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Journal of Controlled Release :... Jun 2024Cancer immunotherapy remains a significant challenge due to insufficient proliferation of immune cells and the sturdy immunosuppressive tumor microenvironment. Herein,...
Cancer immunotherapy remains a significant challenge due to insufficient proliferation of immune cells and the sturdy immunosuppressive tumor microenvironment. Herein, we proposed the hypothesis of cuproptosis-lactate regulation to provoke cuproptosis and enhance anti-tumor immunity. For this purpose, copper-human serum albumin nanocomplex loaded gold nanocages with bacterial membrane coating (BAu-CuNCs) were developed. The targeted delivery and disassembly of BAu-CuNCs in tumor cells initiated a cascade of reactions. Under near infrared (NIR) laser irradiation, the release of copper-human serum albumin (Cu-HSA) was enhanced that reacted with intratumoral glutathione (GSH) via a disulfide exchange reaction to liberate Cu ions and exert cuproptosis. Subsequently, the cuproptosis effect triggered immunogenic cell death (ICD) in tumor by the release of damage associated molecular patterns (DAMPs) to realize anti-tumor immunity via robust production of cytotoxic T cells (CD8) and helper T cells (CD4). Meanwhile, under NIR irradiation, gold nanocages (AuNCs) promoted excessive reactive oxygen species (ROS) generation that played a primary role in inhibiting glycolysis, reducing the lactate and ATP level. The combine action of lower lactate level, ATP reduction and GSH depletion further sensitized the tumor cells to cuproptosis. Also, the lower lactate production led to the significant blockage of immunosuppressive T regulatory cells (Tregs) and boosted the anti-tumor immunity. Additionally, the effective inhibition of breast cancer metastasis to the lungs enhanced the anti-tumor therapeutic impact of BAu-CuNCs + NIR treatment. Hence, BAu-CuNCs + NIR concurrently induced cuproptosis, ICD and hindered lactate production, leading to the inhibition of tumor growth, remodeling of the immunosuppressive tumor microenvironment and suppression of lung metastasis. Therefore, leveraging cuproptosis-lactate regulation, this approach presents a novel strategy for enhanced tumor immunotherapy.
PubMed: 38917953
DOI: 10.1016/j.jconrel.2024.06.059 -
Life Sciences Jun 2024The primary and initial manifestations of hypertension encompass arterial hypoelasticity and histiocyte senescence. Oxidative stress plays a pivotal role in the...
The primary and initial manifestations of hypertension encompass arterial hypoelasticity and histiocyte senescence. Oxidative stress plays a pivotal role in the progression of senescence. Elevated intracellular oxidative stress levels will directly induce cell damage, disrupt normal physiological signal transduction, which can cause mitochondrial dysfunction to accelerate the process of senescence. Alizarin, an anthraquinone active ingredient isolated from Rubia cordifolia L., has a variety of pharmacological effects, including antioxidant, anti-inflammatory and anti-platelet. Nevertheless, its potential in lowering blood pressure (BP) and mitigating hypertension-induced vascular senescence remains uncertain. In this study, we used spontaneously hypertensive rats (SHR) and human umbilical vein endothelial cells (HUVECs) to establish a model of vascular senescence in hypertension. Our aim was to elucidate the mechanisms underpinning the vascular protective effects of Alizarin. By assessing systolic blood pressure (SBP) and diastolic blood pressure (DBP), H&E staining, SA-β-Gal staining, vascular function, oxidative stress levels, calcium ion concentration and mitochondrial membrane potential, we found that Alizarin not only restored SBP and increased endothelium-dependent relaxation (EDR) in SHR, but also inhibited oxidative stress-induced mitochondrial damage and significantly delayed the vascular senescence effect in hypertension, and the mechanism may be related to the activation of VEGFR2/eNOS signaling pathway.
PubMed: 38917872
DOI: 10.1016/j.lfs.2024.122862 -
Biomedical Materials (Bristol, England) Jun 2024N-chloro-N-fluorobenzenesulfonylamide (CFBSA), was a novel chlorinating reagent, which exhibits potential antibacterial activities. In this study, CFBSA was confirmed as...
