Association of bacteriomes with drug susceptibility in lesions of pulmonary tuberculosis patients.

Understanding how the bacteriomes in tuberculous lesions can be influenced by the susceptibility of Mycobacterium tuberculosis (MTB) can provide valuable information for preventing and treating drug resistant tuberculosis (DR-TB). High-throughput 16S rRNA sequencing was employed to analyze the bacteriome in pulmonary TB lesions from 14 patients with DR-TB and 47 patients with drug sensitive tuberculosis (DS-TB), along with 18 normal lung tissues (NT) from 18 lung cancer patients serving as the bacterial baseline. The phylogenetic investigation of communities by reconstruction of unobserved states2 (PICRUSt2) algorithm was utilized to predict bacterial metabolic functions. The major phyla of pulmonary bacteriomes included Proteobacteria, Actinobacteria, Bacteroidetes, Firmicutes and Fusobacteria. Alpha diversity indices, including ACE, Chao1, Shannon and OTU observed, all demonstrated different bacterial communities of DS-TB samples from that of NT samples; while only Shannon indicated difference between DR-TB and NT samples. The analysis of similarity (ANOSIM) showed significantly different bacterial communities within TB lesions compared to NT samples (R = 0.418, p = 0.001). However, difference was not observed between DR-TB and DS-TB samples (ANOSIM, R = 0.069, p = 0.173). The bacterial profiles within each DR-TB individual appeared unique, with no obvious clusters corresponding to drug-resistant phenotypes. Nevertheless, indicator genera identified in DR-TB and DS-TB lesions demonstrated distinctive micro-ecological environments. Most COG functions were enriched in TB lesions, and the most significant one was [J] translation, ribosomal structure and biogenesis. The distinct enrichment patterns of bacterial enzymes in DR-TB and DS-TB lesions suggest that pulmonary bacterial activities can be modulated by the susceptibility of MTB bacilli. This study provides fresh perspectives and strategies for the precise diagnosis and assessment of drug resistance tuberculosis.

Case report: Systemic multi-organ involvement in an adult-onset immunodeficiency patient infected with Talaromyces marneffei.

Adult-onset immunodeficiency (AOID) mediated by anti-interferon-γ autoantibodies (AIGA) is a rare condition, particularly prevalent in Southeast Asia and southern China. We present a case study of a 62-year-old female with AOID who developed a severe pulmonary infection caused by Talaromyces marneffei (TM), leading to acute respiratory failure, generalized rash, multiple lymphadenopathies, bone destruction, and a mediastinal mass. Treatment included mechanical ventilation, antifungal medication, and corticosteroids, resulting in complete recovery and discharge. This case underscores the challenges of managing complex infections in AOID patients and highlights the importance of early diagnosis through metagenomic next-generation sequencing (mNGS) and appropriate intervention to improve clinical outcomes.

De novo design of type-l photosensitizer agents based on structure-inherent low triplet energy for hypoxia photodynamic therapy.

Photodynamic therapy (PDT), owing to its low invasiveness, high efficiency, fewer side effects, spatiotemporal controllability and good selectivity, has attracted increasing attention for its tremendous potential in revolutionizing conventional strategies of tumor treatment. However, hypoxia is a common feature of most malignancies and has become the Achilles' heel of PDT. Currently, Type II photosensitizers (PSs) have inadequate efficacy for PDT due to the inherent oxygen consumption of the anoxic tumor microenvironment. Moreover, due to the absence of a general molecular design strategy and the limitations imposed by the energy gap law, Type-I PSs are less reported. Therefore, the development of Type-I PSs with hypoxia resistant capabilities is urgently required. Herein, in this study, we have obtained pure Type-I materials for the first time by employing a strategy that decreases the triplet energy levels of the π-conjunction bridge. A sufficient donor-acceptor interaction reduces the lowest triplet energy level and aids in the transfer of excitons from singlet to triplet levels. With this strategy, dibenzofulvene derivatives (FEs) displayed purely Type-I ROS generation. Among them, FE-TMI exhibits superior Type-I reactive oxygen species-generation performance, showcasing the great potential of PDT in treating tumor cells under hypoxic conditions and several types of solid tumors in mouse in vivo experiments. This work provides a practical solution for the future design of Type-I PDT materials and is aimed at enhancing PDT efficiency.

