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1.
Nanoscale Adv ; 2024 Aug 20.
Article in English | MEDLINE | ID: mdl-39247870

ABSTRACT

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer, characterized by aggressive malignancy and a poor prognosis. Emerging nanomedicine-based combination therapy represents one of the most promising strategies for combating TNBC. Polypyrrole nanoparticles (PPY) are excellent drug delivery vehicles with outstanding photothermal performances. However, the impact of morphology on PPY's drug loading efficiency and photothermal properties remains largely unexplored. In this study, we propose that pluronic P123 can assist in the synthesis of polypyrrole nanoparticles with rough surfaces (rPPY). During the synthesis, P123 formed small micelles around the nanoparticle surface, which were later removed, resulting in small pits and cavities in rPPY. Subsequently, the rPPY was loaded with the chemotherapy drug gemcitabine (Gem@rPPY) for chemo-photothermal therapy against TNBCs. Our results demonstrate that rPPY exhibited superior photothermal performance and significantly enhanced drug loading efficiency by five times compared to smooth PPY nanoparticles. In vitro assessments confirmed Gem@rPPY's robust photothermal properties by efficiently converting light into heat. Cell culture experiments with 4T1 cells and a TNBC mice model revealed significant tumor suppression upon Gem@rPPY administration, emphasizing its efficacy in inducing apoptosis. Toxicity evaluations demonstrated minimal adverse effects both in vitro and in vivo, highlighting the biocompatibility of Gem@rPPY. Overall, this study introduces a promising combination therapy nanoplatform that underscores the importance of surface engineering to enhance therapeutic outcomes and overcome current limitations in TNBC therapy.

3.
Int Immunopharmacol ; 140: 112844, 2024 Oct 25.
Article in English | MEDLINE | ID: mdl-39094363

ABSTRACT

OBJECTIVE: To investigate the impact of the glucagon-like peptide-1 (GLP-1) receptor agonist Exendin-4 on the proportion of myeloid-derived suppressor cells (MDSCs) in male ApoE-/- mice, and investigate alterations in the concentrations of inflammatory factors in plasma and spleen tissues and assess their correlation with MDSCs. METHODS: Thirty male ApoE-/- mice were randomly divided into five groups (n = 6 per group): control group (CON), model group (MOD), Exendin-4 intervention group (MOD/Ex-4), Exendin-9-39 intervention group (MOD/Ex-9-39), and Exendin-4 + Exendin-9-39 combined intervention group (MOD/Ex-4 + Ex-9-39). After 4 weeks of drug intervention, changes in aortic plaque were observed using Oil Red O staining and H&E staining. Flow cytometry was employed to detect the content of myeloid-derived suppressor cells (MDSCs) in bone marrow and peripheral blood. ELISA was utilized to measure the concentrations of inflammatory factors in mouse peripheral blood plasma, while RT-qPCR was employed to quantify the expression levels of inflammatory factors in the spleen. Pearson correlation analysis was conducted to assess the relationship between MDSCs and inflammatory factors. RESULTS: Mice in the MOD group had significantly higher body weight compared to the CON group, with a statistically significant difference (P<0.05). Following Exendin-4 intervention, body weight was reduced compared to the MOD group (P<0.05). Additionally, Exendin-4 treatment led to a significant reduction in atherosclerotic plaque compared to the MOD group (P<0.001). After Exendin-4 intervention, the proportion of MDSCs in the bone marrow was higher than in the MOD group (P<0.001), and the proportion of MDSCs in peripheral blood was significantly higher than in the MOD group (P<0.05). Further investigation revealed that Exendin-4 could regulate lipid levels in mice, decreasing concentrations of TG (P<0.01), TC (P<0.0001), and LDL-C (P<0.0001), while increasing HDL-C concentrations (P<0.01). Moreover, after Exendin-4 treatment, the level of the cytokine IL-6 in peripheral plasma was significantly lower compared to the MOD group (P<0.0001), while levels of IL-10 and TGF-ß were significantly higher compared to the MOD group (P<0.0001). In the spleen, levels of the cytokines IL-10 (P<0.0001) and TGF-ß (P<0.001) were significantly increased compared to the MOD group. Pearson correlation analysis showed that the proportion of MDSCs in peripheral blood was positively correlated with IL-10 and TGF-ß levels in both the spleen and peripheral blood. Additionally, the proportion of MDSCs in the bone marrow was positively correlated with IL-10 and TGF-ß levels in the spleen and peripheral blood. CONCLUSION: Exendin-4 alleviates the severity of atherosclerosis. This process may be achieved by promoting the secretion of myeloid-derived suppressor cells (MDSCs) in the bone marrow and peripheral blood of atherosclerotic ApoE-/- mice, regulating the ratio of inflammatory factors in the body, reducing mouse body weight, and lowering blood lipids.


