Non-Apoptotic Programmed Cell Death as Targets for Diabetic Retinal Neurodegeneration.

Diabetic retinopathy (DR) remains the leading cause of blindness among the global working-age population. Emerging evidence underscores the significance of diabetic retinal neurodegeneration (DRN) as a pivotal biomarker in the progression of vasculopathy. Inflammation, oxidative stress, neural cell death, and the reduction in neurotrophic factors are the key determinants in the pathophysiology of DRN. Non-apoptotic programmed cell death (PCD) plays a crucial role in regulating stress response, inflammation, and disease management. Therapeutic modalities targeting PCD have shown promising potential for mitigating DRN. In this review, we highlight recent advances in identifying the role of various PCD types in DRN, with specific emphasis on necroptosis, pyroptosis, ferroptosis, parthanatos, and the more recently characterized PANoptosis. In addition, the therapeutic agents aimed at the regulation of PCD for addressing DRN are discussed.

Characteristics of "do not resuscitate" orders among elderly patients receiving mechanical ventilation in the intensive care unit in Taiwan.

Objective: As patient life expectancy has increased and people are living longer than before, the rate of mechanical ventilation among elderly patients in the intensive care unit has increased. Older patients who receive mechanical ventilation and have multiple comorbidities are more likely to have a do not resuscitate order than are younger patients with fewer comorbidities. The aim of our study was to describe the patient characteristics and predictive factors of do not resuscitate orders during hospitalization among elderly patients who received ventilation in the intensive care unit. Methods: This was a retrospective review of the electronic medical records of patients in the intensive care unit of a teaching hospital in southern Taiwan. We enrolled patients admitted to the general intensive care unit from January 1, 2018, to September 31, 2020, and patients older than 80 years who experienced respiratory failure, were intubated and received mechanical ventilation. We analyzed patient demographics, disease severity during hospitalization and comorbidities. If a patient had multiple admissions to the intensive care unit, only the first admission was recorded. Results: Of the 305 patients over 80 years of age with respiratory failure who were intubated and placed on a ventilator, 66 were excluded because of incomplete data, and 13 were excluded because they had already signed a do not resuscitate order prior to admission to the hospital. Ultimately, 226 patients were included in this study. A higher acute physiology and chronic health evaluation II score (>30) was also associated with an increased likelihood of a do not resuscitate order (odds ratio (OR) = 3.85, 95% CI = 1.09-13.62, p = 0.0362). Patients who had acute kidney injury or cerebrovascular accident were more likely to have a do not resuscitate order (OR = 2.74, 95% CI = 1.03-7.28, p = 0.0428 and OR = 7.32, 95% CI = 2.02-26.49, p = 0.0024, respectively). Conclusion: Our study showed that older age, greater disease severity, and certain critical interventions were associated with a greater propensity for do not resuscitate orders, which is crucial for understanding patient preferences and guiding end-of-life care discussions. These findings highlight the importance of clinical severity and specific health events in predicting end-of-life care preferences in older patient groups.

Health-related quality of life by veterans RAND 12 and healthcare resource utilization in cancer patients with sleep disorders: insights from the Medical Expenditure Panel Survey.

PURPOSE: This study aims to investigate the joint effects of cancer and sleep disorders on the health-related quality of life (HRQoL), healthcare resource utilization, and expenditures among US adults. METHODS: Utilizing the 2018-2019 Medical Expenditure Panel Survey (MEPS) database, a sample of 25,274 participants was categorized into four groups based on cancer and sleep disorder status. HRQoL was assessed using the VR-12 questionnaire. Generalized linear model (GLM) with a log-linear regression model combined gamma distribution was applied for the analysis of healthcare expenditure data. RESULTS: Individuals with both cancer and sleep disorders (C+/S+) exhibited notably lower physical health (PCS) and mental health (MCS) scores-1.45 and 1.87 points lower, respectively. They also showed significantly increased clinic visits (2.12 times), outpatient visits (3.59 times), emergency visits (1.69 times), and total medical expenditures (2.08 times) compared to those without cancer or sleep disorders (C-/S-). In contrast, individuals with sleep disorders alone (C-/S+) had the highest number of prescription drug usage (2.26 times) and home health care days (1.76 times) compared to the reference group (C-/S-). CONCLUSIONS: Regardless of cancer presence, individuals with sleep disorders consistently reported compromised HRQoL. Furthermore, those with cancer and sleep disorders experienced heightened healthcare resource utilization, underscoring the considerable impact of sleep disorders on overall quality of life. IMPLICATIONS FOR CANCER SURVIVORS: The findings of this study address the importance of sleep disorders among cancer patients and their potential implications for cancer care. Healthcare professionals should prioritize screening, education, and tailored interventions to support sleep health in this population.

Shock index to predict outcomes in patients with trauma following traffic collisions: a retrospective cohort study.