A Review of the Development of Titanium-Based and Magnesium-Based Metallic Glasses in the Field of Biomedical Materials.

This article reviews the research and development focus of metallic glasses in the field of biomedical applications. Metallic glasses exhibit a short-range ordered and long-range disordered glassy structure at the microscopic level, devoid of structural defects such as dislocations and grain boundaries. Therefore, they possess advantages such as high strength, toughness, and corrosion resistance, combining characteristics of both metals and glasses. This novel alloy system has found applications in the field of biomedical materials due to its excellent comprehensive performance. This review discusses the applications of Ti-based bulk metallic glasses in load-bearing implants such as bone plates and screws for long-term implantation. On the other hand, Mg-based metallic glasses, owing to their degradability, are primarily used in degradable bone nails, plates, and vascular stents. However, metallic glasses as biomaterials still face certain challenges. The Young's modulus value of Ti-based metallic glasses is higher than that of human bones, leading to stress-shielding effects. Meanwhile, Mg-based metallic glasses degrade too quickly, resulting in the premature loss of mechanical properties and the formation of numerous bubbles, which hinder tissue healing. To address these issues, we propose the following development directions: (1) Introducing porous structures into titanium-based metallic glasses is an important research direction for reducing Young's modulus; (2) To enhance the bioactivity of implant material surfaces, the surface modification of titanium-based metallic glasses is essential. (3) Developing antibacterial coatings and incorporating antibacterial metal elements into the alloys is essential to maintain the long-term effective antibacterial properties of metallic biomaterials. (4) Corrosion resistance must be further improved through the preparation of composite materials, while ensuring biocompatibility and safety, to achieve controllable degradation rates and degradation modes.

Endothelial cell mechanics and dynamics in angiogenesis.

The efficient distribution of oxygen and metabolites is critical for embryonic development and growth as well as tissue homeostasis. This is achieved by endothelial cells forming and maintaining a closed, circulatory network of tubular blood vessels. Endothelial cells are highly plastic cells with the capability to generate diverse dynamic responses at different stages of vessel development in order to build vessel networks of tissue-specific patterns and morphologies. In this review, we discuss new conceptual advances gained from in vitro and in vivo models of angiogenesis on the control of endothelial cell dynamics. We highlight the complex interplay between mechanical cues, actin cytoskeleton and endothelial behaviors, and the emerging importance of hydrostatic pressure in complementing actin-dependent mechanisms to regulate endothelial cell mechanics and angiogenesis. Understanding these processes provides insights into vascular repair and regeneration mechanisms.

Advancements in Cold-Region Rice Breeding: The 4S Phenotypic-Design Breeding System and Its Applications in Heilongjiang.

Heilongjiang, located in the cold region, is China's largest rice-producing and commercializing province. The variety selection of rice in cold regions (RCR) is indispensable in promoting the rice industry's development, and technological innovation in breeding theory plays a significant role in breeding breakthrough. Based primarily on long-term research, contemplation, and breeding practices, the 4S (selected topic, selected breeding, selected progenies, and selected promotion) phenotypic-design breeding technical system for RCR, which has revolutionized the theoretical basis and deepened the conceptual model, has been developed through systematic analyses and generalization. The system covers several key aspects such as scientific question formulation, breeding objective optimization, parental taxa hybridization, progeny population selection, and innovation dissemination, aiming to improve the foresight, precision, and efficiency of breeding. Furthermore, the system has demonstrated successful cases of rice variety breeding over the past 20 years, such as for Suijing 3, Suijing 4, Suijing 18, and a series of other rice varieties, providing theoretical and technical supports for cold-region rice breeding.

Apoptosis and cuproptosis Co-activated Copper-based metal-organic frameworks for cancer therapy.

