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Excessive formation of macrophage extracellular trap (MET) has been implicated in several autoimmune disease pathogeneses; however, its impact on type 1 diabetes (T1D) and related mechanisms remains enigmatic. We demonstrated the pivotal role of peptidyl arginine deiminase 4 (PAD4) in driving profuse MET formation and macrophage M1 polarization in intestinal inflammation in NOD mice. Genetic knockout of PAD4 or adoptive transfer of METs altered the proportion of proinflammatory T cells in the intestine, subsequently influencing their migration to the pancreas. Combining RNA sequencing and CUT&Tag analysis, we found activated PAD4 transcriptionally regulated CXCL10 expression. This study comprehensively investigated how excessive PAD4-mediated MET formation in the colon increases the aggravation of intestinal inflammation and proinflammatory T-cell migration and finally is involved in T1D progression, suggesting that inhibition of MET formation may be a potential therapeutic target in T1D. Article Highlights: The role of macrophage extracellular trap (MET) formation in the pathology of type 1 diabetes (T1D) remains unclear. We aimed to investigate the impact of MET formation on intestinal inflammation and its subsequent effect on the pathogenesis of T1D in NOD mice. Activated peptidyl arginine deiminase 4 (PAD4) facilitates MET formation and transcriptionally regulates CXCL10 expression, leading to accelerated T1D through the activation and migration of proinflammatory T cells via the gut/pancreas axis. Findings suggest that targeting PAD4-mediated MET formation could emerge as a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of pure oxygen ventilation under normothermia for different durations on the neurological outcome inarat model of asphyxia cardiac arrest. Methods Atotal of 32 male SD rats were treated with cardiopulmonary resuscitation 6 min after cardiac arrest induced by asphyxia. After return of spontaneous circulation (ROSC), the rats were randomly divided into 4 groups according to the duration of ventilation of pure oxygen (8 in each group), that is, 0 min group (O2-0 min), 20 min group (O2-20 min), 60 min group (O2-60 min) and 180 min group (O2-180 min). Physiological parameters, continuous electroencephalography (EEG) waveforms, and EEG power of each band during post-resuscitation were recorded and compared among the groups. The serum contents of cardiac troponinT(cTnT) and S100 β protein were measured by enzyme-linked immunosorbent assay (ELISA) at the basic state and 6hafter resuscitation. The neurological deficit score (NDS), 96-hour survival rate and histological changes of hippocampus were compared in the groups. Results After resuscitation, the mean arterial pressure (MAP) was decreased significantly, and the left ventricular ejection fraction (LVEF) was decreased first and then increased in the 4 groups. The 2 indicators were significantly higher in the O2-180 min group than the O2-0 min group (P < 0.05). With the increase of oxygen ventilation, shorter EEG recovery time and gradually stronger EEG power spectrum energy were observed in all the groups. The O2-180 min group had significantly shorter time and stronger energy than the O2-0 min group (P < 0.05). At 6hafter resuscitation, cerebral and myocardial injuries were obviously milder in the O2-180 min group than the O2-0 min group (S100β, P < 0.01; cTnT, P < 0.05). NDS, survival rate and hippocampal injury were significantly improved in the O2-180 min group when compared with the O2-0 min group. Conclusions In this rat model of asphyxia cardiac arrest, prolonged pure oxygen inhalation under normothermia can alleviate cerebral injury, improve neurological outcome and increase the survival rate.

Objective To investigate the effect and mechanism of chromogranin (CGA)-derived polypeptide bCAT combined with caspofungin (CAS) on hypha and mature biofilm in Candida albicans (C. albicans). Methods Standard strain ATCC 10231 of C. albicans was employed as the study objective. The changes of biofilm metabolic activity after bCAT and CAS treatment alone or combined together (RPMI1640 as control group) were detected by XTT assay, and the results were calculated for the minimal biofilm inhibitory concentration (MBIC50). The expression of agglutinin-like sequence 3 (ALS3) was detected by RT-PCR, and the production of reactive oxygen content (ROS) was observed by DCFH-DA. SYTO9/PI staining was used to detect the fungal membrane permeability. Results The MBIC50 after bCAT and CAS treatment was 3 105 and 128 μg/mL, respectively. And the MBIC50 of bCAT combined with CAS was decreased to 776 μg/mL and 4 μg/mL, respectively. The expression of ALS3 in the bCAT+CAS group was (1.71±0.65)%, which had statistical differences from that of the control, bCAT (776 μg/mL) and CAS (4 μg/mL) groups (P < 0.05). The ROS content was (428.96±47.67)%, with significant difference compared with the control, bCAT (776 μg/mL) and CAS (4 μg/mL) groups (P < 0.05). There were more dead C. albicans in mature biofilm in the bCAT+CAS group, and the fungal hypha were decreased significantly. Conclusion CGA-derived polypeptide bCAT combined with CAS has the synergistic anti-mature biofilm effect, and the mechanism may be associated with decreased expression of ALS3 and inhibition of hypha formation, and oxidative damage caused by increased ROS content.

The baroreceptor reflex is a powerful neural feedback that regulates arterial pressure (AP). Mechanosensitive channels transduce pulsatile AP to electrical signals in baroreceptors. Here we show that tentonin 3 (TTN3/TMEM150C), a cation channel activated by mechanical strokes, is essential for detecting AP changes in the aortic arch. TTN3 was expressed in nerve terminals in the aortic arch and nodose ganglion (NG) neurons. Genetic ablation of Ttn3 induced ambient hypertension, tachycardia, AP fluctuations, and impaired baroreflex sensitivity. Chemogenetic silencing or activation of [TTN3.sup.+] neurons in the NG resulted in an increase in AP and heart rate, or vice versa. More important, overexpression of Ttn3 in the NG of [Ttn3.sup.-/-] mice reversed the cardiovascular changes observed in Ttn3rh mice. We conclude that TTN3 is a molecular component contributing to the sensing of dynamic AP changes in baroreceptors., Introduction Arterial pressure (AP) is maintained at a constant level by cardiovascular reflexes. The baroreflex is a cardiovascular reflex that is essential for blood pressure homeostasis (1, 2). It is [...]