Subject(s)
Apolipoproteins E , Atherosclerosis , Cytokines , Exenatide , Myeloid-Derived Suppressor Cells , Animals , Exenatide/pharmacology , Exenatide/therapeutic use , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/drug effects , Myeloid-Derived Suppressor Cells/metabolism , Atherosclerosis/drug therapy , Atherosclerosis/immunology , Male , Cytokines/metabolism , Cytokines/blood , Mice , Apolipoproteins E/genetics , Spleen/immunology , Spleen/drug effects , Plaque, Atherosclerotic/drug therapy , Mice, Inbred C57BL , Glucagon-Like Peptide-1 Receptor/metabolism , Glucagon-Like Peptide-1 Receptor/agonists , Mice, Knockout , Disease Models, Animal , Inflammation Mediators/metabolism , Peptide Fragments
5.
J Mater Chem B ; 12(26): 6442-6451, 2024 Jul 03.
Article in English | MEDLINE | ID: mdl-38860876

ABSTRACT

Self-assembled DNA nanostructures hold great promise in biosensing, drug delivery and nanomedicine. Nevertheless, challenges like instability and inefficiency in cellular uptake of DNA nanostructures under physiological conditions limit their practical use. To tackle these obstacles, this study proposes a novel approach that integrates the cationic polymer polyethyleneimine (PEI) with DNA self-assembly. The hypothesis is that the positively charged linear PEI can facilitate the self-assembly of DNA nanostructures, safeguard them against harsh conditions and impart them with the cellular penetration characteristic of PEI. As a demonstration, a DNA nanotube (PNT) was successfully synthesized through PEI mediation, and it exhibited significantly enhanced stability and cellular uptake efficiency compared to conventional Mg2+-assembled DNA nanotubes. The internalization mechanism was further found to be both clathrin-mediated and caveolin-mediated endocytosis, influenced by both PEI and DNA. To showcase the applicability of this hybrid nanostructure for biomedical settings, the KRAS siRNA-loaded PNT was efficiently delivered into lung adenocarcinoma cells, leading to excellent anticancer effects in vitro. These findings suggest that the PEI-mediated DNA assembly could become a valuable tool for future biomedical applications.


Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Nanotubes , Polyethyleneimine , Proto-Oncogene Proteins p21(ras) , RNA, Small Interfering , Humans , A549 Cells , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/pathology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , DNA/chemistry , Drug Carriers/chemistry , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Nanotubes/chemistry , Particle Size , Polyethyleneimine/chemistry , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , RNA, Small Interfering/chemistry , RNA, Small Interfering/pharmacology
6.
Chembiochem ; : e202400249, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38819725

ABSTRACT

Herein, we report the finding that a naturally sunflower pollen-derived microspheres (HSECs) with hierarchical structures can selectively absorb polyC and polyA with high efficiency and affinity. HSECs exhibit the capability to selectively absorb polyC and polyA ssDNA under neutral and acidic conditions. It has been observed that the presence of metal cations, specifically Ca2+, enhances the absorption efficiency of HSECs. Mechanically, this absorption phenomenon can be attributed to both electrostatic interactions and cation-π interactions. Such an appealing property enables the functionalization of HSECs for broad potential biomedical applications, such as microRNA detection.