Lung cancer, predominantly non-small cell lung cancer (NSCLC), remains a significant global health challenge, with limited therapeutic options for patients with KRAS-mutated tumors. Herein, a copper-based metal-organic framework (Cu-MOF) was applied as a novel cuproptosis-mediated nanoplatform for lung cancer therapy. Cu-MOF would disassemble and liberate copper ions under the acidic microenvironment of lysosomes of cancer cells, initiating a cascade of cellular events. The released copper ions catalyzes the Fenton reaction, generating hydroxyl radicals that induce oxidative damage, leading to cytoskeletal disruption and activation of caspase-3, ultimately triggering apoptosis. Simultaneously, with the mediation of the key regulatory factor FDX1, we found that the copper ions binding to the mitochondrial protein DLAT could result in the loss of iron-sulfur cluster proteins and aggregation of lipoylated proteins, which culminated in proteotoxic stress-induced cuproptosis. The pronounced anti-tumor effects of Cu-MOF with apoptosis and cuproptosis were confirmed both in vitro and in vivo experiments. Such dual induction of apoptosis and cuproptosis by Cu-MOF presents a promising therapeutic strategy for NSCLC, particularly for KRAS-mutated tumors, and expands potential applications of Cu-based nanomateirals for other cancers.

Molecular characteristics of sea spray aerosols during aging with the participation of marine volatile organic compounds.

Sea spray aerosols (SSAs) are one of the largest natural sources of aerosols globally, known to affect the earth's radiation budget and to play a pivotal role in air quality and climate. The physical and chemical properties of organic components in SSA change during long-distance atmospheric transport over the ocean. To characterize the evolution of organic components during the aging process of SSA, in this study, we use a flow reactor to simulate the oxidation processes of SSA produced by authentic seawater via OH radicals (in the presence of organic gases evaporated from seawater) and to present the molecular signatures of the nascent and aged SSA. We found, under our experimental conditions, that oxidation of headspace organic gases during aging leads to significant formation of new particles and changes in the chemical constituents of SSA. In the nascent and aged SSA samples, we retained 129 and 340 products, respectively. The formation of high O/C and low carbon-number products was observed during the aging process, corresponding to functionalization and fragmentation reactions. Moreover, the significant contributions of compounds containing multiple nitrogen atoms and sulfate groups were observed in aged SSA for the first time, which can be attributed to the accretion reaction driven by OH heterogeneous oxidation and the formation of organic sulfur compounds, respectively. These findings provide additional insights into the atmospheric transformation of organic components in marine aerosols, which is important for understanding the global carbon cycle.

Tanshinone IIA potentiates the chemotherapeutic effect of doxorubicin against breast cancer cells and attenuates the cardiotoxicity of doxorubicin by regulating ERK1/2 pathway.

Doxorubicin (Dox) is frequently employed as a chemotherapy agent for breast cancer. As the chemotherapy moves forward, breast cancer cells tend to develop resistance to Dox, besides that, Dox are also easy to cause cardiotoxicity related to cumulative dose. Therefore, how to potentiate the chemosensitivity of breast cancer cells to Dox while attenuating its cardiotoxicity has become a research hotspot. Tanshinone IIA (Tan IIA) is known for its anticancer activity as well as for its cardioprotective effects. In view of the aforementioned facts, we assessed whether Tan IIA possesses synergism and attenuation effect on Dox for breast cancer chemotherapy. Our studies in vitro indicated that, Tan IIA could potentiate the effect of Dox on breast cancer cells proliferation inhibition and apoptosis promotion by inhibiting ERK1/2 pathway, but interestingly, Tan IIA attenuated the cytotoxicity of Dox to myocardial cells by activating ERK1/2 pathway. Additionally, our studies in vivo also suggested that Tan IIA potentiated the chemotherapeutic effect of Dox against breast cancer while attenuating Dox-induced myocardial injury. Given that Tan IIA had a synergism and attenuation effect on Dox, we believed that Tan IIA can be used as an ideal drug in combination with Dox for breast cancer therapy.

Integrating Bulk and Single-Cell RNA-Seq Data to Identify Prognostic Features Related to Activated Dendritic Cells in Clear-Cell Renal-Cell Carcinoma.

