Disulfidptosis: A new type of cell death.

Disulfidptosis is a novel form of cell death that is distinguishable from established programmed cell death pathways such as apoptosis, pyroptosis, autophagy, ferroptosis, and oxeiptosis. This process is characterized by the rapid depletion of nicotinamide adenine dinucleotide phosphate (NADPH) in cells and high expression of solute carrier family 7 member 11 (SLC7A11) during glucose starvation, resulting in abnormal cystine accumulation, which subsequently induces andabnormal disulfide bond formation in actin cytoskeleton proteins, culminating in actin network collapse and disulfidptosis. This review aimed to summarize the underlying mechanisms, influencing factors, comparisons with traditional cell death pathways, associations with related diseases, application prospects, and future research directions related to disulfidptosis.

The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives.

Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence. Furthermore, it is usually diagnosed at an advanced stage with a very dismal prognosis. Due to the high heterogeneity, metabolic reprogramming, and dense stromal environment associated with pancreatic cancer, patients benefit little from current conventional therapy. Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification, thus expanding clinical therapeutic options. In this review, we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression. We further discuss potential biomarkers for pancreatic cancer diagnosis, prediction, and surveillance based on novel liquid biopsies. We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models. Finally, we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.

The Effect of Intraoperative Cerebral Oximetry Monitoring on Postoperative Cognitive Dysfunction and ICU Stay in Adult Patients Undergoing Cardiac Surgery: An Updated Systematic Review and Meta-Analysis.

AIM: Determining whether intraoperative cerebral oximetry monitoring-guided intervention reduces the risk of postoperative cognitive dysfunction remains controversial. The objective of this study was to conduct an up-to-date meta-analysis to comprehensively assess the effects of regional cerebral oxygen saturation (rSO2) monitoring-guided intervention on cognitive outcomes after cardiac surgery. METHODS: PubMed, EMBASE, Ovid, and Cochrane Library databases were systematically searched using the related keywords for cardiac surgical randomized-controlled trials (RCTs) published from their inception to July 31, 2021. The primary outcome was postoperative delirium (POD). The secondary outcomes were postoperative cognitive decline (POCD) and other major postoperative outcomes. The odds ratio (OR) or weighted mean differences (WMDs) with 95% confidence interval (CI) were used to pool the data. The random-effect model was used for the potential clinical inconsistency. We performed meta-regression and subgroup analyses to assess the possible influence of rSO2 monitoring-guided intervention on clinical outcomes. RESULTS: In total, 12 RCTs with 1,868 cardiac surgical patients were included. Compared with controls, the incidences of POD (n = 6 trials; OR, 0.28; 95% CI, 0.09-0.84; p = 0.02; I 2 = 81%) and POCD (n = 5 trials; OR, 0.38; 95% CI, 0.16-0.93; p = 0.03; I 2 = 78%) were significantly lower in the intervention group. Cerebral oximetry desaturation also showed a positive association with the incidence of POD (n = 5 trials; OR, 2.02; 95% CI, 1.25-3.24; p = 0.004; I 2 = 81%). The duration of intensive care unit (ICU) stay was markedly shorter in the intervention group than in the control group (n = 10 trials; WMD, -0.22 days; 95% CI, -0.44 to -0.00; p = 0.05; I 2 = 74%). Univariate meta-regression analyses showed that the major sources of heterogeneity were age (p = 0.03), body mass index (BMI, p = 0.05), and the proportion of congenital heart disease (CHD, p = 0.02) for POD, age (p = 0.04) for POCD, diabetes mellitus (DM, p = 0.07), cerebrovascular accident (CVA, p = 0.02), and chronic obstructive pulmonary disease (COPD, p = 0.09) for ICU stay. Subsequent subgroup analyses also confirmed these results. CONCLUSION: Available evidence from the present study suggests that an intraoperative cerebral oximetry desaturation is associated with an increased POD risk, and the rSO2 monitoring-guided intervention is correlated with a lower risk of POD and POCD, and a shorter ICU stay in adults undergoing cardiac surgery. These clinical benefits may be limited in patients with older age, diabetes status, high BMI, non-CHD, non-COPD, or a previous cardiovascular accident.Systematic Review Registration: [PROSPREO], identifier: [CRD42021252654].

Blood exosomal micro ribonucleic acid profiling reveals the complexity of hepatocellular carcinoma and identifies potential biomarkers for differential diagnosis.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, but there is a shortage of effective biomarkers for its diagnosis. AIM: To explore blood exosomal micro ribonucleic acids (miRNAs) as potential biomarkers for HCC diagnosis. RESULTS: The principal component analysis suggested that daily alcohol consumption could alter the blood exosomal miRNA profiles of hepatitis B virus positive non-HCC patients through miR-3168 and miR-223-3p. The miRNA profiles also revealed the tumor stages of HCC patients. High expression of miR-455-5p and miR-30c-5p, which significantly correlated with better overall survival in tumor tissues, could also be detected in blood exosomes. Two pairs of miRNAs (miR-584-5p/miR-106-3p and miR-628-3p/miR-941) showed a 94.1% sensitivity and 68.4% specificity to differentiate HCC patients from non-HCC patients. The specificity of the combination was substantially influenced by alcohol consumption habits. CONCLUSION: This study suggested that blood exosomal miRNAs can be used as new non-invasive diagnostic tools for HCC. However, their accuracy could be affected by tumor stage and alcohol consumption habits.

