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Over the past few decades, mechanisms of programmed cell death have attracted the scientific community because they are involved in diverse human diseases. Initially, apoptosis was considered as a crucial mechanistic pathway for programmed cell death; recently, an alternative regulated mode of cell death was identified, mimicking the features of both apoptosis and necrosis. Several lines of evidence have revealed that dysregulation of necroptosis leads to pathological diseases such as cancer, cardiovascular, lung, renal, hepatic, neurodegenerative, and inflammatory diseases. Regulated forms of necrosis are executed by death receptor ligands through the activation of receptor-interacting protein kinase (RIPK)-1/3 and mixed-lineage kinase domain-like (MLKL), resulting in the formation of a necrosome complex. Many papers based on genetic and pharmacological studies have shown that RIPKs and MLKL are the key regulatory effectors during the progression of multiple pathological diseases. This review focused on illuminating the mechanisms underlying necroptosis, the functions of necroptosis-associated proteins, and their influences on disease progression. We also discuss numerous natural and chemical compounds and novel targeted therapies that elicit beneficial roles of necroptotic cell death in malignant cells to bypass apoptosis and drug resistance and to provide suggestions for further research in this field.

Mitochondrial dysfunction contributes to the pathophysiology of acute kidney injury (AKI). Mitophagy selectively degrades damaged mitochondria and thereby regulates cellular homeostasis. RNA‐binding proteins (RBPs) regulate RNA processing at multiple levels and thereby control cellular function. In this study, we aimed to understand the role of human antigen R (HuR) in hypoxia‐induced mitophagy process in the renal tubular cells. Mitophagy marker expressions (PARKIN, p‐PARKIN, PINK1, BNIP3L, BNIP3, LC3) were determined by western blot analysis. Immunofluorescence studies were performed to analyze mitophagosome, mitolysosome, co‐localization of p‐PARKIN/TOMM20 and BNIP3L/TOMM20. HuR‐mediated regulation of PARKIN/BNIP3L expressions was determined by RNA‐immunoprecipitation analysis and RNA stability experiments. Hypoxia induced mitochondrial dysfunction by increased ROS, decline in membrane potential and activated mitophagy through up‐regulated PARKIN, PINK1, BNIP3 and BNIP3L expressions. HuR knockdown studies revealed that HuR regulates hypoxia‐induced mitophagosome and mitolysosome formation. HuR was significantly bound to PARKIN and BNIP3L mRNA under hypoxia and thereby up‐regulated their expressions through mRNA stability. Altogether, our data highlight the importance of HuR in mitophagy regulation through up‐regulating PARKIN/BNIP3L expressions in renal tubular cells.

Extracorporeal cardiopulmonary resuscitation (ECPR) is increasingly performed as an adjunct to conventional cardiopulmonary resuscitation (CCPR) for refractory out-of-hospital cardiac arrest (OHCA). However, the specific benefits of ECPR concerning survival with favorable neurological outcomes remain uncertain. This study aimed to investigate the potential advantages of ECPR in the management of refractory OHCA. We conducted a retrospective cohort study involved OHCA patients between January 2016 and May 2021. Patients were categorized into ECPR or CCPR groups. The primary endpoint assessed was survival with favorable neurological outcomes, and the secondary outcome was survival rate. Multivariate logistic regression analyses, with and without 1:2 propensity score matching, were employed to assess ECPR’s effect. In total, 1193 patients were included: 85underwent ECPR, and 1108 received CCPR. Compared to the CCPR group, the ECPR group exhibited notably higher survival rate (29.4% vs. 2.4%; p  < 0.001). The ECPR group also exhibited a higher proportion of survival with favorable neurological outcome than CCPR group (17.6% vs. 0.7%; p  < 0.001). Multivariate logistic regression analysis demonstrated that ECPR correlated with increased odds of survival with favorable neurological outcome (adjusted odds ratio: 13.57; 95% confidence interval (CI) 4.60–40.06). Following propensity score matching, the ECPR group showed significantly elevated odds of survival with favorable neurological outcomes (adjusted odds ratio: 13.31; 95% CI 1.61–109.9). This study demonstrated that in comparison to CCPR, ECPR may provide survival benefit and increase the odds of favorable neurological outcomes in selected OHCA patients.

