Multiple RNA Rapid In Situ Imaging Based on Cas9 Code Key System.

Existing RNA in situ imaging strategies mostly utilize parallel repetitive nucleic acid self-assembly to achieve multiple analysis, with limitations of complicated systems and cumbersome steps. Here, a Cas9 code key system with key probe (KP) encoder and CRISPR/Cas9 signal exporter is developed. This system triggers T-protospacer adjacent motif (T-PAM structural transitions of multiple KP encoders to form coding products with uniform single-guide RNA (sgRNA) target sequences as tandem nodes. Only single sgRNA/Cas9 complex is required to cleave multiple coding products, enabling efficient "many-to-one" tandem signaling, and non-collateral cleavage activity-dependent automatic signaling output through active introduction of mismatched bases. Compared with conventional parallel multiple signaling analysis model, the proposed system greatly simplifies reaction process and enhances detection efficiency. Further, a rapid multiple RNA in situ imaging system is developed by combining the Cas9 code key system with a T-strand displacement amplification (T-SDA) signal amplifier. The constructed system is applied to tumor cells and clinicopathology slices, generating clear multi-mRNA imaging profiles in less than an hour with just one step. Therefore, this work provides reliable technical support for clinical tumor typing and molecular mechanism investigation.

Local anesthetic delivery systems for the management of postoperative pain.

Postoperative pain (POP) is a major clinical challenge. Local anesthetics (LAs), including amide-type LAs, ester-type LAs, and other potential ion-channel blockers, are emerging as drugs for POP management because of their effectiveness and affordability. However, LAs typically exhibit short durations of action and prolonging the duration by increasing their dosage or concentration may increase the risk of motor block or systemic local anesthetic toxicity. In addition, techniques using LAs, such as intrathecal infusion, require professional operation and are prone to catheter displacement, dislodgement, infection, and nerve damage. With the development of materials science and nanotechnology, various LAs delivery systems have been developed to compensate for these disadvantages. Numerous delivery systems have been designed to continuously release a safe dose in a single administration to ensure minimal systemic toxicity and prolong pain relief. LAs delivery systems can also be designed to control the duration and intensity of analgesia according to changes in the external trigger conditions, achieve on-demand analgesia, and significantly improve pain relief and patient satisfaction. In this review, we summarize POP pathways, animal models and methods for POP testing, and highlight LAs delivery systems for POP management. STATEMENT OF SIGNIFICANCE: Postoperative pain (POP) is a major clinical challenge. Local anesthetics (LAs) are emerging as drugs for POP management because of their effectiveness and affordability. However, they exhibit short durations and toxicity. Various LAs delivery systems have been developed to compensate for these disadvantages. They have been designed to continuously release a safe dose in a single administration to ensure minimal toxicity and prolong pain relief. LAs delivery systems can also be designed to control the duration and intensity of analgesia to achieve on-demand analgesia, and significantly improve pain relief and patient satisfaction. In this paper, we summarize POP pathways, animal models, and methods for POP testing and highlight LAs delivery systems for POP management.

Microneedle Delivery Platform Integrated with Codelivery Nanoliposomes for Effective and Safe Androgenetic Alopecia Treatment.

Although topical application of minoxidil is a widely used, FDA-approved therapy for androgenetic alopecia (AGA) treatment, it suffers from low bioavailability, the requirement for frequent long-term use, and side effects. With a similar structure as minoxidil, kopexil and kopyrrol are less toxic and have been commercialized, but show an inferior hair regeneration effect compared to minoxidil. Herein, we developed a hyaluronic acid (HA)-based dissolvable microneedles (MNs) delivery platform integrated with kopexil and kopyrrol coencapsulated nanoliposomes (KK-NLPs) to effectively and safely treat AGA. Facilitated by nanoliposomes and MNs, the encapsulated KK-NLPs performed efficient skin penetration and enhanced cellular internalization into human dermal papilla cells. Furthermore, within the target cells, the codelivered kopexil and kopyrrol show synergistic effects by orchestrating an upregulation in the expression of Ki67, ß-catenin, vascular endothelial growth factor (VEGF), and CD31. These molecular responses collectively foster cell proliferation, migration, and antioxidative effects, thereby facilitating the expedited progression of hair follicles (HFs) into the anagen phase and promoting peripheral angiogenesis. Notably, the KK-NLPs-integrated MNs treatment group exhibits noteworthy enhanced hair regeneration in vivo, with identical or superior therapeutic effects at a much lower dosage than that of minoxidil. These results suggest the great potential of this kopexil and kopyrrol codelivery nanoliposomes-integrated MNs platform for AGA treatment in a safe and efficient way.

