Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral anti-diabetic drugs, implicated in pleiotropic secondary cardioprotective effects. The aim of the study was to unveil the unknown and possible cardioprotective targets that can be exerted by sitagliptin (Sitg) against ischemia-reperfusion (I/R) injury. Male wistar rats received 2 weeks’ Sitg oral treatment of different doses (25, 50, 100, and 150 mg/kg/day), or saline as a Control. Hearts were then isolated and subjected to two different I/R injury protocols: 10 min perfusion, 45 min regional ischemia, and 120 min reperfusion for infarct size (IS) measurement, or: 10 min perfusion, 45 min regional ischemia and 10 min reperfusion for biochemical analysis: nitric oxide synthases (NOSs) and DPP-4 activity, glucagon-like peptide-1 (GLP-1), Calcium, transient receptor potential vanilloid (TRPV)-1 and calcitonin gene-related peptide (CGRP) levels, transient receptor potential canonical (TRPC)-1 and e-NOS protein expression. NOS inhibitor (l-NAME) and TRPV-1 inhibitor (Capsazepine) were utilized to confirm the implication of both signaling mechanisms in DPP-4 inhibition-induced at the level of IS. Findings show that Sitg (50 mg) resulted in significant decrease in IS and DPP-4 activity, and significant increase in GLP-1, NOS activity, e-NOS expression, TRPV-1 level and TRPC-1 expression, compared to controls. Results of CGRP are in line with TRPV-1, as a downstream regulatory effect. NOS system and transient receptor potential (TRP) channels can contribute to DPP-4 inhibition-mediated cardioprotection against I/R injury using Sitagliptin.

Cardiovascular diseases (CVDs) continue to be the leading cause of mortality worldwide, necessitating the development of novel therapies. Despite therapeutic advancements, the underlying mechanisms remain elusive. Reactive oxygen species (ROS) show detrimental effects at high concentrations but act as essential signalling molecules at physiological levels, playing a critical role in the pathophysiology of CVD. However, the link between pathologically elevated ROS and CVDs pathogenesis remains poorly understood. Recent research has highlighted the remodelling of the epigenetic landscape as a crucial factor in CVD pathologies. Epigenetic changes encompass alterations in DNA methylation, post-translational histone modifications, adenosine triphosphate (ATP)-dependent chromatin modifications, and noncoding RNA transcripts. Unravelling the intricate link between ROS and epigenetic changes in CVD is challenging due to the complexity of epigenetic signals in gene regulation. This review aims to provide insights into the role of ROS in modulating the epigenetic landscape within the cardiovascular system. Understanding these interactions may offer novel therapeutic strategies for managing CVD by targeting ROS-induced epigenetic changes. It has been widely accepted that epigenetic modifications are established during development and remain fixed once the lineage-specific gene expression pattern is achieved. However, emerging evidence has unveiled its remarkable dynamism. Consequently, it is now increasingly recognized that epigenetic modifications may serve as a crucial link between ROS and the underlying mechanisms implicated in CVD.

Inflammatory bowel diseases (IBDs) are autoimmune disorders of the gut. It is increasingly clear that voluntary exercise (VE) may exert protection against IBDs, but the exact background mechanism needs to be elucidated. In the present study, we aimed to investigate the possible role of NETosis and the antioxidant peroxiredoxin (Prdx) enzyme family in VE-induced protection. Wistar Han rats were randomly divided into two groups: sedentary (SED) and VE. After the 6-week voluntary wheel running, animals were treated with 2,4,6-trinitrobenzene sulphonic acid (TNBS) as a model of colitis. Here, we found that VE significantly decreased inflammation and ulceration of the colon in the VE TNBS group compared with SED TNBS. We also found that VE significantly decreased the expression of protein arginine deiminase 4 (PAD4) and myeloperoxidase (MPO), and markedly reduced citrullinated histone H3 (citH3) compared with SED TNBS. Furthermore, VE caused a significant increase in the levels of Prdx6 in the control and TNBS groups. Taken together, we found that a prior 6-week VE effectively reduces inflammation in TNBS-induced colitis, and we suggest that the protective effect of VE may be mediated via the inhibition of NETosis and upregulation of Prdx6 antioxidant.