8.
Nanoscale ; 16(17): 8378-8389, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38602041

ABSTRACT

Bacterial infection is one of the most serious clinical complications, with life-threatening outcomes. Nature-inspired biomaterials offer appealing microscale and nanoscale architectures that are often hard to fabricate by traditional technologies. Inspired by the light-harvesting nature, we engineered sulfuric acid-treated sunflower sporopollenin exine-derived microcapsules (HSECs) to capture light and bacteria for antimicrobial photothermal therapy. Sulfuric acid-treated HSECs show a greatly enhanced photothermal performance and a strong bacteria-capturing ability against Gram-positive bacteria. This is attributed to the hierarchical micro/nanostructure and surface chemistry alteration of HSECs. To test the potential for clinical application, an in situ bacteria-capturing, near-infrared (NIR) light-triggered hydrogel made of HSECs and curdlan is applied in photothermal therapy for infected skin wounds. HSECs and curdlan suspension that spread on bacteria-infected skin wounds of mice first capture the local bacteria and then form hydrogels on the wound upon NIR light stimulation. The combination shows a superior antibacterial efficiency of 98.4% compared to NIR therapy alone and achieved a wound healing ratio of 89.4%. The current study suggests that the bacteria-capturing ability and photothermal properties make HSECs an excellent platform for the phototherapy of bacteria-infected diseases. Future work that can fully take advantage of the hierarchical micro/nanostructure of HSECs for multiple biomedical applications is highly promising and desirable.


Subject(s)
Biopolymers , Capsules , Carotenoids , Helianthus , Photothermal Therapy , Pollen , Animals , Mice , Helianthus/chemistry , Pollen/chemistry , Capsules/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Hydrogels/chemistry , Hydrogels/pharmacology , Staphylococcus aureus/drug effects , Wound Healing/drug effects , Infrared Rays
9.
Biomater Sci ; 12(9): 2331-2340, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38488889

ABSTRACT

Pseudomonas aeruginosa (PA) is one of the most common multidrug-resistant pathogens found in clinics, often manifesting as biofilms. However, due to the emergence of superbugs in hospitals and the overuse of antibiotics, the prevention and treatment of PA infections have become increasingly challenging. Utilizing DNA nanostructures for packaging and delivering antibiotics presents an intervention strategy with significant potential. Nevertheless, construction of functional DNA nanostructures with multiple functionalities and enhanced stability in physiological settings remains challenging. In this study, the authors propose a magnesium-free assembly method that utilizes tobramycin (Tob) as a mediator to assemble DNA nanostructures, allowing for the functionalization of DNA nanostructures by combining DNA and antibiotics. Additionally, our study incorporates maleimide-modified DNA into the nanostructures to act as a targeting moiety specifically directed towards the pili of PA. The targeting ability of the constructed functional DNA nanostructure significantly improves the local concentration of Tob, thereby reducing the side effects of antibiotics. Our results demonstrate the successful construction of a maleimide-decorated Tob/DNA nanotube (NTTob-Mal) for the treatment of PA-infected lung inflammation. The stability and biocompatibility of NTTob-Mal are confirmed, highlighting its potential for clinical applications. Furthermore, its specificity in recognizing and adhering to PA has been validated. In vitro experiments have shown its efficacy in inhibiting PA biofilm formation, and in a murine model, NTTob-Mal has exhibited significant therapeutic effectiveness against PA-induced pneumonia. In summary, the proposed antibiotic drug-mediated DNA nanostructure assembly approach holds promise as a novel strategy for targeted treatment of PA infections.


Subject(s)
Anti-Bacterial Agents , DNA , Nanostructures , Pneumonia , Pseudomonas Infections , Pseudomonas aeruginosa , Tobramycin , Pseudomonas aeruginosa/drug effects , Tobramycin/pharmacology , Tobramycin/administration & dosage , Tobramycin/chemistry , Animals , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/administration & dosage , Nanostructures/chemistry , Nanostructures/administration & dosage , Mice , DNA/chemistry , DNA/administration & dosage , Pneumonia/drug therapy , Pneumonia/microbiology , Humans , Biofilms/drug effects , Microbial Sensitivity Tests
10.
Langmuir ; 40(12): 6353-6362, 2024 Mar 26.
Article in English | MEDLINE | ID: mdl-38470331

ABSTRACT

The biological NO3- removal process might be accompanied by high CO2 emissions and operation costs. Capacitive deionization (CDI) has been widely studied as a very efficient method to purify water. Here, a porous carbon material with a tunable nitrogen configuration was developed. Characterization and density functional theory calculation show that nitrogenous functional groups have a higher NO3- binding energy than Cl-, SO42-, and H2PO4-. In addition, the selectivity of NO3- is improved after the introduction of micropores by using the pore template. The NO3- ion removal and selectivity of MN-C-12 are 4.57 and 3.46-5.42 times that of activated carbon (AC), respectively. The high NO3- selectivity and electrosorption properties of MN-C-12 (the highest N content and micropore area) are due to the synergistic effect of the affinity of nitrogen functional groups to NO3- and microporous ion screening. A CDI unit for the removal of nitrogen from municipal wastewater was constructed and applied to treat wastewater meeting higher discharge standards of A (N: 15 mg L-1) and B (N: 20 mg L-1) ((GB18918-2002), China). This work provides new insights into enhanced carbon materials for the selective electrosorption of wastewater by CDI technology.

