Hemoglobin nanoclusters-mediated regulation of KPNA4 in hypoxic tumor microenvironment enhances photodynamic therapy in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant tumor known for its hypoxic environment, which contributes to resistance against the anticancer drug Sorafenib (SF). Addressing SF resistance in HCC requires innovative strategies to improve tumor oxygenation and effectively deliver therapeutics. RESULTS: In our study, we explored the role of KPNA4 in mediating hypoxia-induced SF resistance in HCC. We developed hemoglobin nanoclusters (Hb-NCs) capable of carrying oxygen, loaded with indocyanine green (ICG) and SF, named HPRG@SF. In vitro, HPRG@SF targeted HCC cells, alleviated hypoxia, suppressed KPNA4 expression, and enhanced the cytotoxicity of PDT against hypoxic, SF-resistant HCC cells. In vivo experiments supported these findings, showing that HPRG@SF effectively improved the oxygenation within the tumor microenvironment and countered SF resistance through combined photodynamic therapy (PDT). CONCLUSION: The combination of Hb-NCs with ICG and SF, forming HPRG@SF, presents a potent strategy to overcome drug resistance in hepatocellular carcinoma by improving hypoxia and employing PDT. This approach not only targets the hypoxic conditions that underlie resistance but also provides a synergistic anticancer effect, highlighting its potential for clinical applications in treating resistant HCC.

Metabolic impairments associated with type 2 diabetes mellitus and the potential effects of exercise therapy: An exploratory randomized trial based on untargeted metabolomics.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a common condition that is characterized by metabolic impairments. Exercise therapy has proven effective in improving the physiological and psychological states of patients with T2DM; however, the influence of different exercise modalities on metabolic profiles is not fully understood. This study first aimed to investigate the metabolic changes associated with T2DM among patients and then to evaluate the potential physiological effects of different exercise modalities (Tai Chi and brisk walking) on their metabolic profiles. METHODS: This study included 20 T2DM patients and 11 healthy subjects. Patients were randomly allocated to either the Tai Chi or walking group to perform Dijia simplified 24-form Tai Chi or brisk walking (80-100 m/min), with 90 minutes each time, three times per week for 12 weeks, for a total of 36 sessions. The healthy group maintained daily living habits without intervention. Glycemic tests were conducted at the baseline and after 12 weeks. Serum and urine samples were collected for untargeted metabolomic analyses at baseline and 12 weeks to examine the differential metabolic profiles between T2DM and healthy subjects, and the metabolic alterations of T2DM patients before and after exercise therapy. RESULTS: Compared to the healthy group, T2DM patients exhibited metabolic disturbances in carbohydrates (fructose, mannose, galactose, glycolysis/gluconeogenesis), lipids (inositol phosphate), and amino acids (arginine, proline, cysteine, methionine, valine, leucine, and isoleucine) metabolism, including 20 differential metabolites in the serum and six in the urine. After exercise, the glycemic results showed insignificant changes. However, patients who practiced Tai Chi showed significant improvements in their post-treatment metabolic profiles compared to baseline, with nine serum and six urine metabolites, including branch-chained amino acids (BCAAs); while those in the walking group had significantly altered nine serum and four urine metabolites concerning steroid hormone biosynthesis and arachidonic acid metabolism compared to baseline. CONCLUSION: T2DM patients displayed impaired carbohydrate, lipid, and amino acid metabolism, and exercise therapy improved their metabolic health. Different modalities may act through different pathways. Tai Chi may improve disrupted BCAAs metabolism, whereas brisk walking mainly regulates steroid hormone biosynthesis and arachidonic acid metabolism.

Aging properties of polyethylene and polylactic acid microplastics and their adsorption behavior of Cd(II) and Cr(VI) in aquatic environments.

In this study, we examined the aging characteristics of polyethylene (PE) and polylactic acid (PLA) microplastics (MPs), examining the adsorption behaviors and mechanisms concerning Cd(II) and Cr(VI) under both single and binary systems. The results revealed that aging treatment changed the physicochemical properties of MPs. The aging mechanisms of PLA and PE MPs were shown to be similar by the 2D-FTIR-COS study. These mechanisms involve the formation of oxygen-containing functional groups through the combination of carbon chain breakdown and oxygen. Aged MPs had a greater ability to adsorb metal ions than pristine MPs, with PLA MPs outperforming PE MPs. After 30 days of aging, Cd(II) adsorption increased by 40.61 % and 25.49 % for PE and PLA MPs, respectively, while Cr(VI) adsorption increased by 37.50 % and 69.29 %, respectively. The adsorption ability of PE and PLA MPs with Cd(II) or Cr(VI) under binary systems was less than that under single systems, with Cd(II) exhibiting more adsorption competitiveness than Cr(VI). Humic acid (HA), ionic species and strength, solution pH, and adsorption of Cd(II) and Cr(VI) were found to be significantly correlated. Further investigation into the adsorption mechanisms of Cd(II) and Cr(VI) on PE and PLA MPs revealed that pore-filling, electrostatic interactions, complexation, and hydrogen bonding play important roles in the adsorption process. The study's conclusions are crucial for assessing the risk associated with concurrent contamination by metal ions and microplastics.

