TNF and IFNγ-induced cell death requires IRF1 and ELAVL1 to promote CASP8 expression.

TNFα and IFNγ (TNF/IFNγ) synergistically induce caspase-8 activation and cancer cell death. However, the mechanism of IFNγ in promoting TNF-initiated caspase-8 activation in cancer cells is poorly understood. Here, we found that in addition to CASP8, CYLD is transcriptionally upregulated by IFNγ-induced transcription factor IRF1. IRF1-mediated CASP8 and CYLD upregulation additively mediates TNF/IFNγ-induced cancer cell death. Clinically, the expression levels of TNF, IFNγ, CYLD, and CASP8 in melanoma tumors are increased in patients responsive to immune checkpoint blockade (ICB) therapy after anti-PD-1 treatment. Accordingly, our genetic screen revealed that ELAVL1 (HuR) is required for TNF/IFNγ-induced caspase-8 activation. Mechanistically, ELAVL1 binds CASP8 mRNA and extends its stability to sustain caspase-8 expression both in IFNγ-stimulated and in basal conditions. Consequently, ELAVL1 determines death receptors-initiated caspase-8-dependent cell death triggered from stimuli including TNF and TRAIL by regulating basal/stimulated caspase-8 levels. As caspase-8 is a master regulator in cell death and inflammation, these results provide valuable clues for tumor immunotherapy and inflammatory diseases.

Preoperative geriatric nutritional risk index is useful factor for predicting postoperative delirium among elderly patients with degenerative lumbar diseases.

PURPOSE: It is the first study to evaluate the predictive value of the geriatric nutritional risk index (GNRI) on postoperative delirium (POD) after transforaminal lumber interbody fusion (TLIF) in elderly patients with degenerative lumbar diseases. METHODS: A retrospective study was conducted to assess the outcomes of TLIF surgery in elderly patients with lumbar degenerative disease between the years 2016 and 2022. Delirium was diagnosed by reviewing postoperative medical records during hospitalization, utilizing the Confusion Assessment Method. The geriatric nutritional risk index was calculated using the baseline serum albumin level and body weight. Multivariate logistic regression analysis was employed to identify the association between preoperative GNRI and postoperative delirium (POD). Additionally, a receiver operating characteristic curve was utilized to determine the optimal GNRI cutoff for predicting POD. RESULTS: POD was observed in 50 of the 324 patients. The GNRI was visibly reduced in the delirium group. The mean GNRI was 93.0 ± 9.1 in non-delirium group and 101.2 ± 8.2 in delirium group. On multivariate logistic regression, Risk of POD increases significantly with low GNRI and was an independent factor in predicting POD following TLIF (OR 0.714; 95% CI 0.540-0.944; p = 0.018). On receiver operating characteristic curve, the area under curve (AUC) for GNRI was 0.738 (95% CI 0.660-0.817). The cutoff value for GNRI according to the Youden index was 96.370 (sensitivity: 66.0%, specificity: 70.4%). CONCLUSION: Our study indicated that lower GNRI correlated significantly with POD after TLIF. Performing GNRI evaluation prior to TLIF may be an effective approach of predicting the risk for POD among elderly patients with degenerative lumbar diseases.

Comparison of predictive value for cage subsidence between MRI-based endplate bone quality and vertebral bone quality scores following transforaminal lumbar interbody fusion: a retrospective propensity-matched study.