Downregulation of Na+/Ca2+ Exchanger Isoform 1 Protects Isolated Hearts by Sevoflurane Postconditioning but Not by Delayed Remote Ischemic Preconditioning in Rats.

BACKGROUND:: Calcium regulatory proteins-L-type Ca2+ channels (LTCCs), ryanodine receptor 2 (RyR2), and Na+/Ca2+ exchanger isoform 1 (NCX1) have been recognized as important protective mechanisms during myocardial ischemia-reperfusion injury (I/RI). Both sevoflurane postconditioning (SevoPoC) and delayed remote ischemic preconditioning (DRIPC) have been shown to protect the heart against I/RI. In this study, we aimed to compare the effects of SevoPoC and DRIPC on the expression of the three calcium regulatory proteins in an isolated rat heart model. METHODS:: After 30-min balanced perfusion, isolated hearts from rats were subjected to 30-min ischemia followed by 60-min reperfusion. Totally 40 isolated hearts were randomly assigned to four groups (n = 10/group): time control group, I/RI group, SevoPoC group, and DRIPC group. The effect of SevoPoC (3% v/v) and DRIPC were observed. Myocardial infarct size (IS), cardiac troponin I level, and heart function were measured. The protein and messenger RNA levels of LTCCs, RyR2, and NCX1 were determined. RESULTS:: Both SevoPoC and DRIPC improved the recovery of myocardial function, and reduced cardiac troponin I release after I/RI. The decrease in IS was more significant in the SevoPoC group than that in the DRIPC group (16.50% ± 4.54% in the SevoPoC group [P = 0.0006], and 22.34% ± 4.02% in the DRIPC group [P = 0.0007] vs. 35.00% ± 5.24% in the I/RI group, respectively). SevoPoC, but not DRIPC significantly inhibited the activity of NCX1 (0.59 ± 0.09 in the I/RI group vs. 0.32 ± 0.16 in the SevoPoC group, P = 0.006; vs. 0.57 ± 0.14 in the DRIPC group, P = 0.072). No statistical significant differences were observed in the expression of LTCCs and RyR2 between SevoPoC and DRIPC. In addition, subsequent correlation analysis showed a significantly positive relationship between the cardiac troponin I level and the protein expression of NCX1 (r = 0.505, P = 0.023). CONCLUSION:: SevoPoC may be more effective in the cardioprotection than DRIPC partly due to the deactivation of NCX1.

Restoration of autophagic flux in myocardial tissues is required for cardioprotection of sevoflurane postconditioning in rats.

AIM: Sevoflurane postconditioning (SpostC) has been shown to protect the heart from ischemia-reperfusion (I/R) injury. In this study, we examined whether SpostC affected autophagic flux in myocardial tissues that contributed to its cardioprotective effects in rats following acute I/R injury. METHODS: SD rats underwent 30 min of left anterior descending coronary artery ligation followed by 120 min of reperfusion. The rats were subjected to inhalation of 2.4% (v/v) sevoflurane during the first 5 min of reperfusion, and chloroquine (10 mg/kg, ip) was injected 1 h before I/R. Myocardial infarct size was estimated using TTC staining. Autophagosomes in myocardial tissues were detected under TEM. Expression of LC3B-II, beclin-1, p62/SQSTM1, cathepsin B, caspase-3 and cleaved PARP was assessed using Western blot analysis. Plasma cardiac troponin I was measured using ELISA. Cardiomyocyte apoptosis was evaluated with TUNEL staining. RESULTS: I/R procedure produced severe myocardium infarct and apoptosis accompanied by markedly increased number of autophagosomes, as well as increased levels of LC3B-II, beclin-1 and p62 in myocardial tissues. SpostC significantly reduced infarct size, attenuated myocardial apoptosis, restored intact autophagic flux and improved the lysosomal function in myocardial tissues. Administration of chloroquine that blocked autophagic flux abrogated the cardioprotective effects of SpostC. CONCLUSION: SpostC exerts its cardioprotective effects in rats following I/R injury via restoring autophagic flux in myocardial tissues.

Fish consumption and incidence of heart failure: a meta-analysis of prospective cohort studies.

BACKGROUND: The association between fish consumption and heart failure (HF) incidence is inconsistent. METHODS: We performed a systematic search of Pubmed and Embase (from 1953 to June 2012) using key words related to fish and HF. Studies with at least three categories of fish consumption reporting both relative risk (RR) and corresponding 95% confidence interval (CI) for HF incidence were included. The pooled RR and 95%CI were calculated using a fixed or random-effects model. The generalized least squares regression model was used to quantify the dose-response relationship between fish consumption and HF incidence. RESULTS: Five prospective cohort studies including 4750 HF events of 170 231 participants with an average of 9.7-year follow-up were selected and identified. Compared with those who never ate fish, individuals with higher fish consumption had a lower HF incidence. The pooled RRs for HF incidence was 0.99 (95%CI, 0.91 to 1.08) for fish consumption 1 to 3 times per month, 0.91 (95%CI, 0.84 to 0.99) for once a week, 0.87 (95%CI, 0.81 to 0.95) for 2 to 4 times per week, and 0.86 (95%CI, 0.84 to 0.99) for 5 or more times per week. An increment of 20 g of daily fish intake was related to a 6% lower risk of HF (RR: 0.94, 95%CI, 0.90 to 0.97; P for trend = 0.001). CONCLUSIONS: This meta-analysis suggests that there is a dose-dependent inverse relationship between fish consumption and HF incidence. Fish intake once or more times a week could reduce HF incidence.