N-chloro-N-fluorobenzenesulfonylamide (CFBSA), was a novel chlorinating reagent, which exhibits potential antibacterial activities. In this study, CFBSA was confirmed as a wide-broad antimicrobial and bactericidal drug against different gram-negative bacteria, gram-positive bacteria and fungi, while it was found to have low cytotoxicity for eukaryotic cells. In addition, microorganism morphology assay and oxidative stress test was used to determine the antimicrobial mechanisms of CFBSA. According to the results, CFBSA probably had a target on cell membrane and killed microorganism by disrupting its cell membrane. Then, CFBSA was first combined with PLCL/SF via electrospinning and applied in wound dressings. The characterization of different PLCL/SF of CFBSA-loaded nanofibrous mats was investigated by SEM, water contact angle, FTIR, cell compatibility and antimicrobial test. CFBSA-loaded PLCL/SF nanofibrous mats showed excellent antimicrobial activities. In order to balance of the biocompatibility and antibacterial efficiency, SP-2.5 was selected as the ideal loading concentration for further application of CFBSA-loaded PLCL/SF. In conclusion, the electrospun CFBSA-loaded PLCL/SF nanofibrous mat with its broad-spectrum antimicrobial and bactericidal activity and good biocompatibility showed enormous potential for wound dressing.
PubMed: 38917818
DOI: 10.1088/1748-605X/ad5ba4 -
Biomedical Materials (Bristol, England) Jun 2024The multiphase bioactive socket plug is designed to overcome the natural healing process of the extraction socket by maintaining the three-dimensional (3D) volume of...
The multiphase bioactive socket plug is designed to overcome the natural healing process of the extraction socket by maintaining the three-dimensional (3D) volume of extraction sockets, particularly in sockets with wall defects, and later provide sufficient alveolar bone volume for implant placement. The study aimed to fabricate and evaluate the physical, mechanical, and biological performance of a multiphase bioactive socket plug in vitro. A multiphase bioactive socket plug was fabricated through freeze-drying and layer-by-layer assembly, comprised of a base serving as a scaffold, a central portion for promoting bone regeneration, an upper buccal portion for maintaining alveolar socket dimension with a covering collagen membrane (Memb) on the top and upper buccal surface to prevent soft tissue infiltration. The multiphase bioactive socket plug (BP) as the experimental group, and a pure collagen plug (CP) as a control group were investigated and compared in physicochemical and in vitro biological properties. Scanning electron microscopy (SEM), radiograph and Energy-dispersive spectroscopy (EDS) mapping confirmed the four-part BP was successfully assembled and fabricated. Swelling rate analysis indicated that BP, CP, and Memb reached swelling equilibrium within 1 hour. BP exhibited a high percentage of the remaining weight in collagenase solution (68.81 ± 2.21% on day 90) and sustained calcium ion release, reaching the maximum 0.13 ± 0.04 mmol/L on day 14. In biological assays, BP exhibited excellent cell proliferation (The OD value increased from 0.02 on day 1 to 0.23 on day 21.). The BP group exhibited higher alkaline phosphatase (ALP) activity and Osteocalcin (OCN) content compared to the CP group within 21 days. Memb and BP exhibited outstanding barrier function, as evidenced by Hematoxylin and eosin (H&E) staining. In summary, the multiphase bioactive socket plug represents a promising scaffold for alveolar ridge preservation application.
PubMed: 38917815
DOI: 10.1088/1748-605X/ad5ba7 -
Current Biology : CB Jun 2024Plants have evolved mechanisms to abscise organs as they develop or when exposed to unfavorable conditions. Uncontrolled abscission of petals, fruits, or leaves can...
Plants have evolved mechanisms to abscise organs as they develop or when exposed to unfavorable conditions. Uncontrolled abscission of petals, fruits, or leaves can impair agricultural productivity. Despite its importance for abscission progression, our understanding of the IDA signaling pathway and its regulation remains incomplete. IDA is secreted to the apoplast, where it is perceived by the receptors HAESA (HAE) and HAESA-LIKE2 (HSL2) and somatic embryogenesis receptor kinase (SERK) co-receptors. These plasma membrane receptors activate an intracellular cascade of mitogen-activated protein kinases (MAPKs) by an unknown mechanism. Here, we characterize brassinosteroid signaling kinases (BSKs) as regulators of floral organ abscission in Arabidopsis. BSK1 localizes to the plasma membrane of abscission zone cells, where it interacts with HAESA receptors to regulate abscission. Furthermore, we demonstrate that YODA (YDA) has a leading role among other MAPKKKs in controlling abscission downstream of the HAESA/BSK complex. This kinase axis, comprising a leucine-rich repeat receptor kinase, a BSK, and an MAPKKK, is known to regulate stomatal patterning, early embryo development, and immunity. How specific cellular responses are obtained despite signaling through common effectors is not well understood. We show that the identified abscission-promoting allele of BSK1 also enhances receptor signaling in other BSK-mediated pathways, suggesting conservation of signaling mechanisms. Furthermore, we provide genetic evidence supporting independence of BSK1 function from its kinase activity in several developmental processes. Together, our findings suggest that BSK1 facilitates signaling between plasma membrane receptor kinases and MAPKKKs via conserved mechanisms across multiple facets of plant development.
