Background: Extrachromosomal circular DNAs (eccDNAs) exist in human blood and somatic cells, and are essential for oncogene plasticity and drug resistance. However, the presence and impact of eccDNAs in type 2 diabetes mellitus (T2DM) remains inadequately understood. Methods: We purified and sequenced the serum eccDNAs obtained from newly diagnosed T2DM patients and normal control (NC) subjects using Circle-sequencing. We validated the level of a novel circulating eccDNA named sorbin and SH3‐domain‐ containing‐1^{circle97206791–97208025} (SORBS1^circle) in 106 newly diagnosed T2DM patients. The relationship between eccDNA SORBS1^circle and clinical data was analyzed. Furthermore, we explored the source and expression level of eccDNA SORBS1^circle in the high glucose and palmitate (HG/PA)-induced hepatocyte (HepG2 cell) insulin resistance model. Results: A total of 22,543 and 19,195 eccDNAs were found in serum samples obtained from newly diagnosed T2DM patients and NC subjects, respectively. The T2DM patients had a greater distribution of eccDNA on chromosomes 1, 14, 16, 17, 18, 19, 20 and X. Additionally, 598 serum eccDNAs were found to be upregulated, while 856 eccDNAs were downregulated in T2DM patients compared with NC subjects. KEGG analysis demonstrated that the genes carried by eccDNAs were mainly associated with insulin resistance. Moreover, it was validated that the eccDNA SORBS1^circle was significantly increased in serum of newly diagnosed T2DM patients (106 T2DM patients vs. 40 NC subjects). The serum eccDNA SORBS1^circle content was positively correlated with the levels of glycosylated hemoglobin A1C (HbA1C) and homeostasis model assessment of insulin resistance (HOMA-IR) in T2DM patients. Intracellular eccDNA SORBS1^circle expression was significantly enhanced in the high glucose and palmitate (HG/PA)-induced hepatocyte (HepG2 cell) insulin resistance model. Moreover, the upregulation of eccDNA SORBS1^circle in the HG/PA-treated HepG2 cells was dependent on generation of apoptotic DNA fragmentation. Conclusions: These results provide a preliminary understanding of the circulating eccDNA patterns at the early stage of T2DM and suggest that eccDNA SORBS1^circle may be involved in the development of insulin resistance.

Resiniferatoxin (RTX), a selective transient receptor potential vanilloid 1 (TRPV1) receptor agonist, can eliminate TRPV1+ primary sensory afferents and blunt cardiac sympathetic afferent reflex for a relatively long period. The present study determined the effects of intrathecal RTX administration on transverse aortic constriction (TAC)-induced cardiac dysfunction and cardiac remodeling in rats. Five days before TAC, RTX (2 μg/10 μl) was injected intrathecally into the T2/T3 interspace of rats. Cardiac sympathetic nerve activities (CSNAs) and cardiac structure and function were determined eight weeks after TAC. Intrathecal RTX administration abolished TRPV1 expression in the dorsal horn and reduced over-activated CSNA in the TAC rat model. Hemodynamic analysis revealed that RTX reduced left ventricular end-diastolic pressure, indicating the improvement of cardiac compliance. Histologic analysis, real-time reverse transcription-polymerase chain reaction, and Western blots showed that RTX prevented TAC-induced cardiac hypertrophy, cardiac fibrosis, and cardiac apoptosis and reduced the expression of apoptotic proteins and myocardial mRNAs. In conclusion, these results demonstrate that focal chemo-ablation of TRPV1+ afferents in the spinal cord protects the heart from pressure overload-induced cardiac remodeling and cardiac dysfunction, which suggest a novel promising therapeutic method for cardiac hypertrophy and diastolic dysfunction.

Phosphorylation of the eukaryotic translation initiation factor 2 α-subunit (eIF2ɑ)，which subsequently upregulates activating transcription factor 4 (ATF4), is the core event in the integrated stress response (ISR) pathway. Previous studies indicate phosphorylation of eIF2ɑ in atrial tissue in response to atrial fibrillation (AF). This study investigated the role of ISR pathway in experimental AF by using a small-molecule ISR inhibitor (ISRIB). Accordingly, rats were subjected to coronary artery occlusion to induce myocardial infarction (MI), or sham operation, and received either trans-ISRIB (2 mg/kg/day, i.p.) or vehicle for seven days. Thereafter, animals were subjected to the AF inducibility test by transesophageal rapid burst pacing followed by procurement of left atrium (LA) for assessment of atrial fibrosis, inflammatory indices, autophagy-related proteins, ISR activation, ion channel, and connexin43 expression. Results showed a significant increase in the AF vulnerability and the activation of ISR in LA as evidenced by enhanced eIF2α phosphorylation. ISRIB treatment suppressed upregulation of ATF4, fibrosis as indexed by determination of α-smooth muscle actin and collagen levels, inflammatory macrophage infiltration (i.e., CD68 and iNOS/CD68-positive macrophage) and autophagy as determined by expression of LC3. Further, ISRIB treatment reversed the expression of relevant ion channel (i.e., Nav1.5, Cav1.2, and Kv4.3) and Cx43 remodeling. Collectively, the results suggest that the ISR is a key pathway in pathogenesis of AF, post-MI, and represents a novel target for treatment of AF. Significance Statement Activation of integrated stress response (ISR) pathway as evidenced by enhanced eIF2α phosphorylation in left atrium plays a key role in atrial fibrillation (AF). A small-molecule ISR inhibitor (ISRIB) reduces AF and atrial arrhythmogenic substrate. The mechanism of ISRIB may be mediated by suppressing ISR pathway-related cardiac fibrosis, inflammatory macrophage infiltration, autophagy, and restoring the expression of ion channel and Cx43. This study suggests a key dysfunctional role for ISR in pathogenesis of AF with implications for novel treatment.

Cardiac hypertrophy is characterized by an increased volume of individual cardiomyocytes rather than an increase in their number. Myocardial hypertrophy due to pathological stimuli encountered by the heart, which reduces pressure on the ventricular walls to maintain cardiac function, is known as pathological hypertrophy. This eventually progresses to heart failure. Certain varieties of regulated cell death (RCD) pathways, including apoptosis, pyroptosis, ferroptosis, necroptosis, and autophagy, are crucial in the development of pathological cardiac hypertrophy. This review summarizes the molecular mechanisms and signaling pathways underlying these RCD pathways, focusing on their mechanism of action findings for pathological cardiac hypertrophy. It intends to provide new ideas for developing therapeutic approaches targeted at the cellular level to prevent or reverse pathological cardiac hypertrophy.