BACKGROUND CONTEXT: Cage subsidence after lumbar fusion can lead to many adverse outcomes. Low bone mineral density (BMD) is a widely recognized risk factor for cage subsidence. Conventional methods can predict and evaluate BMD, but there are many shortcomings. Recently, MRI-based assessment of bone quality in specific parts of the vertebral body has been proposed, including scores for vertebral bone quality (VBQ) and endplate bone quality (EBQ). However, the predictive accuracy of the two scoring systems for cage subsidence after transforaminal lumbar interbody fusion (TLIF) remains unknown. Therefore, we investigated MRI-based VBQ and EBQ scores for assessing bone quality and compared their predictive value for cage subsidence after TLIF. PURPOSE: To compare the predictive value between MRI-based VBQ and EBQ scores for cage subsidence after TLIF. STUDY DESIGN/SETTING: A retrospective case-control study. PATIENTS SAMPLE: Patients with degenerative lumbar diseases underwent single-level TLIF at our medical center between 2014 and 2020, all of whom had preoperative MRIs available. OUTCOMES MEASURES: Cage subsidence, disc height, VBQ score, EBQ score, upper and lower vertebral body bone quality (UL-VBQ) score. METHODS: Data were retrospectively examined for a consecutive sample of 346 patients who underwent TLIF at our medical center between 2014 and 2020. Patients who subsequently experienced cage subsidence or not were matched to each other based on propensity scoring, and the two matched groups (52 patients each) were compared using conditional logistic regression to investigate the association between the potential radiographic factors and cage subsidence. Scores for VBQ and EBQ were assessed for their ability to predict cage subsidence in the matched patients based on the area under the receiver operative characteristic curve (AUC). RESULTS: Among matched patients, those who suffered cage subsidence had significantly higher VBQ score (3.7 vs 3.1, p<.001) and EBQ score (5.0 vs 4.3, p<.001), and regression linked greater risk of subsidence to higher VBQ score (OR 4.557, 95% CI 1.076-19.291, p=.039) and higher EBQ score (OR 5.396, 95% CI 1.158-25.146, p=.032). A cut-off VBQ score of 3.4 predicted the cage subsidence among matched patients with an AUC of 0.799, sensitivity of 84.6%, and specificity of 69.2%. A cut-off EBQ score of 4.7 predicted subsidence with an AUC of 0.829, sensitivity of 76.9%, and specificity of 82.7%. CONCLUSION: Higher VBQ and EBQ scores are associated with a greater risk of cage subsidence following TLIF, and EBQ may perform better because of greater specificity.

Effects of deep frying and baking on the quality attributes, water distribution, and flavor characteristics of duck jerky.

Introduction: The nutritional value of duck meat is well acknowledged due to its low cholesterol and high protein content. Nevertheless, the impacts of deep-frying and baking on its quality characteristics are not extensively documented in literature. Methods: The objective of this study is to examine the effects of deep-frying, pre-boilingdeep-frying, baking, and pre-boiling-baking on the quality attributes, water distribution, microstructure, and flavor characteristics of duck jerky. Results and discussion: The findings revealed that the deep-frying group had better quality attributes than the baking, pre-boiling-deep-frying, and pre-boiling-baking groups. The deepfried duck jerky had a higher a* value (4.25) and a lower b* value (5.87), with a more appropriate texture profile, and had the highest comprehensive impression score (5.84). Moreover, the drying rate was faster, and the intensity of the free water and oil signal was significantly elevated in the deep-frying group. The microstructure results indicated that the muscle fibers in the deep-frying group were closely packed, whereas those in the baking group were relatively loose. Furthermore, the GC-IMS test revealed that the deep-fried duck jerky had a wider range of volatile flavor compounds, including 11 unique compounds that were only found in this particular product.

The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death.

Apoptosis, the first regulated form of cell death discovered in mammalian cells, is executed by caspase-3/7, which are dormant in living cells but become activated by upstream caspase-8 or caspase-9 in responding to extracellular cytokines or intracellular stress signals, respectively. The same cell death-inducing cytokines also cause necroptosis when caspase-8 is inhibited, resulting in the activation of receptor-interacting protein kinase 3 (RIPK3), which phosphorylates pseudokinase MLKL to trigger its oligomerization and membrane-disrupting activity. Caspase-1/4/5/11, known as inflammatory caspases, instead induce pyroptosis by cleaving gasdermin D, whose caspase-cleaved N terminus forms pores on the plasma membrane. The membrane protein NINJ1 amplifies the extent of membrane rupture initiated by gasdermin D. Additionally, disturbance of peroxidation of polyunsaturated fatty acid tails of membrane phospholipids triggers ferroptosis, an iron-dependent and caspases-independent necrotic death. This review will discuss how these regulated cell death pathways act individually and interconnectively in particular cell types to carry out specific physiological and pathological functions.

Simplified S1 vertebral bone quality (vbq) score to assess proximal junctional kyphosis after Lenke 5 adolescent idiopathic scoliosis surgery.