Oral squamous cell carcinomas (OSCCs), like several solid tumours, contain heterogeneous subpopulations of a small subset of cancer cells, termed cancer stem cells (CSCs), that are highly relevant to cancer metastasis and invasive properties. CSCs have also shown a high capacity to survive against various stressful environments, such as hypoxia. However, the molecular underpinnings behind the high potential of CSCs to survive under this stress remain unclear. The current study aimed to investigate the significance of autophagy systems in oral CSC maintenance and survival under stress conditions. Human OSCC cell lines OECM‐1 and OECM‐1 CSCs were cultured in different hypoxic time periods for proliferation and cytotoxicity analyses. The stemness property of CSCs is evaluated by sphere formation, transwell and wound healing assays protein expression of stemness, and epithelial‐to‐mesenchymal transition markers. Mitochondrial functions, including mitochondrial ROS generation, mitochondria dynamics, mitophagy, and mitochondrial metabolism (glycolysis and oxidative phosphorylation [OXPHOS]) were examined by western blotting, immunohistochemistry, and XF‐seahorse assays, respectively. Under hypoxia, oral CSCs showed a higher proliferation rate with increased invasion/migration/EMT properties than OECM‐1 cells. Further, hypoxia‐induced BNIP3‐driven mitophagy was activated in OECM‐1 CSCs than in OECM‐1 cells, which also triggered a metabolic shift towards OXPHOS, and BNIP3/‐L silencing by siRNA significantly attenuated OECM‐1 CSCs stemness features. TCGA data analyses also revealed a higher BNIP3 expression in head and neck squamous carcinoma patients' tumour samples associated with lower patient survival. Collectively, our results revealed a BNIP3/‐L‐driven autophagy contributes to the OECM‐1 CSCs stemness features under hypoxia, suggesting a novel therapeutic strategy involving BNIP3 and autophagy inhibition in oral CSCs.

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder with limited clinical treatments. The occurrence of PD includes both genetic and environmental toxins, such as the pesticides paraquat (PQ), as major contributors to PD pathology in both invertebrate and mammalian models. Calycosin, an isoflavone phytoestrogen, has multiple pharmacological properties, including neuroprotective activity. However, the paucity of information regarding the neuroprotective potential of calycosin on PQ-induced neurodegeneration led us to explore whether calycosin can mitigate PD-like phenotypes and the underlying molecular mechanisms. We used a PQ-induced PD model in Drosophila as a cost-effective in vivo screening platform to investigate the neuroprotective efficacy of natural compounds on PD. We reported that calycosin shows a protective role in preventing dopaminergic (DA) neuronal cell death in PQ-exposed Canton S flies. Calycosin-fed PQ-exposed flies exhibit significant resistance against PQ-induced mortality and locomotor deficits in terms of reduced oxidative stress, loss of DA neurons, the depletion of dopamine content, and phosphorylated JNK-caspase-3 levels. Additionally, mechanistic studies show that calycosin administration improves PQ-induced mitochondrial dysfunction and stimulates mitophagy and general autophagy with reduced pS6K and p4EBP1 levels, suggestive of a maintained energy balance between anabolic and catabolic processes, resulting in the inhibition of neuronal cell death. Collectively, this study substantiates the protective effect of calycosin against PQ-induced neurodegeneration by improving DA neurons’ survival and reducing apoptosis, likely via autophagy induction, and it is implicated as a novel therapeutic application against toxin-induced PD pathogenesis.

