Protective Agents

The recombinant herpes zoster (shingles) vaccine may reduce risks of cardiovascular disease. However, existing studies have compared vaccine recipients with non-recipients and, thus, are susceptible to confounding. To mitigate these biases, we conducted a natural experiment created by the rapid transition from the live attenuated to the recombinant shingles vaccine in the United States. We compared incidences of a composite cardiovascular endpoint (ischemic heart disease, heart failure or ischemic stroke) among adults aged ≥60 years vaccinated immediately before versus immediately after this transition. The recombinant vaccine was associated with a 9% decrease in cardiovascular burden over 7 years (restricted mean time lost (RMTL) ratio = 0.91, 95% confidence interval (CI): 0.88-0.95). The association attenuated over time and was significant for ischemic heart disease (10% decrease in burden; RMTL ratio = 0.90, 95% CI: 0.87-0.94) and heart failure (12% decrease in burden; RMTL ratio = 0.88, 95% CI: 0.83-0.93) in both sexes and ischemic stroke in males (12% decrease; RMTL ratio = 0.88, 95% CI: 0.78-0.98). An association was also seen for atrial fibrillation (7% decrease in burden; RMTL = 0.93, 95% CI: 0.88-0.98) but not other cardiac, peripheral and cerebrovascular outcomes. Results were consistent in secondary analyses. These results justify clinical trials and mechanistic studies to investigate potential cardioprotective effects of shingles vaccines.

ObjectiveDiabetic cardiomyopathy (DCM) lacks targeted therapies. This study investigated naringenin (NAR), a citrus flavonoid, in a streptozotocin (STZ)-induced diabetic rat model with cardiac complications, focusing on SIRT1-mediated mechanisms.MethodsRats (n = 8/group) included control, NAR, DCM, DCM + NAR, and DCM + NAR + EX-527 (SIRT1 inhibitor). After 8 weeks, metabolic profiles, cardiac function, histopathology, oxidative stress (Nuclear Factor Erythroid-Related Factor 2 [Nrf2], MDA, SOD, and GSH), inflammation (nuclear factor kappa B [NF-κB], TNF-α, and IL-6), apoptosis (Bax/Bcl-2 and Caspase-3), fibrosis (transforming growth factor beta [TGF-β] and Smad2), and SIRT1 signaling were analyzed.ResultsNAR exhibited hypoglycemic effects, stimulated the release of insulin, and enhanced the lipid profile, thus maintaining the structural integrity of cardiomyocytes and preventing an increase in heart weight, while also restoring the histomorphology in DCM rats. Moreover, NAR influenced both systolic and diastolic blood pressure; reduced serum levels of CK-MB, BNP, and troponin T; downregulated the activity of TGF-β, Smad2, and Caspase-3; and decreased the Bax/Bcl-2 ratio. Crucially, NAR upregulated SIRT1 and modulated the levels of Nrf2, NF-κB, Smad2, and Forkhead Box Protein O1 (FOXO1) in the cardiac tissues of the DCM group. These findings were associated with a significant reduction in oxidative stress and inflammation, alongside diminished NF-κB activity, while promoting Nrf2 activity and Bcl-2. Importantly, the effects of NAR were counteracted by EX-527.ConclusionNAR protects against DCM primarily through SIRT1 activation, integrating hypoglycemic, antioxidant, anti-inflammatory, antifibrotic, and antiapoptotic actions. SIRT1 represents a promising target for flavonoid-based DCM therapy.

BackgroundOxidative stress and inflammation are mutually reinforcing physiological processes. The transcription factor Nrf2 (Nuclear factor erythroid 2-related factor 2) acts as the master regulator of redox homeostasis and anti-inflammatory signaling. To overcome the off-target limitations of conventional electrophilic Nrf2 activators, this study investigates selective peptide-based modulators. We present data indicating that an innate defense regulator (IDR)-1002 peptide is able to activate the Nrf2-mediated antioxidant response and mitigate inflammation in an endothelial cell model.MethodsWe first screened several IDR peptides IDR-1 (Lys-Ser-Arg-Ile-Val-Pro-Ala-Ile-Pro-Val-Ser-Leu-Leu), IDR-1018 (Val-Arg-Leu-Ile-Val-Ala-Val-Arg-Ile-Trp-Arg-Arg), HH2 (Val-Gln-Leu-Arg-Ile-Arg-Val-Ala-Val-Ile-Arg-Ala) and IDR-1002 (Val-Gln-Arg-Trp-Leu-Ile-Val-Trp-Arg-Ile-Arg-Lys) for their ability to induce Nrf2 nuclear translocation in HEK293 and bovine endothelial cells (BEC) via Western blot and ELISA. Transcriptional activity was assessed in HepG2 cells using an ARE (Antioxidant Response Element)-luciferase reporter assay to determine the EC 50. Downstream expression of antioxidant enzymes, including HO-1 (Heme Oxygenase-1), NQO1 (NAD(P)H:quinone oxidoreductase 1), and GCLM (Glutamate-Cysteine Ligase Modifier Subunit), was quantified by ELISA. GST (Glutathione S-Transferase) activity induced by IDR-1002 was measured using a CDNB-GSH conjugation assay. Finally, the functional capacity to reduce H 2O 2-induced ROS (Reactive Oxygen Species) and TNF-stimulated inflammation was measured in BECs.ResultsAmong the tested peptides, IDR-1002 induced the most potent concentration-dependent nuclear translocation of Nrf2 in both cell lines. IDR-1002 activated ARE-dependent transcription with an EC 50 of 18.57 μM. This activation led to a significant time-dependent increase in HO-1, NQO1, and GCLM protein levels, alongside enhanced GST activity. Functionally, IDR-1002 pretreatment resulted in a dose-dependent reduction of intracellular reactive oxygen species (ROS) production (up to 5.4-fold at 50 μM) and a significant decrease in TNF-α expression in stimulated BECs.ConclusionsIDR-1002 acts as a distinct dual-function regulator that simultaneously modulates the Nrf2 antioxidant response and inhibits NF-κB-mediated inflammation. These findings highlight the potential of IDR-1002 as a promising molecular template for the design of new therapeutic approaches against chronic diseases characterized by the interplay between oxidative stress and inflammation.

Molecular hydrogen is known to selectively convert hydroxyl radicals into harmless water and thereby mitigating oxidative stress. Due to hydrogen molecules have masses comparable to protons and neutrons, can also decelerate neutrons and protons present in environmental radiation, thus exerting a physical shielding effect. Through this dual action, chemical radical scavenging and physical radiation shielding, hydrogen may protect cellular integrity and potentially promote biological longevity. In contrast, hydrogen can intervene at the stage of preventing biomolecular damage induced by environmental radiation and provide comprehensive protection at the tissue and cellular levels, uniquely minimizing radiation-induced damage. This review systematically summarizes existing knowledge regarding the antioxidant and radioprotective effects of hydrogen, discusses its role in mitigating oxidative stress and protecting cells from environmental radiation, and proposes a novel hypothesis that hydrogen has universally protected from radiation-induced damage, highlighting its potential for promoting biological longevity.