Drug-Loaded Mesoporous Polydopamine Nanoparticles in Chitosan Hydrogels Enable Myocardial Infarction Repair through ROS Scavenging and Inhibition of Apoptosis.

In this study, we synthesized mesoporous polydopamine nanoparticles (MPDA NPs) using an emulsion-induced interface assembly strategy and loaded epigallocatechin gallate (EGCG) into MPDA NPs via electrostatic attraction to form EGCG@MPDA NPs. In the post myocardial infarction (MI) environment, these interventions specifically aimed to eliminate reactive oxygen species (ROS) and facilitate the repair of MI. We further combined them with a thermosensitive chitosan (CS) hydrogel to construct an injectable composite hydrogel (EGCG@MPDA/CS hydrogel). Utilizing in vitro experiments, the EGCG@MPDA/CS hydrogel exhibited excellent ROS-scavenging ability of H9C2 cells under the oxidative stress environment and also could inhibit their apoptosis. The EGCG@MPDA/CS hydrogel significantly promoted left ventricular ejection fraction (LVEF) in infarcted rat models post injection for 28 days compared to the PBS group (51.25 ± 1.73% vs 29.31 ± 0.78%, P < 0.05). In comparison to the PBS group, histological analysis revealed a substantial increase in left ventricular (LV) wall thickness in the EGCG@MPDA/CS hydrogel group (from 0.58 ± 0.03 to 1.39 ± 1.11 mm, P < 0.05). This work presents a novel approach to enhance MI repair by employing the EGCG@MPDA/CS hydrogel. This hydrogel effectively reduces local oxidative stress by ROS and stimulates the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway.

Inhibition of the RXRA-PPARα-FABP4 signaling pathway alleviates vascular cellular aging by an SGLT2 inhibitor in an atherosclerotic mice model.

Atherosclerosis is the pathological cause of atherosclerotic cardiovascular disease (ASCVD), which rapidly progresses during the cellular senescence. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce major cardiovascular events in patients with ASCVD and have potential antisenescence effects. Here, we investigate the effects of the SGLT2 inhibitor dapagliflozin on cellular senescence in atherosclerotic mice. Compared with ApoE-/- control mice treated with normal saline, those in the ApoE-/- dapagliflozin group, receiving intragastric dapagliflozin (0.1 mg kg-1 d-1) for 14 weeks, exhibited the reduction in the total aortic plaque area (48.8%±6.6% vs. 74.6%±8.0%, P<0.05), the decrease in the lipid core area ((0.019±0.0037) mm2vs. (0.032±0.0062) mm2, P<0.05) and in the percentage of senescent cells within the plaques (16.4%±3.7% vs. 30.7%±2.0%, P<0.01), while the increase in the thickness of the fibrous cap ((21.6±2.1) µm vs. (14.6±1.5) µm, P<0.01). Transcriptome sequencing of the aortic arch in the mice revealed the involvement of the PPARα and the fatty acid metabolic signaling pathways in dapagliflozin's mechanism of ameliorating cellular aging and plaque progression. In vitro, dapagliflozin inhibited the expression of PPARα and its downstream signal FABP4, by which the accumulation of senescent cells in human aortic smooth muscle cells (HASMCs) was reduced under high-fat conditions. This effect was accompanied by a reduction in the intracellular lipid content and alleviation of oxidative stress. However, these beneficial effects of dapagliflozin could be reversed by the PPARα overexpression. Bioinformatics analysis and molecular docking simulations revealed that dapagliflozin might exert its effects by directly interacting with the RXRA protein, thereby influencing the expression of the PPARα signaling pathway. In conclusion, the cellular senescence of aortic smooth muscle cells is potentially altered by dapagliflozin through the suppression of the RXRA-PPARα-FABP4 signaling pathway, resulting in a deceleration of atherosclerotic progression.

Association between Human Blood Proteome and the Risk of Myocardial Infarction.

Background: The objective of this study is to estimate the causal relationship between plasma proteins and myocardial infarction (MI) through Mendelian randomization (MR), predict potential target-mediated side effects associated with protein interventions, and ensure a comprehensive assessment of clinical safety. Methods: From 3 proteome genome-wide association studies (GWASs) involving 9775 European participants, 331 unique blood proteins were screened and chosed. The summary data related to MI were derived from a GWAS meta-analysis, incorporating approximately 61,000 cases and 577,000 controls. The assessment of associations between blood proteins and MI was conducted through MR analyses. A phenome-wide MR (Phe-MR) analysis was subsequently employed to determine the potential on-target side effects of protein interventions. Results: Causal mediators for MI were identified, encompassing cardiotrophin-1 (CT-1) (odds ratio [OR] per SD increase: 1.16; 95% confidence interval [CI]: 1.13-1.18; p = 1.29 × 10 - 31 ), Selenoprotein S (SELENOS) (OR: 1.16; 95% CI: 1.13-1.20; p = 4.73 × 10 - 24 ), killer cell immunoglobulin-like receptor 2DS2 (KIR2DS2) (OR: 0.93; 95% CI: 0.90-0.96; p = 1.08 × 10 - 5 ), vacuolar protein sorting-associated protein 29 (VPS29) (OR: 0.92; 95% CI: 0.90-0.94; p = 8.05 × 10 - 13 ), and histo-blood group ABO system transferase (NAGAT) (OR: 1.05; 95% CI: 1.03-1.07; p = 1.41 × 10 - 5 ). In the Phe-MR analysis, memory loss risk was mediated by CT-1, VPS29 exhibited favorable effects on the risk of 5 diseases, and KIR2DS2 showed no predicted detrimental side effects. Conclusions: Elevated genetic predictions of KIR2DS2 and VPS29 appear to be linked to a reduced risk of MI, whereas an increased risk is associated with CT-1, SELENOS, and NAGAT. The characterization of side effect profiles aids in the prioritization of drug targets. Notably, KIR2DS2 emerges as a potentially promising target for preventing and treating MI, devoid of predicted detrimental side effects.