12.
Front Immunol ; 15: 1266230, 2024.
Article in English | MEDLINE | ID: mdl-38361921

ABSTRACT

Background: It is unclear what the causal relationship is between the gut microbiota and sepsis. Therefore, we employed Mendelian randomization (MR) to determine whether a causal link exists between the two. Methods: This study used publicly available genome-wide association studies (GWAS) summary data of gut microbiota, sepsis, sepsis (critical care), and sepsis (28-day death in critical care) to perform a two-sample MR analysis. To ensure the robustness of the results, we also conducted a sensitivity analysis. Results: For sepsis susceptibility, inverse variance weighted (IVW) estimates revealed that Victivallales (OR = 0.86, 95% CI, 0.78-0.94, p = 0.0017) was protective against sepsis, while Lentisphaerae (OR = 0.89, 95% CI, 0.80-0.99), Gammaproteobacteria (OR = 1.37, 95% CI, 1.08-1.73), Clostridiaceae1 (OR = 1.21, 95% CI, 1.04-1.40), RuminococcaceaeUCG011 (OR = 1.10, 95% CI, 1.01-1.20), Dialister (OR = 0.85, 95% CI, 0.74-0.97), and Coprococcus2 (OR = 0.81, 95% CI, 0.69-0.94) presented a suggestive association with the development of sepsis (all p < 0.05). For sepsis (critical care), IVW estimates indicated that Lentisphaerae (OR = 0.70, 95% CI, 0.53-0.93), Victivallales (OR = 0.67, 95% CI, 0.50-0.91), Anaerostipes (OR = 0.49, 95% CI, 0.31-0.76), LachnospiraceaeUCG004 (OR = 0.51, 95% CI, 0.34-0.77), and Coprococcus1 (OR = 0.66, 95% CI, 0.44-0.99) showed a suggestive negative correlation with sepsis (critical care) (all p < 0.05). For sepsis (28-day death in critical care), IVW estimates suggested that four bacterial taxa had a normally significant negative correlation with the risk of sepsis-related death, including Victivallales (OR = 0.54, 95% CI, 0.30-0.95), Coprococcus2 (OR = 0.34, 95% CI, 0.14-0.83), Ruminiclostridium6 (OR = 0.43, 95% CI, 0.22-0.83), and Coprococcus1 (OR = 0.45, 95% CI, 0.21-0.97), while two bacterial taxa were normally significantly positively linked to the risk of sepsis-related death, namely, Mollicutes (OR = 2.03, 95% CI, 1.01-4.08) and Bacteroidales (OR = 2.65, 95% CI, 1.18-5.96) (all p < 0.05). The robustness of the above correlations was verified by additional sensitivity analyses. Conclusion: This MR research found that several gut microbiota taxa were causally linked to the risk of sepsis, sepsis in critical care, and sepsis-related 28-day mortality in critical care.


Subject(s)
Gastrointestinal Microbiome , Sepsis , Humans , Genome-Wide Association Study , Mendelian Randomization Analysis , Sepsis/genetics , Bacteroidetes/genetics
13.
Free Radic Biol Med ; 212: 271-283, 2024 02 20.
Article in English | MEDLINE | ID: mdl-38169213

ABSTRACT

Macrophage dysfunction is a significant contributor to more than 70 % of sepsis-related deaths, specifically secondary bacterial infections, during the immunosuppression stage of sepsis. Nevertheless, the role of Rab26 in this context remains unclear. In this study, we observed a substantial decrease in Rab26 expression in macrophages during the immunosuppressive phase of sepsis, which was also found to be suppressed by high extracellular levels of HMGB1. During the progression of sepsis, Rab26 deficiency promotes a polarization shift from the M1 to the M2-like phenotype in macrophages, rendering them susceptible to ferroptosis. Subsequent experimentation has revealed that Rab26 deficiency facilitates the degradation of GPX4, thereby aggravating macrophage ferroptosis through the upregulation of levels of lipid ROS, MDA, and ferrous iron induced by RSL3, a ferroptosis inducer. Additionally, Rab26-deficient mice in the immunosuppressed phase of sepsis exhibit heightened susceptibility to secondary infections, leading to exacerbated lung tissue damage and increased mortality rate. Overall, these findings indicate that Rab26 plays a crucial role in sepsis-induced macrophage immunosuppression by regulating macrophage ferroptosis and polarization. Hence, it represents a potential novel target for sepsis therapy.