BACKGROUND: Proximal junctional kyphosis (PJK) is a common complication following corrective surgery for adolescent idiopathic scoliosis (AIS) with a Lenke 5 curve. Previous studies have suggested that PJK may be associated with osteopenia, which is prevalent in AIS patients. MRI-based vertebral bone quality (VBQ) scores have been proposed as a valuable tool to assess preoperative bone quality. However, accurately measuring VBQ scores in Lenke 5 AIS patients with a structural lumbar curve can be challenging. Recently, a simplified S1 VBQ score has been proposed as an alternative method when the traditional VBQ score is not applicable. This study aims to evaluate the predictive value of the simplified S1 VBQ score in predicting the occurrence of PJK after corrective surgery for Lenke 5 AIS. METHODS: We conducted a retrospective analysis of patient data to assess the predictive utility of the S1 VBQ score for PJK in Lenke 5 AIS patients. Demographic, radiographic, and surgical data were collected, and S1 VBQ scores were calculated based on preoperative T1-weighted MRI images. Univariate analysis, linear regression, and multivariate logistic regression were performed to identify potential risk factors for PJK and to assess the correlation between other variables and the S1 VBQ score. Receiver operating characteristic analysis and area under the curve values were used to evaluate the predictive efficiency of the S1 VBQ score for PJK. RESULTS: A total of 105 patients (aged 15.50 ± 2.36 years) were included in the analysis, of whom 24 (22.9%) developed PJK. S1 VBQ scores were significantly higher in the PJK group compared to the non-PJK group (2.83 ± 0.44 vs. 2.48 ± 0.30, P < 0.001), and there was a significant positive correlation between the S1 VBQ score and proximal junctional angle (PJA) (r = 0.46, P < 0.0001). Multivariate analysis revealed that the S1 VBQ scores and preoperative thoracic kyphosis (TK) were significant predictors of PJK. CONCLUSION: This study provided evidence that higher S1 VBQ scores were independently associated with PJK occurrence following corrective surgery for Lenke 5 AIS. Preoperative measurement of the S1 VBQ score on MRI may serve as a valuable tool in planning surgical correction for Lenke 5 AIS.

Forearm bone mineral density predicts screw loosening after lumbar fusion similar to lumbar Hounsfield unit value in patients with lumbar spondylolisthesis.

Preoperative bone density assessment is necessary to predict screw loosening. The forearm BMD is a useful predictor of BMD-related complications after lumbar operation. Our results show that the forearm BMD is as effective a predictor of screw loosening as the lumbar average HU value. Measurement of the forearm BMD may be a useful adjunct in predicting screw loosening following lumbar fusion. PURPOSE: To determine the relationship between forearm bone mineral density (BMD) and the risk of pedicle screw loosening in patients with lumbar spondylolisthesis. METHODS: We retrospectively evaluated 270 patients who underwent posterior lumbar interbody fusion for lumbar spondylolisthesis. The patients were divided into two groups on the basis of the with or without loose screws: the loosening group and the non-loosening group. The patient's gender, age, BMI, smoking and diabetes histories, and the operative segment were recorded as the basic information. The Hounsfield unit (HU) value for the BMD of the L1-4 lumbar was measured using computed tomography. The patient's distal one-third of the length of the radius and ulna of the non-dominant forearm was chosen as the site for dual-energy X-ray (DXA) bone density testing. RESULTS: The rate of screw loosening was 13% at a minimum 12 months follow-up. Average forearm BMD (0.461 ± 0.1 vs 0.577 ± 0.1, p < 0.001) and mean HU value (L1-4) (121.1 ± 27.3 vs 155.6 ± 32.2, p < 0.001) were lower in the screw loosening group than those in the non-loosening group. In multivariate logistic regression analysis, the forearm BMD (OR 0.840; 95%CI 0.797-0.886) and HU value (L1-4) (OR 0.952; 95%CI 0.935-0.969) were independent risk factor for screw loosening. The area under the curve (AUC) for the forearm BMD and HU value for prediction of pedicle screw loosening was 0.802 and 0.811. The forearm BMD cut-off for predicting pedicle screw loosening was 0.543 (sensitivity, 0.800; specificity, 0.864). CONCLUSIONS: The forearm BMD was an independent risk factor for loosening of the lumbar pedicle screws. The forearm BMD was a valid predictor of pedicle screw loosening in patients undergoing lumbar fusion, as was the CT HU value.

Vertebral bone quality score as a novel predictor of proximal junctional kyphosis after thoracic adolescent idiopathic scoliosis surgery.