Background Lactate dynamics reflects restoration of tissue perfusion and has prognostic value in critical illness. However, the temporal evolution of lactate and its prognostic implications after out-of-hospital cardiac arrest (OHCA) have not been fully elucidated. Methods We retrospectively analyzed adult patients with OHCA with sustained return of spontaneous circulation (ROSC) at a tertiary medical center in Taiwan between 2016 and 2022. Serial lactate levels were measured at 2, 6, 12, and 24 h after ROSC. The primary outcome was a favorable neurological status at discharge, and a key secondary outcome was survival to discharge. Linear mixed-effects models were applied to evaluate longitudinal lactate trajectories and their associations with outcomes, accounting for repeated measures and adjusting for age, initial rhythm, bystander cardiopulmonary resuscitation (CPR), CPR duration, public location, witnessed status, targeted temperature management, percutaneous coronary intervention, and extracorporeal membrane oxygenation. Results Of the 496 included patients, 90 (18.1%) achieved a favorable neurological outcome and 241 (48.6%) survived to discharge. Lactate levels declined significantly over time in both groups ( p  < 0.001), but patients with favorable neurological outcomes and survivors showed a steeper decline between 12 and 24 h. Interaction analyses revealed significant time × outcome effects for neurological outcome at 12 h (β = − 0.33, 95% CI − 0.65 to − 0.001, p  = 0.049) and 24 h (β = − 0.61, 95% CI − 0.91 to − 0.30, p  < 0.001), and for survival at 12 h (β = − 0.38, 95% CI − 0.64 to − 0.13, p  = 0.002) and 24 h (β = − 0.48, 95% CI − 0.72 to − 0.24, p  < 0.001). Conclusion Serial lactate trajectories within the first 24 h after ROSC were strongly associated with survival and neurological recovery in OHCA patients. Modeling lactate as a continuous dynamic biomarker using LMM captured prognostic information beyond single time points and may help guide individualized post-resuscitation management.

The prognostic significance of conversion into a shockable rhythm in patients who experienced out-of-hospital cardiac arrest (OHCA) with an initially nonshockable rhythm is controversial, perhaps due to the timing of rhythm conversion not being considered previously. We aimed to compare the different prognoses of patients with OHCA and early and late conversion of their rhythm into a shockable rhythm. This was a single-centre retrospective cohort study. We enrolled patients with OHCA who were sent to a medical centre in central Taiwan from 2016 to 2020. Patients <18 years old, those with cardiac arrest due to trauma or a circumstantial cause, and those for whom resuscitation was not attempted were excluded. Patients were divided into two groups in accordance with presentation with an initially shockable rhythm. Those with an initially nonshockable rhythm were divided into three subgroups: early-conversion, late-conversion, and nonconversion groups. The primary outcome was the neurological functional status upon discharge from hospital. A total of 1645 patients with OHCA were included: initially shockable rhythm group, 339; early conversion group, 68; late-conversion group, 166; and nonconversion group, 1072. After adjustment, multivariate logistic regression revealed that a favourable neurological outcome was more common in the early conversion group than the nonconversion group (odds ratio [OR] 2.4; 95% confidence interval [CI], 1.1–5.3; p = 0.035), whereas the late-conversion group did not significantly differ from the nonconversion group (OR 0.5; 95% CI, 0.1–1.5; p = 0.211). The proportions of sustained return of spontaneous circulation and survival to discharge were also higher in the early conversion group than the late-conversion group (OR 2.9 95% CI 1.6–5.5, p = 0.001 and OR 4.5, 1.8–11.0, p = 0.001, respectively). In patients who experience OHCA and have an initially nonshockable rhythm, early conversion into a shockable rhythm resulted in a better prognosis, whereas late conversion was not significantly different from nonconversion. •17.91% initial nonshockable out-of-hospital cardiac arrest patients convert into a shockable rhythm during resuscitation.•Spontaneous conversion to a shockable rhythm does not necessarily have a favourable prognosis.•25 min is a reasonable cut-off point to distinguish between early and late conversion.•Early conversion into a shockable rhythm resulted in a better prognosis.•Late conversion into a shockable rhythm was not significantly different from nonconversion group.