Subject(s)
Ferroptosis , Sepsis , Animals , Mice , Ferroptosis/genetics , Immunosuppression Therapy , Sepsis/genetics , Immunosuppressive Agents , Macrophages
14.
Calcif Tissue Int ; 114(2): 119-128, 2024 02.
Article in English | MEDLINE | ID: mdl-38036697

ABSTRACT

The study was aimed to investigate microarchitecture of osteochondral junction in patients with osteonecrosis of the femoral head (ONFH). We hypothesis that there were microarchitecture alternations in osteochondral junction and regional differences between the necrotic region (NR) and adjacent non-necrotic region(ANR) in patients with ONFH. Femoral heads with ONFH or femoral neck fracture were included in ONFH group (n = 11) and control group (n = 11). Cylindrical specimens were drilled on the NR/ANR of femoral heads in ONFH group and matched positions in control group (CO.NR/ CO.ANR). Histology, micro-CT, and scanning electron microscope were used to investigate microarchitecture of osteochondral junction. Layered analysis of subchondral bone plate was underwent. Mankin scores on NR were higher than that on ANR or CO.NR, respectively (P < 0.001, P < 0.001). Calcified cartilage zone on the NR and ANR was thinner than that on the CO.NR and CO.ANR, respectively (P = 0.002, P = 0.002). Tidemark roughness on the NR was larger than that on the ANR (P = 0.002). Subchondral bone plate of NR and ANR was thicker than that on the CON.NR and CON.ANR, respectively (P = 0.002, P = 0.009). Bone volume fraction of subchondral bone plate on the NR was significantly decreasing compared to ANR and CON.NR, respectively (P = 0.015, P = 0.002). Subchondral bone plate on the NR had larger area percentages and more numbers of micropores than ANR and CON.NR (P = 0.002/0.002, P = 0.002/0.002). Layered analysis showed that bone mass loss and hypomineralization were mainly on the cartilage side of subchondral bone plate in ONFH. There were microarchitecture alternations of osteochondral junction in ONFH, including thinned calcified cartilage zone, thickened subchondral bone plate, decreased bone mass, altered micropores, and hypomineralization of subchondral bone plate. Regional differences in microarchitecture of osteochondral junction were found between necrotic regions and adjacent non-necrotic regions. Subchondral bone plate in ONFH had uneven distribution of bone volume fraction and bone mineral density, which might aggravate cartilage degeneration by affecting the transmission of mechanical stresses.


Subject(s)
Bone Diseases, Metabolic , Cartilage, Articular , Femur Head Necrosis , Humans , Femur Head/pathology , Bone Density , Cartilage, Articular/pathology , Stress, Mechanical , Bone Diseases, Metabolic/pathology
15.
Eur J Clin Invest ; 54(4): e14145, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38041600

ABSTRACT

BACKGROUND: Evidence supports the observational correlations between human blood metabolites and sepsis. However, whether these associations represent a causal relationship is unknown. In this study, we applied two-sample Mendelian randomization (MR) analyses to examine causality between genetically proxied 486 blood metabolites and sepsis risk. METHODS: We used summary data from genome-wide association studies (GWAS) on 486 metabolites involving 7824 individuals as exposure and a sepsis GWAS including 11,643 cases and 474,841 controls as the outcome. The inverse-variance weighted (IVW) was the primary method to estimate the causal relationship between exposure and outcome, with MR-Egger and weighted median serving as supplements. Sensitivity analyses were implemented with Cochrane's Q test, MR-Egger intercept, MR-PRESSO and leave-one-out analysis. In addition, we performed replication MR, meta-analysis, Steiger test, linkage disequilibrium score (LDSC) regression and multivariable MR (MVMR) to thoroughly verify the causation. RESULTS: We identified that genetically determined high levels of 1-oleoylglycerophosphoethanolamine (odds ratio (OR) = .52, 95% confidence interval (CI): .31-.87, p = .0122), alpha-glutamyltyrosine (OR = .75, 95% CI: .60-.93, p = .0102), heptanoate (7:0) (OR = .51, 95% CI: .33-.81, p = .0041) and saccharin (OR = .84, 95% CI: .74-.94, p = .0036) were causally associated with a lower risk of sepsis. MVMR analysis demonstrated the independent causal effect of these metabolites on sepsis. CONCLUSIONS: These findings indicated that four blood metabolites have a protective impact on sepsis, thus providing novel perspectives into the metabolite-mediated development mechanism of sepsis by combining genomics and metabolomics.