Preimplantation genetic testing for monogenic disorders (PGT-M) offers an alternative strategy to prevent children from being born with hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes: a retrospective study.

BACKGROUND: Preimplantation genetic testing for monogenic disorders (PGT-M) is now widely used as an effective strategy to prevent various monogenic or chromosomal diseases. MATERIAL AND METHODS: In this retrospective study, couples with a family history of hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes and/or carrying the pathogenic genes underwent PGT-M to prevent children from inheriting disease-causing gene mutations from their parents and developing known genetic diseases. After PGT-M, unaffected (i.e., normal) embryos after genetic detection were transferred into the uterus of their corresponding mothers. RESULTS: A total of 43 carrier couples with the following hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes underwent PGT-M: Duchenne muscular dystrophy (13 families); methylmalonic acidemia (7 families); spinal muscular atrophy (5 families); infantile neuroaxonal dystrophy and intellectual developmental disorder (3 families each); Cockayne syndrome (2 families); Menkes disease, spinocerebellar ataxia, glycine encephalopathy with epilepsy, Charcot-Marie-Tooth disease, mucopolysaccharidosis, Aicardi-Goutieres syndrome, adrenoleukodystrophy, phenylketonuria, amyotrophic lateral sclerosis, and Dravet syndrome (1 family each). After 53 PGT-M cycles, the final transferable embryo rate was 12.45%, the clinical pregnancy rate was 74.19%, and the live birth rate was 89.47%; a total of 18 unaffected (i.e., healthy) children were born to these families. CONCLUSIONS: This study highlights the importance of PGT-M in preventing children born with hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes.

An injectable polyacrylamide/chitosan-based hydrogel with highly adhesive, stretchable and electroconductive properties loaded with irbesartan for treatment of myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion injury (MIRI) significantly contributes to the high incidence of complications and mortality associated with acute myocardial infarction. Recently, injectable electroconductive hydrogels (IECHs) have emerged as promising tools for replicating the mechanical, electroconductive, and physiological characteristics of cardiac tissue. Herein, we aimed to develop a novel IECH by incorporating irbesartan as a drug delivery system (DDS) for cardiac repair. Our approach involved merging a conductive poly-thiophene derivative (PEDOT: PSS) with an injectable dual-network adhesive hydrogel (DNAH) comprising a catechol-branched polyacrylamide network and a chitosan-hyaluronic acid covalent network. The resulting P-DNAH hydrogel, benefitting from a high conducting polymer content, a chemically crosslinked network, a robust dissipative matrix, and dynamic oxidation of catechol to quinone exhibited superior mechanical strength, desirable conductivity, and robust wet-adhesiveness. In vitro experiments with the P-DNAH hydrogel carrying irbesartan (P-DNAH-I) demonstrated excellent biocompatibility by cck-8 kit on H9C2 cells and a rapid initial release of irbesartan. Upon injection into the infarcted hearts of MIRI mouse models, the P-DNAH-I hydrogel effectively inhibited the inflammatory response and reduced the infarct size. In conclusion, our results suggest that the P-DNAH hydrogel, possessing suitable mechanical properties and electroconductivity, serves as an ideal IECH for DDS, delivering irbesartan to promote heart repair.

Metal exsolution from perovskite-based anodes in solid oxide fuel cells.