Dendritic cells (DCs) serve as key regulators in tumor immunity, with activated DCs potentiating antitumor responses through the secretion of pro-inflammatory cytokines and the expression of co-stimulatory molecules. Most current studies focus on the relationship between DC subgroups and clear-cell renal-cell carcinoma (ccRCC), but there is limited research on the connection between DCs and ccRCC from the perspective of immune activation. In this study, activated DC genes were identified in both bulk and single-cell RNA-seq data. A prognostic model related to activated DCs was constructed using univariate, multivariate Cox regression and LASSO regression. The prognostic model was validated in three external validation sets: GSE167573, ICGC, and E-MTAB-1980. The prognostic model consists of five genes, PLCB2, XCR1, IFNG, HLA-DQB2, and SMIM24. The expression of these genes was validated in tissue samples using qRT-PCR. Stratified analysis revealed that the prognostic model was able to better predict outcomes in advanced ccRCC patients. The risk scores were associated with tumor progression, tumor mutation burden, immune cell infiltration, and adverse outcomes of immunotherapy. Notably, there was a strong correlation between the expression of the five genes and the sensitivity to JQ1, a BET inhibitor. Molecular docking indicated high-affinity binding of the proteins encoded by these genes with JQ1. In conclusion, our study reveals the crucial role of activated DCs in ccRCC, offering new insights into predicting immune response, targeted therapy effectiveness, and prognosis for ccRCC patients.

Risk factors for hospitalization-associated disability among older patients: A systematic review and meta-analysis.

BACKGROUND: The outcomes of older patients are significantly limited by hospitalization-associated disability (HAD), and there are currently few available management options for HAD. This review aimed to identify and quantify the risk factors for HAD, to provide reliable evidence for developing a HAD prevention program centered on risk factor management among older patients. METHODS: The MEDLINE, Embase, PsycINFO, CINAHL, and PubMed databases were searched in March 2024 to identify cross-sectional and cohort studies that used multivariable analysis to examine risk factors for HAD among older patients. RESULTS: We screened 883 studies, 21 of which met our inclusion criteria. Our findings revealed a substantial association between various risk factors and HAD among older patients. Specifically, advanced age, female sex, Caucasian ethnicity, comorbidity burden, better activities of daily living at admission, dementia diagnosis, and longer lengths of stay were significant risk factors for HAD. Furthermore, frailty, poor physical function, immobility, and delirium were identified as confirmed risk factors for HAD among older patients. CONCLUSIONS: This review provided a comprehensive synthesis of available evidence on risk factors for HAD among older patients, serving as a valuable guide for the development of HAD prevention strategies both prior to and during hospitalization.

Fungicidal Activity of Novel 6-Isothiazol-5-ylpyrimidin-4-amine-Containing Compounds Targeting Complex I Reduced Nicotinamide Adenine Dinucleotide Oxidoreductase.

To discover novel inhibitors of the complex I reduced nicotinamide adenine dinucleotide (NADH) oxidoreductase as fungicides, a series of 6-isothiazol-5-ylpyrimidin-4-amine-containing compounds were designed using a computer-aided pesticide design method and splicing of substructures from diflumetorim and isotianil. In vitro fungicidal bioassays indicated that compounds T17-T24 showed high inhibitory activity against Rhizoctonia solani with an effective concentration (EC50) value falling between 2.20 and 23.85 µg/mL, which were more active than or equivalent to the lead diflumetorim with its EC50 of 19.80 µg/mL. In vivo antifungal bioassays demonstrated that, at a concentration of 200 µg/mL, T7 and T21 showed higher inhibition against Pseudoperonospora cubensis than all other compounds, while T23 exhibited the highest inhibition against Sphaerotheca fuliginea. T23 showed an approximately twofold lower inhibition potency against R. solani complex I NADH oxidoreductase than diflumetorim. Molecular docking and transcriptomic analyses indicated that T23 and diflumetorim both might share the same mode of action, targeting NADH oxidoreductase. T23 as a good fungicidal candidate against R. solani is worthy of further investigation.

Marine compressed air source array acoustic field characterization from at-sea measurements: Long-range propagationa).