PubMed: 38917797
DOI: 10.1016/j.cub.2024.05.057 -
Biomedicine & Pharmacotherapy =... Jun 2024Ferroptosis is a lipid peroxidation-driven and iron-dependent form of programmed cell death, which is involved in a variety of physical processes and multiple diseases.... (Review)
Review
Ferroptosis is a lipid peroxidation-driven and iron-dependent form of programmed cell death, which is involved in a variety of physical processes and multiple diseases. Numerous reports have demonstrated that ferroptosis is closely related to the pathophysiological processes of Mycobacterium tuberculosis (M. tuberculosis) infection and is characterized by the accumulation of excess lipid peroxides on the cell membrane. In this study, the various functions of ferroptosis, and the therapeutic strategies and diagnostic biomarkers of tuberculosis, were summarized. Notably, this review provides insights into the molecular mechanisms and functions of M. tuberculosis-induced ferroptosis, suggesting potential future therapeutic and diagnostic markers for tuberculosis.
PubMed: 38917759
DOI: 10.1016/j.biopha.2024.117030 -
Journal of Hazardous Materials Jun 2024The propagation of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) induced by the release of antibiotics poses great threats to ecological...
The propagation of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) induced by the release of antibiotics poses great threats to ecological safety and human health. In this study, periodate (PI)/FeS/simulated sunlight (SSL) system was employed to remove representative ARB, ARGs and antibiotics in water. 1 × 10 CFU mL of gentamycin-resistant Escherichia coli was effectively disinfected below limit of detection in PI/FeS/SSL system under different water matrix and in real water samples. Sulfadiazine-resistant Pseudomonas and Gram-positive Bacillus subtilis could also be efficiently sterilized. Theoretical calculation showed that (110) facet was the most reactive facet on FeS to activate PI for the generation of reactive species (·OH, ·O, h and Fe(IV)=O) to damage cell membrane and intracellular enzyme defense system. Both intracellular and extracellular ARGs could be degraded and the expression levels of multidrug resistance-related genes were downregulated during the disinfection process. Thus, horizontal gene transfer (HGT) of ARB was inhibited. Moreover, PI/FeS/SSL system could disinfect ARB in a continuous flow reactor and in an enlarged reactor under natural sunlight irradiation. PI/FeS/SSL system could also effectively degrade the HGT-promoting antibiotic (ciprofloxacin) via hydroxylation and ring cleavage process. Overall, PI/FeS/SSL exhibited great promise for the elimination of antibiotic resistance from water.
PubMed: 38917629
DOI: 10.1016/j.jhazmat.2024.134982 -
Journal of Hazardous Materials Jun 2024Bivalve hemocytes are oyster immune cells composed of several cellular subtypes with different functions. Hemocytes accumulate high concentrations of copper (Cu) and...
Bivalve hemocytes are oyster immune cells composed of several cellular subtypes with different functions. Hemocytes accumulate high concentrations of copper (Cu) and exert critical roles in metal sequestration and detoxification in oysters, however the specific biochemical mechanisms that govern this have yet to be fully uncovered. Herein, we demonstrate that Cu(I) is predominately sequestered in lysosomes via the Cu transporter ATP7A in hemocytes to reduce the toxic effects of intracellular Cu(I). We also found that Cu(I) is translocated along tunneling nanotubes (TNTs) relocating from high Cu(I) cells to low Cu(I) cells, effectively reducing the burden caused by overloaded Cu(I), and that ATP7A facilitates the efflux of intracellular Cu(I) in both TNTs and hemocyte subtypes. We identify that elevated glutathione (GSH) contents and heat-shock protein (Hsp) levels, as well as the activation of the cell cycle were critical in maintaining the cellular homeostasis and function of hemocytes exposed to Cu. Cu exposure also increased the expression of membrane proteins (MYOF, RalA, RalBP1, and cadherins) and lipid transporter activity which can induce TNT formation, and activated the lysosomal signaling pathway, promoting intercellular lysosomal trafficking dependent on increased hydrolase activity and ATP-dependent activity. This study explores the intracellular and intercellular transport and detoxification of Cu in oyster hemocytes, which may help in understanding the potential toxicity and fate of metals in marine animals.