Plasma metabolomics identifies S-adenosylmethionine as a biomarker and potential therapeutic target for vascular aging in older adult males.

Brachial-ankle pulse wave velocity (baPWV) is a noninvasive index of vascular aging. However, the metabolic profile underlying vascular aging has not yet been fully elucidated. The current study aimed to identify circulating markers of vascular aging as assessed by baPWV and to elucidate its mechanism from a metabolomic perspective in older adults. A total of 60 and 61 Chinese male participants aged ≥80 years were recruited to the metabolome and validation cohorts, respectively. The baPWV of participants was measured using an automatic waveform analyzer. Plasma metabolic profile was investigated using ultra-performance liquid chromatography coupled with triple quadrupole linear ion trap tandem mass spectrometry. Orthogonal partial least squares (OPLS) regression modeling established the association between metabolic profile and baPWV to determine important metabolites predictive of vascular aging. Additionally, an enzyme-linked immunosorbent assay was employed to validate the metabolites in plasma and culture media of vascular smooth muscle cells in vitro. OPLS modeling identified 14 and 22 metabolites inversely and positively associated with baPWV, respectively. These 36 biomarkers were significantly enriched in seven metabolite sets, especially in cysteine and methionine metabolism (p <0.05). Notably, among metabolites involved in cysteine and methionine metabolism, S-adenosylmethionine (SAM) level was inversely related to baPWV, with a significant correlation coefficient in the OPLS model (p <0.05). Furthermore, the relationship between SAM and vascular aging was reconfirmed in an independent cohort and at the cellular level in vitro. SAM was independently associated with baPWV after adjustments for clinical covariates (ß = -0.448, p <0.001) in the validation cohort. In summary, plasma metabolomics identified an inverse correlation between SAM and baPWV in older males. SAM has the potential to be a novel biomarker and therapeutic target for vascular aging.

A systematic review and meta-analysis of endocrine-related adverse events associated with interferon.

Objectives: To perform a systematic review and meta-analysis of interferon and endocrine side effects, including their incidence, evaluation, and management. Methods: PubMed was searched through March 7th, 2021, by 2 authors independently (LH Wang and H Zhao). Early phase I/II, phase III experimental trials, prospective and retrospective observational studies were included. Stata 16.0 (StataCorp LLC, 16.0) was the main statistical software for meta-analysis. The weighted incidence and risk ratio were estimated for primary thyroid disease and diabetes mellitus. Results: A total of 108 studies involving 46265 patients were included. Hypothyroidism was the most common thyroid disorder, followed by hyperthyroidism. IFN α+RBV treated patients experienced hypothyroidism in 7.8% (95%CI, 5.9-9.9), which was higher than IFN α (5.2%; 95%CI, 3.7-6.8) and IFN ß (7.0%; 95%CI, 0.06-23.92). IFN α+RBV treated patients experienced hyperthyroidism in 5.0% (95%CI, 3.6-6.5), which was higher than IFN α (3.5%; 95%CI, 2.5-4.8) and IFN ß (3.4%; 95%CI, 0.9-7.5). The summary estimated incidence of painless thyroiditis was 5.8% (95%CI, 2.8-9.8) for IFN α, and 3.5% (95%CI,1.9-5.5) for IFN α+RBV. The summary estimated incidence of diabetes was 1.4% (95%CI, 0.3-3.1) for IFN, 0.55% (95%CI, 0.05-1.57) for IFN α, 3.3% (95%CI,1.1-6.6) for IFN α+RBV. Conclusions: Our meta-analysis shows a high incidence of endocrine adverse events provoked by IFN, further reinforced by combined RBV treatment. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022334131.

Characteristics of Interferon-Associated Diabetes Mellitus in Past 30 Years: A Review.

Interferon (IFN) is a broad-spectrum antiviral agent that activates cell surface receptors and causes cells to produce antiviral proteins, inhibiting viral replication. Interferon use has long been associated with diabetes. The PubMed database was searched for articles related to diabetes and interferon from March 30, 2020. Patients were divided into type 1 diabetes group and type 2 diabetes group. We reviewed the relevant literature to compare interferon-associated T1D and interferon-associated T2D differences. Interferon treatment shortened the incubation period of T2D and changed the original T2D to T1D. The onset of interferon-associated T1D required longer periods of IFN treatment than interferon-associated T2D, and the interferon-associated T1D group had higher GADA positive rates, lower BMI, lower fasting blood glucose, and greater insulin dependence (p<0.05). More patients in the T1D group were positive for HLA-DRB1*04, DRB1*03, DRB1*09, DRB1*14, HLA-DQB1*04, HLA-DQB1*02, HLA-DQB1*03, and HLA-DQB1*05. The combined detection of GAD antibodies and HLA alleles may be an effective method to predict the incidence of T1D after IFN treatment.