structure, the fluorescence will be quenched and the excitation energy released in the form of non-radiative energy. When an electron donor is added to block the LMCT process, as expected, the fluorescence of the MOF nanomaterials is recovered. Therefore, the intramolecular LMCT process acts as a fluorescent switch in MOF nanomaterials that can effectively quench or enable their fluorescence. Additionally, the LMCT process is not affected by the morphology of the coordination compounds, even when the MOF nanomaterials are ground into amorphous structures. These results confirm that the fluorescence of MOF nanomaterials can be regulated by the LMCT process. This study has significance for guiding the design and synthesis of MOF nanomaterials with photoluminescence properties.

Dual-Stimuli-Responsive Multifunctional Gd2Hf2O7 Nanoparticles for MRI-Guided Combined Chemo-/Photothermal-/Radiotherapy of Resistant Tumors.

The design and synthesis of a novel generation of a nanoscaled platform with imaging-guided therapy remain a real challenge. It can not only improve the imaging sensitivity of tumor tissues for guiding all kinds of treatments but also reduce the harm for healthy tissues. Here, polydopamine (PDA), polyethylene glycol (PEG), and c(RGDyK) peptide (RGD)-modified and cisplatin-loaded Gd2Hf2O7 nanoparticles (Gd2Hf2O7@PDA@PEG-Pt-RGD NPs) are designed for magnetic resonance imaging (MRI)-guided combined chemo-/photothermal-/radiotherapy of resistant tumors. The as-prepared NPs display high relaxivity (r1 = 38.28 mM-1 s-1) as an MRI contrast agent because of their ultrasmall size and surface modification with polyacrylic acid and PDA. Gd2Hf2O7@PDA@PEG-Pt-RGD NPs exhibit pH and NIR dual-stimuli responsiveness for cisplatin release. Based on competent NIR absorption and high X-ray attenuation efficiency, Gd2Hf2O7@PDA@PEG-Pt-RGD NPs show potential photothermal effect by exposing to an 808 nm NIR laser and significantly improve the generation of reactive oxygen species after X-ray radiation. Combined chemo-/photothermal-/radiotherapy can effectively treat the resistant A549R cells, providing the enhanced therapeutic efficiency to cancer tissues and the reduced side effect to healthy tissues. Furthermore, Gd2Hf2O7@PDA@PEG-Pt-RGD NPs present no obvious toxicity during the treatment, which demonstrates the potential as an efficient MRI-guided combined chemo-/photothermal-/radiotherapy nanoplatform for drug-resistant tumors.

Micron-Sized Ultrathin Metal-Organic Framework Sheet.

The two-dimensional thin metal-organic frameworks (MOF) sheet has emerged as a promising hybrid material for applications in catalysis and optoelectronic devices. However, the small size and large thickness of an MOF sheet still pose barriers toward its potential applications. Herein, a micron-sized ultrathin MOF sheet is synthesized with the assistance of benzoic acid. Benzoic acid promoted the coordination of the porphyrin center with copper ions, reduced H-stacking and J-aggregation between the layers, and induced anisotropic growth of the MOF sheet. The results reveal the growth mechanism and provide a viable method for the synthesis of ultrathin MOF sheet. The as-prepared micron-sized ultrathin MOF sheet has good dispersion and high stability, which can ensure the long-term application properties of this material. The ultrathin thickness in combination with its micron size can make MOF as useful as graphene in practical applications. The synthesis of a micron-sized ultrathin MOF sheet similar to the thickness of graphene can pave the way for effective applications of two-dimensional MOF materials.

Metal-Organic Frameworks with Enhanced Photodynamic Therapy: Synthesis, Erythrocyte Membrane Camouflage, and Aptamer-Targeted Aggregation.

Here, ferric oxide-loaded metal-organic framework (FeTCPP/Fe2O3 MOF) nanorice was designed and constructed by the liquid diffusion method. The introduction of iron metal nodes and the loading of Fe2O3 can effectively catalyze the Fenton reaction to produce hydroxyl radicals (•OH) and overcome the hypoxic environment of tumor tissue by generating oxygen. The monodispersity and porosity of the porphyrin photosensitizers in the MOF structure exposed more active sites, which promoted energy exchange between porphyrin molecules and oxygen molecules for photodynamic therapy (PDT) treatment. Therefore, the generated hydroxyl radicals and singlet oxygen (1O2) can synergistically act on tumor cells to achieve the purpose of improving tumor therapy. Then the erythrocyte membrane was camouflaged to enhance blood circulation and tissue residence time in the body, and finally, the targeted molecule AS1411 aptamer was modified to achieve the high enrichment of MOF photosensitizers on a tumor domain. As a result, the MOF nanorice camouflaged by the erythrocyte membrane can effectively reduce side effects and improve the therapeutic effect of PDT and chemo-dynamic therapy (CDT). The study not only improved the efficacy of PDT and CDT in essence from the MOF nanorice but also used the camouflage method to further concentrate FeTCPP/Fe2O3 on the tumor sites, achieving the goal of multiple gains. These results will provide theoretical and practical directions for the development of tumor-targeted MOF nanomaterials.

Targeting Hypertension: Superoxide Anions are Involved in Apelininduced Long-term High Blood Pressure and Sympathetic Activity in the Paraventricular Nucleus.

AIM: To determine whether apelin in paraventricular nucleus (PVN) can be a therapeutic target for hypertension. BACKGROUND: Apelin is a specific endogenous ligand of orphan G protein-coupled receptor APJ. OBJECTIVE: This study was designed to determine how apelin chronically regulates sympathetic nerve activity and blood pressure in PVN of rats. METHODS: Apelin and APJ antagonist F13A were infused into PVN with osmotic minipumps. The NAD(P)H oxidase activity and superoxide anions levels in PVN of rats were determined by chemiluminescence. RESULTS: Infusion of apelin into PVN of Wistar-Kyoto (WKY) rats induced chronic increases in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), plasma norepinephrine (NE) level, maximal depressor response to hexamethonium (Hex), NAD(P)H oxidase activity, superoxide anions levels, and Nox4 expression. Infusion of F13A into PVN of spontaneously hypertensive rats (SHRs) caused chronic decreases in SBP, DBP, MAP, plasma NE level, maximal depressor response to Hex, NAD(P)H oxidase activity, and superoxide anions levels. Hex, a sympathetic ganglion blocker, inhibited apelin-induced increases in SBP, DBP and MAP. SOD overexpression in PVN of SHRs inhibited the apelin-induced increase in SBP, DBP, MAP, plasma NE level, and maximal depressor response to Hex. PVN Nox4 knockdown also attenuated the apelin-induced increase in SBP, DBP, MAP, plasma NE level, and maximal depressor response to Hex. Chronic injection of F13A into PVN reduced fibrosis of renal artery, thoracic aorta, and heart in SHRs. CONCLUSION: These results demonstrated that in PVN apelin induced long-term high blood pressure and sympathetic activity via increasing oxidative stress.