PubMed: 38917627
DOI: 10.1016/j.jhazmat.2024.135003 -
International Journal For Parasitology.... Jun 2024Toxoplasma gondii and Neospora caninum are major worldwide morbidity-causing pathogens. Bumped kinase inhibitors (BKIs) are a compound class that has been optimized to...
Efficacy of the bumped kinase inhibitor BKI-1708 against the cyst-forming apicomplexan parasites Toxoplasma gondii and Neospora caninum in vitro and in experimentally infected mice.
Toxoplasma gondii and Neospora caninum are major worldwide morbidity-causing pathogens. Bumped kinase inhibitors (BKIs) are a compound class that has been optimized to target the apicomplexan calcium-dependent protein kinase 1 (CDPK1) - and several members of this class have proven to be safe and highly active in vitro and in vivo. BKI-1708 is based on a 5-aminopyrazole-4-carboxamide scaffold, and exhibited in vitro IC values of 120 nM for T. gondii and 480 nM for N. caninum β-galactosidase expressing strains, and did not affect human foreskin fibroblast (HFF) viability at concentrations up to 25 μM. Electron microscopy established that exposure of tachyzoite-infected fibroblasts to 2.5 μM BKI-1708 in vitro induced the formation of multinucleated schizont-like complexes (MNCs), characterized by continued nuclear division and harboring newly formed intracellular zoites that lack the outer plasma membrane. These zoites were unable to finalize cytokinesis to form infective tachyzoites. BKI-1708 did not affect zebrafish (Danio rerio) embryo development during the first 96 h following egg hatching at concentrations up to 2 μM. Treatments of mice with BKI-1708 at 20 mg/kg/day during five consecutive days resulted in drug plasma levels ranging from 0.14 to 4.95 μM. In vivo efficacy of BKI-1708 was evaluated by oral application of 20 mg/kg/day from day 9-13 of pregnancy in mice experimentally infected with N. caninum (NcSpain-7) tachyzoites or T. gondii (TgShSp1) oocysts. This resulted in significantly decreased cerebral parasite loads and reduced vertical transmission in both models without drug-induced pregnancy interference.
PubMed: 38917582
DOI: 10.1016/j.ijpddr.2024.100553 -
Journal of Nanobiotechnology Jun 2024Parkinson's disease (PD) is the second largest group of neurodegenerative diseases, and its existing drug treatments are not satisfactory. Natural cell membrane drugs...
Parkinson's disease (PD) is the second largest group of neurodegenerative diseases, and its existing drug treatments are not satisfactory. Natural cell membrane drugs are used for homologous targeting to enhance efficacy. In this study, microfluidic electroporation chip prepared mesenchymal stem cell-derived neuron-like cell membrane-coated curcumin PLGA nanoparticles (MM-Cur-NPs) was synthesized and explored therapeutic effect and mechanism in PD. MM-Cur-NPs can protect neuron from damage, restore mitochondrial membrane potential and reduce oxidative stress in vitro. In PD mice, it also can improve movement disorders and restore damaged TH neurons. MM-Cur-NPs was found to be distributed in the brain and metabolized with a delay within 24 h. After 1 h administration, MM-Cur-NPs were distributed in brain with a variety of neurotransmitters were significantly upregulated, such as dopamine. Differentially expressed genes of RNA-seq were enriched in the inflammation regulation, and it was found the up-expression of anti-inflammatory factors and inhibited pro-inflammatory factors in PD. Mechanically, MM-Cur-NPs can not only reduce neuronal apoptosis, inhibit the microglial marker IBA-1 and inflammation, but also upregulate expression of neuronal mitochondrial protein VDAC1 and restore mitochondrial membrane potential. This study proposes a therapeutic strategy provide neuroprotective effects through MM-Cur-NPs therapy for PD.
PubMed: 38918856
DOI: 10.1186/s12951-024-02587-1