Subject(s)
Genome-Wide Association Study , Sepsis , Humans , Mendelian Randomization Analysis , Sepsis/genetics , Dietary Supplements , Nonoxynol
16.
Int J Pharm ; 651: 123750, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38159585

ABSTRACT

Acute lung injury (ALI) is an acute inflammatory process that can result in life-threatening consequences. Programmable DNA nanostructures have emerged as excellent nanoplatforms for microRNA-based therapeutics, offering potential nanomedicines for ALI treatment. Nonetheless, the traditional systematic administration of nanomedicines is constrained by low delivery efficiency, poor pharmacokinetics, and nonspecific side effects. Here, we identify macrophage microRNA-155 as a novel therapeutic target using the magnetic bead sorting technique. We further construct a DNA nanotubular nucleic acid drug antagonizing microRNA-155 (NT-155) for ALI treatment through intratracheal administration. Flow cytometry results demonstrate that NT-155, when inhaled, is taken up much more effectively by macrophages and dendritic cells in the bronchoalveolar lavage fluid of ALI mice. Furthermore, NT-155 effectively silences the overexpressed microRNA-155 in macrophages and exerts excellent inflammation inhibition effects in vitro and ALI mouse models. Mechanistically, NT-155 suppresses microRNA-155 expression and activates its target gene SOCS1, inhibiting the p-P65 signaling pathway and suppressing proinflammatory cytokine secretion. The current study suggests that deliberately designed nucleic acid drugs are promising nanomedicines for ALI treatment and the local administration may open up new practical applications of DNA in the future.


Subject(s)
Acute Lung Injury , MicroRNAs , Mice , Animals , Acute Lung Injury/drug therapy , Inflammation/metabolism , Signal Transduction , MicroRNAs/genetics , DNA/metabolism , Lipopolysaccharides/pharmacology , Lung/metabolism
17.
Nanoscale Adv ; 5(21): 5965-5973, 2023 Oct 24.
Article in English | MEDLINE | ID: mdl-37881696

ABSTRACT

The pathogenesis and development of chronic obstructive pulmonary disease (COPD) are significantly related to cellular senescence. Strategies to eliminate senescent cells have been confirmed to benefit several senescence-related diseases. However, there are few reports of senolytic drugs in COPD management. In this study, we demonstrated elevated FOXO4 expression in cigarette smoke-induced senescent lung fibroblasts both in vitro and in vivo. Additionally, self-assembled DNA nanotubes loaded with single-stranded FOXO4 siRNA (siFOXO4-NT) were designed and synthesized to knockdown FOXO4 in senescent fibroblasts. We found that siFOXO4-NT can concentration- and time-dependently enter human lung fibroblasts (HFL-1 cells), thereby reducing FOXO4 levels in vitro. Most importantly, siFOXO4-NT selectively cleared senescent HFL-1 cells by reducing BCLXL expression and the BCL2/BAX ratio, which were increased in CSE-induced senescent HFL-1 cells. The findings from our work present a novel strategy for senolytic drug development for COPD therapy.

18.
Eur J Clin Invest ; 53(11): e14079, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37589179

ABSTRACT

BACKGROUND: Evidence supports the observational associations of human blood metabolites with the risk of severe COVID-19. However, little is known about the potential pathological mechanisms and the analysis of blood metabolites may offer a better understanding of the underlying biological processes. METHODS: We applied a two-sample Mendelian randomization (MR) analysis to evaluate relationships between 486 blood metabolites and the risk of severe COVID-19. The inverse-variance weighted (IVW) model was used as the primary two-sample MR analysis method to estimate the causal relationship of the exposure on the outcome. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis and the funnel plot. RESULTS: Four hunderd and eighty six metabolites were included for MR analysis following rigorous genetic variants selection. After MR analyses and sensitivity analysis filtration, we found weak evidence of an association between 3-hydroxybutyrate (odds ratio [OR] = 1.21, 95% CI, 1.07-1.38, p = .0036) and the risk of severe COVID-19. A series of sensitivity analyses have been carried out to confirm the rigidity of the above results. CONCLUSION: This study suggested a causal relationship between 3-hydroxybutyrate and the severity of COVID-19, thus providing novel insights into biomarkers and pathways for COVID-19 prevention and clinical interventions.