Solid oxide fuel cells (SOFCs) are highly efficient and environmentally friendly devices for converting fuel into electrical energy. In this regard, metal nanoparticles (NPs) loaded onto the anode oxide play a crucial role due to their exceptional catalytic activity. NPs synthesized through exsolution exhibit excellent dispersion and stability, garnering significant attention for comprehending the exsolution process mechanism and consequently improving synthesis effectiveness. This review presents recent advancements in the exsolution process, focusing on the influence of oxygen vacancies, A-site defects, lattice strain, and phase transformation on the variation of the octahedral crystal field in perovskites. Moreover, we offer insights into future research directions to further enhance our understanding of the mechanism and achieve significant exsolution of NPs on perovskites.

Ropivacaine-loaded hydrogels for prolonged relief of chemotherapy-induced peripheral neuropathic pain and potentiated chemotherapy.

Chemotherapy can cause severe pain for patients, but there are currently no satisfactory methods of pain relief. Enhancing the efficacy of chemotherapy to reduce the side effects of high-dose chemotherapeutic drugs remains a major challenge. Moreover, the treatment of chemotherapy-induced peripheral neuropathic pain (CIPNP) is separate from chemotherapy in the clinical setting, causing inconvenience to cancer patients. In view of the many obstacles mentioned above, we developed a strategy to incorporate local anesthetic (LA) into a cisplatin-loaded PF127 hydrogel for painless potentiated chemotherapy. We found that multiple administrations of cisplatin-loaded PF127 hydrogels (PFC) evoked severe CIPNP, which correlated with increased pERK-positive neurons in the dorsal root ganglion (DRG). However, incorporating ropivacaine into the PFC relieved PFC-induced CIPNP for more than ten hours and decreased the number of pERK-positive neurons in the DRG. Moreover, incorporating ropivacaine into the PFC for chemotherapy is found to upregulate major histocompatibility complex class I (MHC-I) expression in tumor cells and promote the infiltration of cytotoxic T lymphocytes (CD8+ T cells) in tumors, thereby potentiating chemotherapy efficacy. This study proposes that LA can be used as an immunemodulator to enhance the effectiveness of chemotherapy, providing new ideas for painless cancer treatment.

Comprehensive analysis and identification of prognostic biomarkers and immunotherapeutic targets in the NADPH oxidase family (and its regulatory subunits) in pancreatic ductal adenocarcinoma

Purpose This study aimed to evaluate the role of NADPH in pancreatic ductal adenocarcinoma using bioinformatic analyses and experimental validations. Methods We compared the expression levels, performed GO and KEGG analysis of NADPH oxidase family and its regulatory subunits, and determined the survival of patients with pancreatic ductal adenocarcinoma by GEPIA, David and KM plotter. The relationship between their expression with immune infiltration levels, phagocytotic/NK cell immune checkpoints, recruitment-related molecules were detected by Timer 2.0 and TISIDB, respectively. Subsequently, their correlation with NK cell infiltration level was verified by immunohistochemistry. Results The expression of some members of the NADPH oxidase family and its regulatory subunits was significantly increased in pancreatic ductal adenocarcinoma tissues compared to that in normal tissues and was positively correlated with natural killer (NK) cell infiltration. Furthermore, the NADPH oxidase family and its regulatory subunits were associated with survival and immune status in patients with pancreatic ductal adenocarcinoma, including chemokines, immune checkpoints, and immune infiltration levels of NK cells, monocytes, and myeloid-derived suppressor cells. Conclusions These results suggest the NADPH oxidase family and its regulatory subunits might serve as indicators for predicting the responsiveness to immunotherapy and outcome of patients with pancreatic ductal adenocarcinoma, providing a new perspective or strategy for immunotherapy in pancreatic ductal adenocarcinoma (AU)

Rapid in situ RNA imaging based on Cas12a thrusting strand displacement reaction.