INTRODUCTION: Proximal junctional kyphosis (PJK) is one of the most common complications after thoracic AIS surgery. Previous studies reported that the etiology of PJK was associated with osteopenia and meanwhile the AIS patients were found osteopenia which could persist into adulthood. Recently, an MRI-based vertebral bone quality score (VBQ) was reported to be a promising tool which can assess preoperative bone quality. OBJECTIVE: This study aims to evaluate the utility of VBQ score in predicting PJK after corrective surgery for thoracic AIS (Lenke 1 and 2). METHODS: We conducted a retrospective study to identify the predictive efficiency of VBQ score for PJK in thoracic AIS patients. Demographic, radiographic parameters, and surgical variables were collected. VBQ score was calculated using preoperative T1-weighted MRI. Univariate analysis, linear regression, and multivariate logistic regression were performed to determine potential risk factors of PJK and correlation between other parameters and VBQ score. Receiver operating characteristic analysis and area under the curve values were utilized to evaluate the predictive efficiency of VBQ score for PJK. RESULTS: A total of 206 patients (aged 14.4 ± 2.3 years) were included, of which 33 (16.0%) developed PJK. VBQ scores were significantly different between the PJK and non-PJK groups (2.8 ± 0.2 vs 2.5 ± 0.2, P < 0.01). A significant positive correlation was found between VBQ score and PJA (R2 = 0.1728, P < 0.01).On multivariate analysis, VBQ score was the only significant predictor of PJK (odds ratio = 2.178, 95% CI = 1.644-2.885, P < 0.001), with a predictive accuracy of 83%. CONCLUSION: Higher VBQ scores were independently associated with PJK occurrence after corrective surgery for thoracic AIS. Preoperative measurement of VBQ score on MRI may serve as a valuable tool in planning thoracic AIS surgery.

MRI-based vertebral bone quality score for predicting cage subsidence by assessing bone mineral density following transforaminal lumbar interbody fusion: a retrospective analysis.

PURPOSE: This is the first study to evaluate the predictive value of the vertebral bone quality (VBQ) score on cage subsidence after transforaminal lumbar interbody fusion (TLIF) in a Chinese population using the spinal quantitative computed tomography (QCT) as the clinical standard. Meanwhile, the accuracy of the MRI-based VBQ score in bone mineral density (BMD) measurement was verified. METHODS: We performed a retrospective study of patients who underwent single-level TLIF from 2015 to 2020 with at least 1 year of follow-up. Cage subsidence was measured using postoperative radiographic images based on cage protrusion through the endplates more than 2 mm. The VBQ score was measured on T1-weighted MRI. The results were subjected to statistical analysis. RESULTS: A total of 283 patients (61.1% of female) were included in the study. The subsidence rate was with 14.1% (n = 40), and the average cage subsidence was 2.3 mm. There was a significant difference in age, sex, VBQ score and spinal QCT between the subsidence group and the no-subsidence group. The multivariable analysis demonstrated that only an increased VBQ score (OR = 2.690, 95% CI 1.312-5.515, p = 0.007) and decreased L1/2 QCT-vBMD (OR = 0.955, 95% CI 0.933-0.977, p < 0.001) were associated with an increased rate of cage subsidence. The VBQ score was found to be moderately correlated with the spinal QCT (r = -0.426, p < 0.001). The VBQ score was shown to significantly predict cage subsidence, with an accuracy of 82.5%. CONCLUSION: Our findings indicate that the MRI-based VBQ score is a significant predictor of cage subsidence and could be used to assess BMD.

MRI-based Endplate Bone Quality score independently predicts cage subsidence following transforaminal lumbar interbody fusion.