Background: ST-elevation myocardial infarction (STEMI) and Takotsubo syndrome (TS) are two distinct cardiac conditions that both result in sudden loss of cardiac dysfunction and that are difficult to distinguish clinically. This study compared plasma protein changes in 24 women with STEMI and 12 women with TS in the acute phase (days 0–3 post symptom onset) and the stabilization phase (days 7, 14, and 30) to examine the molecular differences between these conditions. Methods: Plasma proteins from STEMI and TS patients were extracted during the acute and stabilization phases and analyzed via quantitative proteomics. Differential expression and functional significance were assessed. Data are accessible on ProteomeXchange, ID PXD051367. Results: During the acute phase, STEMI patients showed higher levels of myocardial inflammation and tissue damage proteins compared to TS patients, along with reduced tissue repair and anti-inflammatory proteins. In the stabilization phase, STEMI patients exhibited ongoing inflammation and disrupted lipid metabolism. Notably, ADIPOQ was consistently downregulated in STEMI patients in both phases. When comparing the acute to the stabilization phase, STEMI patients showed increased inflammatory proteins and decreased structural proteins. Conversely, TS patients showed increased proteins involved in inflammation and the regulatory response to counter excessive inflammation. Consistent protein changes between the acute and stabilization phases in both conditions, such as SAA2, CRP, SAA1, LBP, FGL1, AGT, MAN1A1, APOA4, COMP, and PCOLCE, suggest shared underlying pathophysiological mechanisms. Conclusions: This study presents protein changes in women with STEMI or TS and identifies ADIPOQ, SAA2, CRP, SAA1, LBP, FGL1, AGT, MAN1A1, APOA4, COMP, and PCOLCE as candidates for further exploration in both therapeutic and diagnostic contexts.

Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are the most common subtype of NETs, and their incidence continues to increase worldwide. Many NETs express somatostatin receptors (SSTRs), enabling molecular imaging and treatment with radiolabeled somatostatin analogs (SSTAs). [¹⁷⁷Lu]Lu-DOTATATE is an established treatment for advanced SSTR-positive NETs, but complete and durable responses remain uncommon. This review summarizes current clinical experience with [¹⁷⁷Lu]Lu-DOTATATE and emerging SSTR-targeting radiopharmaceuticals and examines strategies to improve PRRT efficacy. Treatment may be enhanced at several interconnected steps, including increasing receptor availability and tumor targeting, improving radiopharmaceutical uptake and absorbed dose, preventing repair of radiation-induced damage, suppressing cellular stress adaptation and survival, and promoting tumor cell elimination. These approaches include radiation priming and fractionation, somatostatin analog pretreatment, epigenetic modifiers, inhibitors of DNA repair and cellular survival pathways, immunotherapy, and chemotherapy-based combinations. PARP, DNA-PK, and HSP90 inhibitors and chemotherapy-based combinations have shown particularly strong preclinical or clinical evidence, whereas mTOR inhibitors, tyrosine kinase inhibitors, Hedgehog inhibitors, immunotherapy, NAMPT inhibitors, p53 stabilization, and epigenetic modifiers remain under investigation. Ongoing development of novel radiopharmaceuticals, personalized dosimetry, retreatment strategies, and rational combinations is expected to refine PRRT and improve outcomes for patients with NETs.

Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are the most common subtype of NETs, and their incidence continues to increase worldwide. Many NETs express somatostatin receptors (SSTRs), enabling molecular imaging and treatment with radiolabeled somatostatin analogs (SSTAs). [¹⁷⁷Lu]Lu-DOTATATE is an established treatment for advanced SSTR-positive NETs, but complete and durable responses remain uncommon. This review summarizes current clinical experience with [¹⁷⁷Lu]Lu-DOTATATE and emerging SSTR-targeting radiopharmaceuticals and examines strategies to improve PRRT efficacy. Two complementary approaches are emphasized: increasing tumor uptake through modulation of SSTR expression and enhancing radiation response through radiosensitization. SSTR upregulation has been investigated using radiation priming, somatostatin analog pretreatment, epigenetic modifiers, and selected pharmacological agents. Radiosensitization strategies include inhibition of DNA repair, cellular stress-response and oncogenic signaling pathways, tumor metabolism, and immune checkpoint signaling. PARP, DNA-PK, and HSP90 inhibitors and chemotherapy-based combinations have shown particularly strong preclinical or clinical evidence, whereas mTOR inhibitors, tyrosine kinase inhibitors, Hedgehog inhibitors, immunotherapy, NAMPT inhibitors, and epigenetic modifiers remain under investigation. Ongoing development of novel radiopharmaceuticals, personalized dosimetry, retreatment strategies, and rational combinations is expected to refine PRRT and improve outcomes for patients with NETs.