RNA In situ imaging through DNA self-assembly is advantaged in illustrating its structures and functions with high-resolution, while the limited reaction efficiency and time-consuming operation hinder its clinical application. Here, we first proposed a new strand displacement reaction (SDR) model (Cas12a thrusting SDR, CtSDR), in which Cas12a could overcome the inherent reaction limitation and dramatically enhance efficiency through energy replenishment and by-product consumption. The target-initiated CtSDR amplification was established for RNA analysis, with order of magnitude lower limit of detection (LOD) than the Cas13a system. The CtSDR-based RNA in situ imaging strategy was developed to monitor intra-cellular microRNA expression change and delineate the landscape of oncogenic RNA in 66 clinic tissue samples, possessing a clear advantage over classic in situ hybridization (ISH) in terms of operation time (1 h versus 14 h) while showing comparable sensitivity and specificity. This work presents a promising approach to developing advanced molecular diagnostic tools.

Antigen Priming Induces Functional Reprogramming in iNKT Cells via Metabolic and Epigenetic Regulation: An Insight into iNKT Cell-Based Antitumor Immunotherapy.

Dysfunction of intratumoral invariant natural killer T (iNKT) cells hinders their antitumor efficacy, but the underlying mechanisms and the relationship with endogenous antigen priming remain to be explored. Here, we report that antigen priming leads to metabolic reprogramming and epigenetic remodeling, which causes functional reprogramming in iNKT cells, characterized by limited cytokine responses upon restimulation but constitutive high cytotoxicity. Mechanistically, impaired oxidative phosphorylation (OXPHOS) in antigen-primed iNKT cells inhibited T-cell receptor signaling, as well as elevation of glycolysis, upon restimulation via reducing mTORC1 activation, and thus led to impaired cytokine production. However, the metabolic reprogramming in antigen-primed iNKT cells was uncoupled with their enhanced cytotoxicity; instead, epigenetic remodeling explained their high expression of granzymes. Notably, intratumoral iNKT cells shared similar metabolic reprogramming and functional reprogramming with antigen-primed iNKT cells due to endogenous antigen priming in tumors, and thus recovery of OXPHOS in intratumoral iNKT cells by ZLN005 successfully enhanced their antitumor responses. Our study deciphers the influences of antigen priming-induced metabolic reprogramming and epigenetic remodeling on functionality of intratumoral iNKT cells, and proposes a way to enhance efficacy of iNKT cell-based antitumor immunotherapy by targeting cellular metabolism.

Expansion of a frontostriatal salience network in individuals with depression.

Hundreds of neuroimaging studies spanning two decades have revealed differences in brain structure and functional connectivity in depression, but with modest effect sizes, complicating efforts to derive mechanistic pathophysiologic insights or develop biomarkers. 1 Furthermore, although depression is a fundamentally episodic condition, few neuroimaging studies have taken a longitudinal approach, which is critical for understanding cause and effect and delineating mechanisms that drive mood state transitions over time. The emerging field of precision functional mapping using densely-sampled longitudinal neuroimaging data has revealed unexpected, functionally meaningful individual differences in brain network topology in healthy individuals, 2-5 but these approaches have never been applied to individuals with depression. Here, using precision functional mapping techniques and 11 datasets comprising n=187 repeatedly sampled individuals and >21,000 minutes of fMRI data, we show that the frontostriatal salience network is expanded two-fold in most individuals with depression. This effect was replicable in multiple samples, including large-scale, group-average data (N=1,231 subjects), and caused primarily by network border shifts affecting specific functional systems, with three distinct modes of encroachment occurring in different individuals. Salience network expansion was unexpectedly stable over time, unaffected by changes in mood state, and detectable in children before the subsequent onset of depressive symptoms in adolescence. Longitudinal analyses of individuals scanned up to 62 times over 1.5 years identified connectivity changes in specific frontostriatal circuits that tracked fluctuations in specific symptom domains and predicted future anhedonia symptoms before they emerged. Together, these findings identify a stable trait-like brain network topology that may confer risk for depression and mood-state dependent connectivity changes in frontostriatal circuits that predict the emergence and remission of depressive symptoms over time.