In 2007, the Littoral Acoustic Demonstration Center conducted a comprehensive experiment in the northern Gulf of Mexico to measure the three-dimensional acoustic field of a standard marine compressed-air source array used in seismic exploration. This study aims to enhance understanding of long-range acoustic propagation of the array signals, with focus on variations in received sound pressure levels and sound exposure levels (SELs) at various ranges from the source. These variations are influenced by factors, such as receiver depth, array orientation, and propagation conditions. The long-range measurements show that received peak pressure levels and SELs exhibit non-monotonic (oscillatory) behavior with range leading up to 10 dB increase in received levels at longer ranges. At ranges beyond 20 km, acoustic levels at the shallowest hydrophone consistently surpassed those at deeper ones by 3-10 dB, suggesting the impact of surface duct propagation effects. The results demonstrate that range-independent bathymetry leads to approximately 4 dB higher received acoustic levels than range-dependent propagation conditions. The measured long-range propagation acoustic metrics from controlled experiment provide a unique and critical dataset for validating both source and propagation model accuracy in predicting received sound pressure and SEL in the far-field of the source array.

Use of indocyanine green-human serum albumin complexes in fluorescence image-guided laparoscopic anatomical liver resection: a case series study (with video).

BACKGROUND: This study aimed to investigate the feasibility and efficacy of near-infrared fluorescence-guided laparoscopic anatomical hepatectomy (LAH) using a novel indocyanine green (ICG)-human serum albumin complex (HSA) in patients with hepatocellular carcinoma. METHODS: Clinical data of hepatocellular carcinoma patients who underwent ICG-HSA fluorescence-guided LAH at our center from January 2024 to April 2024 were prospectively collected and analyzed. Ultraviolet absorption spectroscopy was used to test the absorption and stability of ICG-HSA complex solutions under different conditions. After determining the optimal ratio, the complex was administered intravenously during surgery to perform negative staining via Glissonean pedicle isolation. LAH was performed along the fluorescence-demarcated boundaries. RESULTS: Thirty-one patients were included (24 men; mean age, 54.61 ± 13.54 years). The median maximum tumor diameter was 2.80 (interquartile range [IQR], 2.00-4.00) cm. S8 segmentectomy (22.6%) and right posterior segmentectomy (19.4%) were the most common resections performed. Successful fluorescence negative staining was achieved in all patients using ICG and HSA at a 1:6 molar ratio at room temperature. Mean operation time was 297.58 ± 85.53 min, Median intraoperative blood loss was 100.0 mL (IQR, 50.0-200.0). The median surgical margin distance was 0.90 cm (IQR, 0.40-1.50). The postoperative complication rate was 45.2% (35.5% Clavien-Dindo grade I and 9.7% grade II). The median length of hospital stay was 5.0 days (IQR, 4.0-5.0). CONCLUSION: ICG-HSA-assisted LAH is safe and feasible. Compared with free ICG, the novel ICG-HSA complex exhibits better optical properties and in vivo stability, which can improve the accuracy of intraoperative liver segment localization and optimize the anatomical dissection plane. It has the potential to become an ideal fluorescent imaging agent for anatomical hepatectomy.

Construction and validation of a nomogram for predicting cancer-specific survival in middle-aged patients with advanced hepatocellular carcinoma: A SEER-based study.

Hepatocellular carcinoma is the predominant form of primary liver cancer and is the leading cause of cancer-related death. The aim of this study was to construct a nomogram to predict cancer-specific survival (CSS) in middle-aged patients with advanced hepatocellular carcinoma. Clinical data were downloaded from the Surveillance, Epidemiology and End Results (SEER) database for middle-aged patients diagnosed with advanced hepatocellular carcinoma (AJCC stage III and IV) from 2000 to 2019. The patients were randomized in a 7:3 ratio into training cohort and validation cohort. Univariate and multivariate Cox regression analyses were performed in the training cohort to screen for independent risk factors associated with cancer-specific survival for the construction of nomogram. The nomogram was examined and evaluated using the consistency index (C-index), area under the curve (AUC), and calibration plots. The clinical application value of the model was evaluated using decision curve analysis (DCA). A total of 3026 patients were selected, including 2244 in the training cohort and 962 in the validation cohort. Multivariate analysis revealed gender, marital status, American Joint Committee on Cancer (AJCC) stage, tumor size, bone metastasis, lung metastasis, alpha-fetoprotein (AFP) level, surgery, radiotherapy, chemotherapy as independent risk factors, which were all included in the construction of the nomogram. In the training cohort, the AUC values were 0.74 (95% CI: 0.76-0.72), 0.78 (95% CI: 0.82-0.75), and 0.82 (95% CI: 0.86-0.78) at 1-, 3-, and 5-year CSS, respectively. The calibration plots showed good consistency between the actual and predicted values. The DCA curves indicated that the nomogram model could more accurately predict CSS at 1-, 3-, and 5-year in middle-aged patients with advanced hepatocellular carcinoma compared with the AJCC staging system. Highly similar results to the training cohort were also observed in the validation cohort. In the risk stratification system, good differentiation was shown between the 2 groups, and Kaplan-Meier survival analysis indicated that surgery could prolong patient survival. In this study, we developed a nomogram and risk stratification system for predicting CSS in middle-aged patients with advanced hepatocellular carcinoma. The prediction model has good predictive performance and can help clinicians in judging prognosis and clinical decision making.