PURPOSE: Taiwan, which has a rate of high vehicle ownership, faces significant challenges in managing trauma caused by traffic collisions. In Taiwan, traffic collisions contribute significantly to morbidity and mortality, with a high incidence of severe bleeding trauma. The shock index (SI) and the modified shock index (MSI) have been proposed as early indicators of hemodynamic instability. In this study, we aimed to assess the efficacy of SI and MSI in predicting adverse outcomes in patients with trauma following traffic collisions. METHODS: This retrospective cohort study was conducted at Chi Mei Hospital from January 2015 to December 2020. The comprehensive analysis included 662 patients, with data collected on vital signs and outcomes such as mortality, blood transfusion, emergent surgical intervention (ESI), transarterial embolization (TAE), and intensive care unit (ICU) admission. Optimal cutoff points for SI and MSI were identified by calculating the Youden index. Logistic regression analysis was used to assess outcomes, adjusting for demographic and injury severity variables. RESULTS: An SI threshold of 1.11 was associated with an increased risk of mortality, while an SI of 0.84 predicted the need for blood transfusion in the context of traffic collisions. Both SI and MSI demonstrated high predictive power for mortality and blood transfusion, with acceptable accuracy for TAE, ESI, and ICU admission. Logistic regression analyses confirmed the independence of SI and MSI as risk factors for adverse outcomes, thus, providing valuable insights into their clinical utility. CONCLUSIONS: SI and MSI are valuable tools for predicting mortality and blood transfusion needs in patients with trauma due to traffic collisions. These findings advance the quality of care for patients with trauma during their transition from the emergency room to the ICU, facilitating prompt and reliable decision-making processes and improving the care of patients with trauma.

LAD: Layer-Wise Adaptive Distillation for BERT Model Compression.

Recent advances with large-scale pre-trained language models (e.g., BERT) have brought significant potential to natural language processing. However, the large model size hinders their use in IoT and edge devices. Several studies have utilized task-specific knowledge distillation to compress the pre-trained language models. However, to reduce the number of layers in a large model, a sound strategy for distilling knowledge to a student model with fewer layers than the teacher model is lacking. In this work, we present Layer-wise Adaptive Distillation (LAD), a task-specific distillation framework that can be used to reduce the model size of BERT. We design an iterative aggregation mechanism with multiple gate blocks in LAD to adaptively distill layer-wise internal knowledge from the teacher model to the student model. The proposed method enables an effective knowledge transfer process for a student model, without skipping any teacher layers. The experimental results show that both the six-layer and four-layer LAD student models outperform previous task-specific distillation approaches during GLUE tasks.

The identification of molecular target of (20S) ginsenoside Rh2 for its anti-cancer activity.

The 20S ginsenoside Rh2 (G-Rh2) effectively inhibits cancer cell growth and survival in both animal models and cell lines. However, its molecular targets and mechanism of action remain largely unknown. By screening for molecules that interact with (20S)G-Rh2 in a phage display assay, we have identified Annexin A2 as a potential target that mediates its anti-cancer activity. Isothermal titration calorimetry and a cellular thermal shift assay demonstrated that (20S)G-Rh2 directly bound to either recombinant or intracellular Annexin A2. This binding inhibited the interaction between Annexin A2 and the NF-кB p50 subunit, which attenuated the nuclear translocations of NF-кB p50 subunit and reduced the transactivation activity of NF-кB. Correspond to this result, (20S)G-Rh2 treatment significantly down-regulated the expression of IAPs (inhibitors of apoptosis), the well-established NF-кB targets that promote cell survival. Moreover, (20S)G-Rh2 synergized with Annexin A2 inactivation to promote apoptosis. Taken together, this study for the first time suggests a cellular target and a molecular pathway by which (20S)G-Rh2 inhibits cancer cell growth. As over-expression of Annexin A2 was evident in human hepatoma, (20S)G-Rh2 might be a promising natural compound for targeted liver cancer therapy.

The interaction of serum albumin with ginsenoside Rh2 resulted in the downregulation of ginsenoside Rh2 cytotoxicity.

BACKGROUND: Ginsenoside Rh2 (G-Rh2) is a ginseng saponin that is widely investigated because of its remarkable antitumor activity. However, the molecular mechanism by which (20S) G-Rh2 triggers its functions and how target animals avoid its cytotoxic action remains largely unknown. METHODS: Phage display was used to screen the human targets of (20S) G-Rh2. Fluorescence spectroscopy and UV-visible absorption spectroscopy were used to confirm the interaction of candidate target proteins and (20S) G-Rh2. Molecular docking was utilized to calculate the estimated free energy of binding and to structurally visualize their interactions. MTT assay and immunoblotting were used to assess whether human serum albumin (HSA), bovine serum albumin (BSA), and bovine serum can reduce the cytotoxic activity of (20S) G-Rh2 in HepG2 cells. RESULTS: In phage display, (20S) G-Rh2-beads and (20R) G-Rh2-beads were combined with numerous kinds of phages, and a total of 111 different human complementary DNAs (cDNA) were identified, including HSA which had the highest rate. The binding constant and number of binding site in the interaction between (20S)-Rh2 and HSA were 3.5 × 105 M-1 and 1, and those in the interaction between (20S) G-Rh2 and BSA were 1.4 × 105 M-1 and 1. The quenching mechanism is static quenching. HSA, BSA and bovine serum significantly reduced the proapoptotic effect of (20S) G-Rh2. CONCLUSION: HSA and BSA interact with (20S) G-Rh2. Serum inhibited the activity of (20S) G-Rh2 mainly due to the interaction between (20S) G-Rh2 and serum albumin (SA). This study proposes that HSA may enhance (20S) G-Rh2 water solubility, and thus might be used as nanoparticles in the (20S) G-Rh2 delivery process.