Combined Effects of Transcranial Magnetic Stimulation and Argatroban on Balance Function and Daily Living Activities in Hemiplegic Patients Following Cerebral Infarction.

Objective: This study aimed to investigate the impact of combining transcranial magnetic stimulation (TMS) with argatroban on balance function and activities of daily living in patients with hemiplegia following cerebral infarction (CI). Methods: A retrospective analysis was conducted on the clinical data of 104 patients with hemiplegia after CI who were admitted to our hospital from July 2020 to July 2021. The patients were randomly assigned to either the experimental group (EG) or the control group (CG), with 52 patients in each group. The EG received TMS in combination with argatroban, while the CG received argatroban alone. The Berg Balance Scale (BBS) and modified Barthel index (BI) were used to assess the balance function and activities of daily living in both groups after treatment. Results: After treatment, the EG demonstrated significantly higher BBS and BI scores compared to the CG (P < .001). Additionally, the EG showed significantly improved upper limb and lower limb Functional Ambulation Profile (FAM) scores compared to the CG (P < .05). Conclusions: The combination of TMS and argatroban proves to be an effective approach for enhancing balance function and activities of daily living in hemiplegic patients with CI. Therefore, it is recommended as a valuable rehabilitation treatment for such patients.

Asymmetric Hairpins DNA Encapsulated Silver Nanoclusters for In Situ Fluorescence Imaging of Fusion Gene Isoforms in Bone Marrow.

Rapid and accurate imaging of the BCR/ABL fusion gene isoforms (e.g., e13a2, e14a2 and co-expression type) of chronic myeloid leukemia (CML) is of vital importance to first-line drug selection, but there is no assay that meets clinical needs (e.g., clinical kits > 18 h without isoforms information). Herein, an in situ imaging platform is developed for the rapid and accurate detection of CML fusion gene isoforms using asymmetric sequence-enhanced hairpins DNA encapsulated silver nanoclusters (ADHA) and catalyzed hairpin assembly (CHA). The specific detection of e13a2 and e14a2 fusion gene isoforms with detection limits of 19.2 am (11.558 copies µL-1 ) and 32.56 am (19.601 copies µL-1 ) in one-pot is achieved. The feasibility of the developed assay for real-world applications are demonstrated by one-step fluorescence imaging (40 min) of e13a2, e14a2 and co-expression type in bone marrow quantitatively (International Standard: 15.66%-168.878%) and further validated by cDNA-sequencing. This work suggests that the developed imaging platform holds great potential for rapid identification of the fusion gene isoforms and isoform related treatment monitoring.

Analgesic and potentiated photothermal therapy with ropivacaine-loaded hydrogels.

Rationale: Tumor ablation can cause severe pain to patients, but there is no satisfactory means of analgesia available. In addition, recurrence of residual tumors due to incomplete ablation threatens patient safety. Photothermal therapy (PTT), a promising approach for tumor ablation, also faces the aforementioned problems. Therefore, developing novel photothermal agents that can efficiently relieve PTT-associated pain and potentiate the PTT efficacy are urgently needed. Methods: The Pluronic F127 hydrogel doped with indocyanine green (ICG) was served as photothermal agent for PTT. Mouse model that inoculation of tumor near the sciatic nerve was constructed to assess the PTT-evoked pain. Subcutaneous and sciatic nerve vicinal tumor-bearing mice were used to test the efficacy of PTT. Results: PTT-evoked pain depends on an increase in tumor temperature and is accompanied by the activation of TRPV1. A simple introduction of local anesthetic (LA) ropivacaine into ICG-loaded hydrogels relieves PTT-induced pain and exerts long-lasting analgesia compared with opioid analgesia. More interestingly, ropivacaine upregulates major histocompatibility complex class I (MHC-I) in tumor cells by impairing autophagy. Therefore, a hydrogel co-doped with ropivacaine, TLR7 agonist imiquimod and ICG was rationally designed. In the hydrogel system, imiquimod primes tumor-specific CD8+ T cells through promoting DCs maturation, and ropivacaine facilitates tumor cells recognition by primed CD8+ T cells through upregulating MHC-I. Consequently, the hydrogel maximumly increases CD8+ T cells infiltration into tumor and potentiates PTT efficacy. Conclusion: This study for the first time provides an LA-dopped photothermal agents for painless PTT and innovatively proposes that a LA can be used as an immunomodulator to potentiate the PTT efficacy.