Perioperative and functional outcomes of single-port versus multi-port robotic-assisted radical cystectomy: evidence-based on controlled studies.

To compare perioperative outcomes of robot-assisted radical cystectomy (RARC) using a single-port (SP) or multi-port (MP) robotic platform. We conducted a comprehensive search of the PubMed, Web of Science, Scopus, and Google Scholar databases until June 2024. For a combined analysis of the data using random effects, Review Manager 5.4 was employed. To compare continuous and categorical variables, the weighted mean difference (WMD) and odds ratio (OR) were employed, respectively. Three original studies were included, comprising a total of 170 patients (SP-RARC: 73 versus MP-RARC: 93).Recovery of bowel function was faster in SP-RARC (WMD -1.02 days, 95% CI - 1.33 to - 0.17; p < 0.001), and lymph-node yield was lower than in MP-RARC patients (WMD - 6.32, 95% CI - 8.90 to - 3.75; p < 0.00001).There were no significant differences between the SP-RARC and MP-RARC groups in terms of other perioperative outcomes such as surgery duration, length of hospital stay, estimated blood loss, major complication rate, positive surgical margin rate, readmission rate, and recurrence rate. The SP robot offers a safe alternative surgical approach to RARC, providing similar postoperative outcomes compared to the MP robot. The SP system remains an attractive option that will require longer follow-up and cohort validation in the future.

Efficacy of robot-assisted gait training on lower extremity function in subacute stroke patients: a systematic review and meta-analysis.

BACKGROUND: Robot-Assisted Gait Training (RAGT) is a novel technology widely employed in the field of neurological rehabilitation for patients with subacute stroke. However, the effectiveness of RAGT compared to conventional gait training (CGT) in improving lower extremity function remains a topic of debate. This study aimed to investigate and compare the effects of RAGT and CGT on lower extremity movement in patients with subacute stroke. METHODS: Comprehensive search was conducted across multiple databases, including PubMed, Web of Science, Cochrane Library, EBSCO, Embase, Scopus, China National Knowledge Infrastructure, Wan Fang, SinoMed and Vip Journal Integration Platform. The database retrieval was performed up until July 9, 2024. Meta-analysis was conducted using RevMan 5.4 software. RESULTS: A total of 24 RCTs were included in the analysis. The results indicate that, compared with CGT, RAGT led to significant improvements in the Fugl-Meyer Assessment for Lower Extremity [MD = 2.10, 95%CI (0.62, 3.59), P = 0.005], Functional Ambulation Category[MD = 0.44, 95%CI (0.23, 0.65), P < 0.001], Berg Balance Scale [MD = 4.55, 95%CI (3.00, 6.11), P < 0.001], Timed Up and Go test [MD = -4.05, 95%CI (-5.12, -2.98), P < 0.001], and 6-Minute Walk Test [MD = 30.66, 95%CI (22.36, 38.97), P < 0.001] for patients with subacute stroke. However, it did not show a significant effect on the 10-Meter Walk Test [MD = 0.06, 95%CI (-0.01, 0.14), P = 0.08]. CONCLUSIONS: This study provides evidence that RAGT can enhance lower extremity function, balance function, walking ability, and endurance levels compared to CGT. However, the quality of evidence for improvements in gait speed remains low.

High-Throughput Screening of Antioxidant Drug Candidates from Natural Antioxidants with a "Zero" Intrinsic Fluorescence Peroxynitrite Sensing Precursor.