Adaptive characteristics of indigenous microflora in an organically contaminated high salinity groundwater.

Salinity, a critical factor, could directly or indirectly affect the microbial community structure and diversity. Changes in salinity levels act as environmental filters that influence the transformation of key microbial species. This study investigates the adaptive characteristics of indigenous microflora in groundwater in relation to external organic pollutants under high salinity stress. A highly mineralized shallow groundwater in Northwest China was conducted as the study area, and six representative sampling points were chosen to explore the response of groundwater hydrochemical parameters and microflora, as well as to identify the tolerance mechanisms of indigenous microflora to combined pollution. The results revealed that the dominant genera found in high salinity groundwater contaminated with organic pollutants possess the remarkable ability to degrade such pollutants even under challenging high salinity conditions, including Halomonas, Pseudomonas, Halothiobacillus, Sphingomonas, Lutibacter, Aquabacterium, Thiomicrospira, Aequorivita, etc. The hydrochemical factors, including total dissolved solids (TDS), sulfide, nitrite, nitrate, oxidation reduction potential (ORP), NH3-N, Na, Fe, benzene series, phenols, and halogenated hydrocarbons, demonstrated a significant influence on microflora. High levels of sulphate and sulfide in groundwater can exhibit dual effects on microflora. On one hand, these compounds can inhibit the growth and metabolism of microorganisms. On the other hand, they can also serve as effective electron donors/receptors during the microbial degradation of organic pollutants. Microorganisms exhibit resilience to the inhibitory effects of high salinity and organic pollutants via a series of tolerance mechanisms, such as strengthening the extracellular membrane barrier, enhancing the synthesis of relevant enzymes, initiating novel biochemical reactions, improving cellular self-healing capabilities, responding to unfavorable environmental conditions by migration, and enhancing the S cycle for the microbial metabolism of organic pollutants.

Cross-catenation between position-isomeric metallacages.

The study of cross-catenated metallacages, which are complex self-assembly systems arising from multiple supramolecular interactions and hierarchical assembly processes, is currently lacking but could provide facile insights into achieving more precise control over low-symmetry/high-complexity hierarchical assembly systems. Here, we report a cross-catenane formed between two position-isomeric Pt(II) metallacages in the solid state. These two metallacages formed [2]catenanes in solution, whereas a 1:1 mixture selectively formed a cross-catenane in crystals. Varied temperature nuclear magnetic resonance experiments and time-of-flight mass spectra are employed to characterize the cross-catenation in solutions, and the dynamic library of [2]catenanes are shown. Additionally, we searched for the global-minimum structures of three [2]catenanes and re-optimized the low-lying structures using density functional theory calculations. Our results suggest that the binding energy of cross-catenanes is significantly larger than that of self-catenanes within the dynamic library, and the selectivity in crystallization of cross-catenanes is thermodynamic. This study presents a cross-catenated assembly from different metallacages, which may provide a facile insight for the development of low-symmetry/high-complexity self-assemble systems.

Inhibition of mitophagy via the EIF2S1-ATF4-PRKN pathway contributes to viral encephalitis.