Impact of Hypocalcemia on the Prognosis of Patients with Acute Myocarditis.

Acute viral myocarditis is a serious complication of viral infectious diseases, including coronavirus disease 2019 (COVID-19). To better understand the pathogenesis of acute viral myocarditis, we retrospectively analyzed the incidence and prognostic significance of hypocalcemia among patients with acute myocarditis, most of whom were considered to have acute viral myocarditis. We retrospectively reviewed the demographic and clinical data of patients with clinically confirmed acute myocarditis treated in our hospital over a 13-year period from 2006 to 2019, including laboratory results, cardiac imaging findings, and clinical outcomes. These data were compared between lower, middle, and higher calcium groups depending on the minimum calcium level measured during hospitalization. Among the 288 patients with acute myocarditis included, the hypocalcemia group (lower calcium group) had poorer clinical and laboratory results, received more medications and device support, and experienced poorer outcomes, including heart failure, arrhythmias, and death. Specifically, the left ventricular ejection fraction was significantly lower, and the length of hospital stay was significantly longer in the hypocalcemia group than in the other two groups. Furthermore, the incidence rates of atrioventricular block, ventricular tachycardia/ventricular fibrillation, cardiogenic shock, and mortality were significantly higher in the hypocalcemia group. Multivariate Cox regression analysis identified hypocalcemia as an independent risk factor for 30-day mortality in patients with acute myocarditis. In conclusion, the clinical evidence provided by the present study indicates that hypocalcemia is a risk factor for poorer outcomes in patients with acute myocarditis that should be considered carefully in the diagnosis and treatment of these patients.

LCZ696 Ameliorates Tachycardia-Induced Cardiac Calcium Dyshomeostasis in the SERCA2α-Dependent Pathway.

The incidence, prevalence, and economic burden of heart failure have continued to increase worldwide. It remains unclear whether LCZ696 can ameliorate calcium reuptake in the sarcoplasmic reticulum via the sarcoplasmic endoplasmic reticulum calcium ion-ATPase 2α (SERCA2α)-dependent pathway during cardiac diastole. We investigated whether LCZ696 could ameliorate tachycardia-induced myocardial injury by modulating cardiac SERCA2α levels. A tachycardia-induced myocardial injury model was established by daily intraperitoneal administration of 60 mg/kg isoprenaline (ISO) for 2 weeks. LCZ696 was orally administered for the following 4 weeks. SERCA2α and calcium ion (Ca2+)-related protein expression was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. For additional in vitro studies, HL-1 cardiomyocytes were used. A SERCA2α overexpression vector was constructed and transfected into HL-1 cells. The expression of SERCA2α and Ca2+-related proteins were also measured using qRT-PCR and western blotting. Our in vivo results demonstrated that myocardial injury was successfully induced by intraperitoneal administration of ISO. The expression of both SERCA2α- and Ca2+-related proteins was impaired. Oral administration of LCZ696 increased the expression of SERCA2α, alleviated Ca2+-related protein impairment and cardiac Ca2+ dyshomeostasis, and ameliorated myocardial injury. These results were compared with our in vitro findings. Ca2+-related proteins are affected by the overexpression of SERCA2α. LCZ696 improved tachycardia-induced myocardial injury by increasing SERCA2α expression, which reversed the development of heart failure in ISO-induced mice. These results provide new insights into how sustained LCZ696 treatment in heart failure improves cardiac function through intracellular Ca2+-regulatory mechanisms.

Comprehensive analysis and identification of prognostic biomarkers and immunotherapeutic targets in the NADPH oxidase family (and its regulatory subunits) in pancreatic ductal adenocarcinoma.