The fluorescence high-throughput screening method is of importance for new antioxidant drug candidate discovery for the treatment of serious hepatorenal syndrome, which displayed an obvious upregulated peroxynitrite level. However, most of the current ONOO- probes possessed incomplete fluorescence quenching efficiency, which can result in non-negligible probe inherent fluorescence. Hence, we utilized the probe conjugated structure disruption strategy to construct hydrogenation phosphorus-substituted rhodamine (H-PRh) with "zero" probe inherent fluorescence character. Based on the precursor, a series of natural products were screened for identifying antioxidant drug candidates. Luteolin was screened out by activating the Sirt1-Nrf2-HO-1 signaling pathway to regulate the accumulation of ONOO- in the hepatorenal syndrome. Overall, the "zero" probe inherent fluorescence ONOO- sensor constructed here applies for a promising and versatile toolbox for illuminating the ONOO--related pathological process in the hepatorenal syndrome. Besides, this strategy of constructing highly sensitive sensors could serve as a valuable reference for further fluorescent probes.

Development of a sequential release nanomaterial for co-delivery of hypoxia-induced tirapazamine and HIF-1α siRNA in cancer therapy.

Unlike traditional drug carriers, sequential drug delivery systems can release different drugs in order, with the first released drug providing a prerequisite for the later released drug to maximize its function, thereby achieving stronger anti-tumor effects. Herein we constructed a temporal sequential system designated TPZ@MSN/HIF-1α siRNA@PDA@GOx (MTRPG) in which mesoporous silica nanoparticles were used as cores to load hypoxia induced chemotherapy drug tirapazamine (TPZ) and gene targeted nucleic acid drug HIF-1α siRNA, polydopamine (PDA) as acid -responsive coating as well as to realize photothermal therapy, and glucose oxidase (GOx) as the outermost layer to achieve starvation therapy and construct a deepened hypoxia to activate TPZ. Through in vitro and in vivo experiments, we demonstrated that the first released glucose oxidase catalyzed the oxidation of glucose, achieving starvation treatment while reducing the acidic environment and further exacerbating hypoxia in tumor cells. The reduced acidic conditions enabled the degradation of PDA, resulting in the release of loaded HIF-1α siRNA and TPZ. At the same time, PDA could also exert photothermal therapy under 808 nm near-infrared (808 nm NIR) laser irradiation. The later released hypoxia induced chemotherapy drug TPZ amplifies its anti-tumor activity under intensified hypoxia conditions. Meanwhile, the released HIF-1α siRNA interfered with the up-regulated HIF-1α induced by the deepened hypoxia condition, which caused hypoxia tolerance in tumors, reduced its expression activity, and achieved synergistic killing of tumor cells with chemotherapy. This work provides an effective multimodal synergistic therapy strategy to promote tumor therapeutic index, which may possess a promising future in clinical application.

In vivo evidence of increased vascular endothelial growth factor in patients with major depressive disorder.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a candidate mediator of blood-brain barrier (BBB) disruption in depression. However, previous studies have mainly focused on peripheral blood VEGF levels, and the results are heterogeneous. Here we use astrocyte-derived extracellular vesicles (ADEVs) isolated from plasma to explore the in vivo changes of VEGF levels in patients with major depressive disorder (MDD). METHODS: Thirty-five unmedicated patients with MDD and 35 healthy controls (HCs) were enrolled, and plasma ADEVs were isolated from each participant. VEGF levels in ADEVs and glial fibrillary acidic protein (GFAP) in plasma were measured. Additionally, Alix and CD81, two established extracellular vesicle markers, were quantified in ADEVs. RESULTS: At baseline, MDD patients exhibited significantly increased levels of VEGF in ADEVs and GFAP in plasma. Following four weeks of selective serotonin reuptake inhibitor treatment, these target protein levels did not significantly change. ROC curve analysis revealed an AUC of 0.711 for VEGF in ADEVs. In exploratory analysis, VEGF levels in ADEVs were positively correlated with Alix and CD81. LIMITATIONS: Multiple factors regulate BBB permeability. This study focused solely on VEGF and the sample size for longitudinal analysis was relatively small. CONCLUSION: Our study is the first to confirm increased ADEV-derived VEGF levels in patients with MDD, thereby providing preliminary evidence supporting the hypothesis that the BBB is disrupted in depression.