The aim of this study is to identify potential biomarkers for early diagnosis of gynecologic cancer in order to improve survival. Cervical cancer (CC) and endometrial cancer (EC) are the most common malignant tumors of gynecologic cancer among women in the world. As the underlying molecular mechanisms in both cervical and endometrial cancer remain unclear, a comprehensive and systematic bioinformatics analysis is required. In our study, gene expression profiles of GSE9750, GES7803, GES63514, GES17025, GES115810, and GES36389 downloaded from Gene Expression Omnibus (GEO) were utilized to analyze differential gene expression between cancer and normal tissues. A total of 78 differentially expressed genes (DEGs) common to CC and EC were identified to perform the functional enrichment analyses, including gene ontology and pathway analysis. KEGG pathway analysis of 78 DEGs indicated that three main types of pathway participate in the mechanism of gynecologic cancer such as drug metabolism, signal transduction, and tumorigenesis and development. Furthermore, 20 diagnostic signatures were confirmed using the least absolute shrink and selection operator (LASSO) regression with 10-fold cross validation. Finally, we used the GEPIA2 online tool to verify the expression of 20 genes selected by the LASSO regression model. Among them, the expression of PAMR1 and SLC24A3 in tumor tissues was downregulated significantly compared to the normal tissue, and found to be statistically significant in survival rates between the CC and EC of patients (p < 0.05). The two genes have their function: (1.) PAMR1 is a tumor suppressor gene, and many studies have proven that overexpression of the gene markedly suppresses cell growth, especially in breast cancer and polycystic ovary syndrome; (2.) SLC24A3 is a sodium–calcium regulator of cells, and high SLC24A3 levels are associated with poor prognosis. In our study, the gene signatures can be used to predict CC and EC prognosis, which could provide novel clinical evidence to serve as a potential biomarker for future diagnosis and treatment.

The main purpose of this study was to develop observation techniques and processing technology for the electrochemical discharge machining (ECDM) of sapphire wafers. To measure the effect of gas-film thickness, discharge-spark conditions, and droplet sliding frequency on machining quality and efficiency in ECDM, this research utilized high-speed cameras to observe the gas film thickness and formation of the gas film during ECDM. Additionally, this study observed the machining-gap phenomena during ECDM. The formation mechanism and machining characteristics of the gas film were understood through experiments. The machining parameters included the liquid level, working voltage, rotation speed, and duty factor. This study analyzed and discussed the effect of each machining parameter on the gas-film thickness, current, electrode consumption, and droplet sliding frequency. Moreover, this study aimed to obtain optimized machining parameters to overcome the difficulty of machining sapphire. The experimental results indicated that utilizing a high-speed camera to capture the phenomena between electrodes during electrochemical discharge could effectively observe the gas-film thickness and the coverage of the gas film. A higher bubble coalescence rate enhanced the machining capability and reduced the lateral discharge. Therefore, this study could obtain better machining-hole depths through observation and analysis to improve gas-film stability and machining capability. This study demonstrated that a liquid level of 700 µm, a working voltage of 48 V, a duty factor of 50%, and a tool electrode rotational speed of 200 rpm could achieve a hole depth of 86.7 µm and a hole diameter of 129.5 µm.

Background Sudden cardiac arrest (SCA) is a critical complication of acute myocardial infarction, especially ST-segment elevation myocardial infarction (STEMI). This study identified the risk factors for SCA in patients with STEMI before receiving catheterization. Methods We retrospectively analyzed the data of patients with STEMI and cardiac arrest who presented to a tertiary care center in Taiwan between January 1, 2016, and December 31, 2019. Only patients with coronary artery disease (CAD) confirmed by coronary angiography were included in this study. We collected the patients’ demographic and clinical data, such as age, sex, medical history, estimated glomerular filtration rate (eGFR), and coronary angiographic findings. The primary outcome of this study was SCA in patients with STEMI. Continuous and nominal variables were compared using the two-sample Student's t -test and chi-squared test, respectively. The results of logistic regression were subjected to multivariate analysis with adjustment for possible confounders. Results A total of 920 patients with STEMI and coronary angiography–documented CAD and 108 patients with SCA who presented between January 1, 2016, and December 31, 2019, were included. The bivariate logistic regression analysis of patients’ demographic data revealed that patients with STEMI and SCA were slightly younger, were more likely to have diabetes mellitus, and had a lower eGFR than did the patients without SCA. The coronary angiographic findings indicated a higher prevalence of left main CAD and three-vessel disease in patients with SCA than in patients without SCA. Multivariate logistic regression revealed that left main CAD (odds ratio [OR]: 3.77; 95% confidence interval [CI], 1.84 to 7.72), a lower eGFR (OR: 0.97; 95% CI, 0.96 to 0.98), and younger age (OR: 0.98; 95% CI, 0.96 to 0.99) were the risk factors for SCA in patients with STEMI. Conclusions Left main CAD, lower eGFR, and younger age are the risk factors for cardiac arrest in patients with acute myocardial infarction.