Betulin induces reactive oxygen species-dependent apoptosis in human gastric cancer SGC7901 cells.

Betulin, an abundant natural compound, significantly inhibited the cell viability of advanced human gastric cancer SGC7901 cells. Mechanism study demonstrated that betulin induced apoptosis through mitochondrial Bax and Bak accumulation-mediated intrinsic apoptosis pathway. Downregulation of the anti-apoptosis proteins Bcl-2 and XIAP was involved during betulin-induced cell apoptosis. Reactive oxygen species (ROS) was generated in cells after betulin treatment in a time- and dose-dependent manner. Addition of antioxidant N-acetyl-L-cysteine (NAC) significantly attenuated betulin-induced ROS generation as well as Bcl-2 and XIAP downregulation. The mitochondrial accumulation of Bax and Bak, as well as caspase activity, was also remarkably inhibited by NAC treatment, indicating that ROS are important signaling intermediates that lead to betulin-induced apoptosis by modulating multiple apoptosis-regulating proteins in SGC7901 cells.

Effect of sun ginseng potentiation on epirubicin and paclitaxel-induced apoptosis in human cervical cancer cells.

BACKGROUND: Sun ginseng (SG), a specific formulation of quality-controlled red ginseng, contains approximately equal amounts of three major ginsenosides (RK1, Rg3, and Rg5), which reportedly has antitumor-promoting activities in animal models. METHODS: MTT assay was used to assess whether SG can potentiate the anticancer activity of epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells; apoptosis status was analyzed by annexin V-FITC and PI and analyzed by flow cytometry; and apoptosis pathway was studied by analysis of caspase-3, -8, and -9 activation, mitochondrial accumulation of Bax and Bak, and cytochrome c release. RESULTS: SG remarkably enhances cancer cell death induced by epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells. Results of the mechanism study highlighted the cooperation between SG and epirubicin or paclitaxel in activating caspase-3 and -9 but not caspase-8. Moreover, SG significantly increased the mitochondrial accumulation of both Bax and Bak triggered by epirubicin or paclitaxel as well as the subsequent release of cytochrome c in the targeted cells. CONCLUSION: SG significantly potentiated the anticancer activities of epirubicin and paclitaxel in a synergistic manner. These effects were associated with the increased mitochondrial accumulation of both Bax and Bak that led to an enhanced cytochrome c release, caspase-9/-3 activation, and apoptosis. Treating cancer cells by combining epirubicin and paclitaxel with SG may prove to be a novel strategy for enhancing the efficacy of the two drug types.

p53-dependent Fas expression is critical for Ginsenoside Rh2 triggered caspase-8 activation in HeLa cells.

We have recently reported that Ginsenoside Rh2 (G-Rh2) induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. However, the molecular mechanism of its death-inducing function remains unclear. Here we show that G-Rh2 stimulated the activation of both caspase-8 and caspase-9 simultaneously in HeLa cells. Under G-Rh2 treatment, membrane death receptors Fas and TNFR1 are remarkably upregulated. However, the induced expression of Fas but not TNFR1 was contributed to the apoptosis process. Moreover, significant increases in Fas expression and caspase-8 activity temporally coincided with an increase in p53 expression in p53-non-mutated HeLa and SK-HEP-1 cells upon G-Rh2 treatment. In contrast, Fas expression and caspase-8 activity remained constant with G-Rh2 treatment in p53-mutated SW480 and PC-3 cells. In addition, siRNA-mediated knockdown of p53 diminished G-Rh2-induced Fas expression and caspase-8 activation. These results indicated that G-Rh2-triggered extrinsic apoptosis relies on p53-mediated Fas over-expression. In the intrinsic apoptotic pathway, G-Rh2 induced strong and immediate translocation of cytosolic BAK and BAX to the mitochondria, mitochondrial cytochrome c release, and subsequent caspase-9 activation both in HeLa and in SW480 cells. p53-mediated Fas expression and subsequent downstream caspase-8 activation as well as p53-independent caspase-9 activation all contribute to the activation of the downstream effector caspase-3/-7, leading to tumor cell death. Taken together, we suggest that G-Rh2 induces cancer cell apoptosis in a multi-path manner and is therefore a promising candidate for anti-tumor drug development.