INTRODUCTION: Mitophagy, a selective form of autophagy responsible for maintaining mitochondrial homeostasis, regulates the antiviral immune response and acts as viral replication platforms to facilitate infection with various viruses. However, its precise role in herpes simplex virus 1 (HSV-1) infection and herpes simplex encephalitis (HSE) remains largely unknown. OBJECTIVES: We aimed to investigate the regulation of mitophagy by HSV-1 neurotropic infection and its role in viral encephalitis, and to identify small compounds that regulate mitophagy to affect HSV-1 infection. METHODS: The antiviral effects of compounds were investigated by Western blot, RT-PCR and plaque assay. The changes of Parkin (PRKN)-mediated mitophagy and Nuclear Factor kappa B (NFKB)-mediated neuroinflammation were examined by TEM, RT-qPCR, Western blot and ELISA. The therapeutic effect of taurine or PRKN-overexpression was confirmed in the HSE mouse model by evaluating survival rate, eye damage, neurodegenerative symptoms, immunohistochemistry analysis and histopathology. RESULTS: HSV-1 infection caused the accumulation of damaged mitochondria in neuronal cells and in the brain tissue of HSE mice. Early HSV-1 infection led to mitophagy activation, followed by inhibition in the later viral infection. The HSV-1 proteins ICP34.5 or US11 deregulated the EIF2S1-ATF4 axis to suppress PRKN/Parkin mRNA expression, thereby impeding PRKN-dependent mitophagy. Consequently, inhibition of mitophagy by specific inhibitor midiv-1 promoted HSV-1 infection, whereas mitophagy activation by PRKN overexpression or agonists (CCCP and rotenone) attenuated HSV-1 infection and reduced the NF-κB-mediated neuroinflammation. Moreover, PRKN-overexpressing mice showed enhanced resistance to HSV-1 infection and ameliorated HSE pathogenesis. Furthermore, taurine, a differentially regulated gut microbial metabolite upon HSV-1 infection, acted as a mitophagy activator that transcriptionally promotes PRKN expression to stimulate mitophagy and to limit HSV-1 infection both in vitro and in vivo. CONCLUSION: These results reveal the protective function of mitophagy in HSE pathogenesis and highlight mitophagy activation as a potential antiviral therapeutic strategy for HSV-1-related diseases.

Targeting MS4A4A: A novel pathway to improve immunotherapy responses in glioblastoma.

INTRODUCTION: Glioblastoma (GBM) remains a challenging brain tumor to treat, with limited response to PD-1 immunotherapy due to tumor-associated macrophages (TAMs), specifically the M2 phenotype. This study explores the potential of MS4A4A (membrane spanning four domains, subfamily A, member 4A) inhibition in driving M2 macrophage polarization toward the M1 phenotype via the ferroptosis pathway to enhance the effectiveness of immunotherapy in GBM. METHODS: Single-cell RNA sequencing and spatial transcriptomic analyses were employed to characterize M2 macrophages and MS4A4A expression in GBM. In vitro studies utilizing TAM cultures, flow cytometry, and western blot validations were conducted to assess the impact of MS4A4A on the tumor immune microenvironment and M2 macrophage polarization. In vivo models, including subcutaneous and orthotopic transplantation in mice, were utilized to evaluate the effects of MS4A4A knockout and combined immune checkpoint blockade (ICB) therapy on tumor growth and response to PD-1 immunotherapy. RESULTS: Distinct subsets of GBM-associated macrophages were identified, with spatial distribution in tumor tissue elucidated. In vivo experiments demonstrated that inhibiting MS4A4A and combining ICB therapy effectively inhibited tumor growth, reshaped the tumor immune microenvironment by reducing M2 TAM infiltration and enhancing CD8+ T-cell infiltration, ultimately leading to complete tumor eradication. CONCLUSION: MS4A4A inhibition shows promise in converting M2 macrophages to M1 phenotype via ferroptosis, decreasing M2-TAM infiltration, and enhancing GBM response to PD-1 immunotherapy. These findings offer a novel approach to developing more effective immunotherapeutic strategies for GBM.

Mosaic RBD Nanoparticles Elicit Protective Immunity Against Multiple Human Coronaviruses in Animal Models.

To combat SARS-CoV-2 variants and MERS-CoV, as well as the potential re-emergence of SARS-CoV and spillovers of sarbecoviruses, which pose a significant threat to global public health, vaccines that can confer broad-spectrum protection against betacoronaviruses (ß-CoVs) are urgently needed. A mosaic ferritin nanoparticle vaccine is developed that co-displays the spike receptor-binding domains of SARS-CoV, MERS-CoV, and SARS-CoV-2 Wild-type (WT) strain and evaluated its immunogenicity and protective efficacy in mice and nonhuman primates. A low dose of 10 µg administered at a 21-day interval induced a Th1-biased immune response in mice and elicited robust cross-reactive neutralizing antibody responses against a variety of ß-CoVs, including a series of SARS-CoV-2 variants. It is also able to effectively protect against challenges of SARS-CoV, MERS-CoV, and SARS-CoV-2 variants in not only young mice but also the more vulnerable mice through induction of long-lived immunity. Together, these results suggest that this mosaic 3-RBD nanoparticle has the potential to be developed as a pan-ß-CoV vaccine.