PURPOSE: This study aimed to evaluate the role of NADPH in pancreatic ductal adenocarcinoma using bioinformatic analyses and experimental validations. METHODS: We compared the expression levels, performed GO and KEGG analysis of NADPH oxidase family and its regulatory subunits, and determined the survival of patients with pancreatic ductal adenocarcinoma by GEPIA, David and KM plotter. The relationship between their expression with immune infiltration levels, phagocytotic/NK cell immune checkpoints, recruitment-related molecules were detected by Timer 2.0 and TISIDB, respectively. Subsequently, their correlation with NK cell infiltration level was verified by immunohistochemistry. RESULTS: The expression of some members of the NADPH oxidase family and its regulatory subunits was significantly increased in pancreatic ductal adenocarcinoma tissues compared to that in normal tissues and was positively correlated with natural killer (NK) cell infiltration. Furthermore, the NADPH oxidase family and its regulatory subunits were associated with survival and immune status in patients with pancreatic ductal adenocarcinoma, including chemokines, immune checkpoints, and immune infiltration levels of NK cells, monocytes, and myeloid-derived suppressor cells. CONCLUSIONS: These results suggest the NADPH oxidase family and its regulatory subunits might serve as indicators for predicting the responsiveness to immunotherapy and outcome of patients with pancreatic ductal adenocarcinoma, providing a new perspective or strategy for immunotherapy in pancreatic ductal adenocarcinoma.

Association between soluble neprilysin and diabetes: Findings from a prospective longitudinal study.

Background: The potential role of neprilysin (NEP) in glucose metabolism has been found by basic studies but lacks population evidence. The objective of this study was to examine the association between serum NEP and diabetes in Chinese adults. Methods: In a prospective longitudinal cohort study - the Gusu cohort (n=2,286, mean age: 52 years, 61.5% females), the cross-sectional, longitudinal, and prospective associations between serum NEP and diabetes were systemically examined by logistic regression adjusting for conventional risk factors. Serum NEP was measured at baseline using commercial ELISA assays. Fasting glucose was repeatedly measured 4 years apart. Results: The cross-sectional analysis found a positive association between serum NEP and fasting glucose at baseline (ß=0.08, P=0.004 for log-transformed NEP). This association persisted after controlling for the dynamic risk profiles during follow-up (ß=0.10, P=0.023 for log-transformed NEP). The prospective analysis found that a higher level of serum NEP at baseline was associated with a higher risk of diabetes during follow-up (OR=1.79, P=0.039 for log-transformed NEP). Conclusions: Serum NEP was not only associated with prevalent diabetes but also predicted the future risk of diabetes development in Chinese adults, independent of many behavioral and metabolic factors. Serum NEP may be a predictor and even a new therapeutic target for diabetes. However, the casualty and mechanisms of NEP in the development of diabetes require further investigation.

Highly specific neutrophil-mediated delivery of albumin nanoparticles to ectopic lesion for endometriosis therapy.

Endometriosis is an estrogen-dependent chronic inflammatory disease. Hormonal and surgical treatments are the most commonly used clinical therapies, but they have many sides effects or are traumatic to the body. Therefore, specific drugs for endometriosis treatment are urgently needed to develop. In this study, we identified two features of endometriosis, namely the continuous recruitment of neutrophils into the ectopic lesions and the higher uptake of glucose by ectopic cells. For the above features, we designed a glucose oxidase-loaded bovine serum albumin nanoparticle (BSA-GOx-NPs) that is inexpensive and facilitates large-scale production. After injection, BSA-GOx-NPs were high specifically delivered to ectopic lesions in a neutrophil-dependent manner. Furthermore, BSA-GOx-NPs deplete glucose and induce apoptosis in the ectopic lesions. Whereupon BSA-GOx-NPs produced excellent anti-endometriosis effects when administrated in both acute and chronic inflammatory phases. These results reveal for the first time that the neutrophil hitchhiking strategy is effective in chronic inflammatory disease and provide a non-hormonal and easy-to-achieve approach for endometriosis treatment.