19.
Phytomedicine ; 120: 155026, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37619320

ABSTRACT

CONTEXT: Traditional Chinese medicine plays an important role in the prevention and treatment of heart failure (HF). Linggui Zhugan decoction has been approved for clinical treatment of chronic HF. However, the mechanism is still unclear. OBJECTIVE: The effect of Linggui Zhugan decoction on the Wnt/ß-catenin signaling pathway in rat myocardium was studied to investigate the mechanism by Linggui Zhugan decoction effects ventricular remodeling in rats with heart failure after myocardial infarction. METHOD: A rat model of HF after myocardial infarction was prepared by ligating the left anterior descending coronary artery. After 6 weeks of intervention with Linggui Zhugan decoction, the effect of Linggui Zhugan decoction on the cardiac function of chronic HF model rats was observed. Myocardial infarct size was measured by triphenyl tetrazolium chloride (TTC) staining. Enzyme linked immunosorbent assays (ELISAs) were used to measure NT-proBNP and sST-2 concentrations in rat serum. Hematoxylin and eosin (H&E) staining, and Masson's trichrome staining were used to observe the morphology of myocardial tissue; immunohistochemistry was used to detect the protein expression of type I collagen and type III collagen in myocardial tissue; and mRNA expression levels of Wnt3a, GSK-3ß, ß-catenin, and c-Myc in the infarct marginal zone were detected using PCR. Protein expression of Wnt3a, p-GSK-3ß, GSK-3ß, and ß-catenin in the infarct marginal zone was detected using western blot. RESULTS: Compared with the control, Linggui Zhugan decoction reduced the levels of serum ST-2 and NT-proBNP, improved cardiac function, and reduced the deposition of collagen fiber. In addition, Linggui Zhugan decoction inhibited the expression of Wnt3a, p-GSK-3ß, and ß-catenin in cardiomyocytes. CONCLUSION: Linggui Zhugan decoction inhibits the expression of several key proteins in the Wnt/ß-catenin signaling pathway, delays cardiomyocyte hypertrophy and fibrosis, and improves cardiac function.


Subject(s)
Heart Failure , Myocardial Infarction , Rats , Animals , Wnt Signaling Pathway , beta Catenin/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Ventricular Remodeling , Heart Failure/metabolism , Myocardial Infarction/drug therapy
20.
Ther Clin Risk Manag ; 19: 675-684, 2023.
Article in English | MEDLINE | ID: mdl-37601141

ABSTRACT

Objective: Hip ankylosis is a prevalent condition in patients with Ankylosing spondylitis (AS) that can significantly impact their psychological well-being. This study aimed to investigate the impact of Total Hip Arthroplasty (THA) on anxiety and depression among AS patients. Methods: 62 AS patients undergoing primary THA were recruited and separated into two groups based on preoperative hip motion. The 40 patients with hip mobility of 0° were assigned to group A, and others were assigned to group NA. Self-rating Anxiety Scale (SAS), Self-rating Depression scale (SDS), Harris hip scores (HHS) and 36-Item Short Form Survey (SF-36) were obtained one week before and there, six and twelve months after THA. Results: The study found that AS patients in group A had significantly higher levels of anxiety and depression (SAS score = 75.05±2.79, SDS index score = 0.74±0.02) compared to group B (SAS score = 54.58±3.35, SDS index score= 0.64±0.03, P=0.01). However, both groups showed significant improvements in anxiety and depression scores from there to twelve months after THA (P<0.001). Correlation analyses revealed that the improvement in group NA was associated with hip pain relief (p<0.001), while the improvement in group A was related to joint function, disease duration, age at THA and spine imaging lesions (p<0.001). Conclusion: Some degree of anxiety and depression was present in both groups of AS patients. Levels of depression and anxiety were higher in patients with combined hip ankylosis. And their improvement was associated with improved hip function and quality of life after THA. Hip pain relief played a significant role in patients without hip joint ankylosis. The impact of the degree of lesion on spinal imaging on psychological status needs to be considered in both groups.

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