BACKGROUND CONTEXT: Cage subsidence following transforaminal lumbar interbody fusion (TLIF) has closely correlated with poor vertebral bone quality. Studies have shown better predictive value for cage subsidence by measuring bone density at specific site. However, few studies have been performed to examine the relationship between site-specific MRI bone assessment and cage subsidence in patients who have undergone lumbar interbody fusion. The association between MRI-based assessment of endplate bone quality and cage subsidence after TLIF remains unclear. PURPOSE: To study the predictive value of MRI-based endplate bone quality (EBQ) score for cage subsidence following TLIF, using QCT bone densitometry as a reference standard. STUDY DESIGN/SETTING: A retrospective study. PATIENT SAMPLE: A total of 280 adult patients undergoing single-segment TLIF for degenerative lumbar spine disease from 2010 to 2020 at our institution who had preoperative T1-weighted MRIs. OUTCOME MEASURES: Cage subsidence, disc height, endplate bone quality (EBQ) score, bone mineral density, fusion rate. METHODS: The retrospective study reviewed patients who underwent TLIF at one institution between March 2010 and October 2020. Cage subsidence was measured with postoperative lumbar X-rays based on the cage protrusion through into the superior or inferior end plate or both by more than 2 mm. The EBQ score was measured from preoperative T1-weighted MRI in accordance with the previously reported method. RESULTS: Cage subsidence was observed in 42 of the 280 patients. Bone densitometry with quantitative computed tomography was visibly reduced in the subsidence group. The mean EBQ scores of the lumbar endplate bone was 4.3±0.9 in nonsubsidence and 5.0±0.6 in subsidence. On multivariate logistic regression, the difference between the two groups was remarkable. Risk of cage subsidence increases significantly with higher EBQ scores (odds ratio [OR]=2.063, 95% confidence interval [CI] 1.365-3.120, p=.001) and was an independent factor in predicting subsidence after TLIF. On receiver operating characteristic curve, the AUC for the EBQ score was 0.820 (95% confidence interval [CI]: 0.755-0.844) and the most suitable threshold for the EBQ score was 4.730 (sensitivity: 76.2%, specificity: 83.2%). CONCLUSIONS: Higher EBQ scores measured on preoperative MRI correlated significantly with cage subsidence following TLIF. Performing EBQ assessment prior to TLIF may be a valid method of predicting the risk of postoperative subsidence.

Effect and mechanism of eugenol on storage quality of fresh-peeled Chinese water chestnuts.

The study aimed to investigate the effect and mechanism of eugenol treatment on fresh-peeled Chinese water chestnuts (CWCs). The results found that eugenol treatment maintained the appearance of fresh-peeled CWCs, accompanied by higher L* value, total solids and O2 contents, as well as lower browning degree, weight loss rate, CO2 content, a* and b* values. In addition, eugenol treatment significantly reduced the activities of peroxidase, phenylalanine ammonia-lyase, and polyphenol oxidase, as well as the total content of soluble quinone in fresh-peeled CWCs. Meanwhile, fresh-peeled CWCs treated with eugenol showed markedly lower content of total flavonoids, which may be related to yellowing. Furthermore, eugenol treatment suppressed the rates of O2·- and OH·- production as well as the contents of H2O2 and malondialdehyde in fresh-peeled CWCs. During the storage, eugenol treatment not only increased the activities of catalase, superoxide dismutase, ascorbate peroxidase and glutathione reductase as well as the DPPH free radical scavenging rate, but also increased the total phenolics, ascorbic acid and glutathione contents. In summary, eugenol treatment delayed the surface discoloration of fresh-peeled CWCs by improving the antioxidant capacity, inhibiting the phenolic compound metabolism and scavenging ROS, thus effectively maintaining the quality of fresh-peeled CWCs while extending their shelf life.

Multiple PDE3A modulators act as molecular glues promoting PDE3A-SLFN12 interaction and induce SLFN12 dephosphorylation and cell death.

The canonical function of phosphodiesterase 3A (PDE3A) is to hydrolyze the phosphodiester bonds in second messenger molecules, such as cyclic AMP (cAMP) and cyclic guanosine monophosphate (cGMP). Recently, a phosphodiesterase-activity-independent role for PDE3A was reported. In this noncanonical function, PDE3A physically interacts with Schlafen 12 (SLFN12) upon treatment of cells with cytotoxic PDE3A modulators. Here, we confirmed that the cytotoxic PDE3A modulators act as molecular glues to initiate the association of PDE3A and SLFN12. The PDE3A-SLFN12 interaction increases the protein stability of SLFN12 located in the cytoplasm, while at the same time also inducing SLFN12 dephosphorylation (including serines 368 and 573). Mutational analysis demonstrates that dephosphorylation is required for cell death induced by cytotoxic PDE3A modulators. Finally, we found that dephosphorylation promoted the rRNA RNase activity of SLFN12 and show that this nucleolytic activity is essential for SLFN12's cell-death-inducing function. Thus, our study deepens the understanding of the biochemical mechanisms underlying SLFN12-mediated cell death.

Biochemical Mechanism of Fresh-Cut Lotus (Nelumbo nucifera Gaertn.) Root with Exogenous Melatonin Treatment by Multiomics Analysis.

Browning limits the commercial value of fresh-cut lotus root slices. Melatonin has been reported to play crucial plant roles in growth and development. However, the mechanisms in repressing the browning of fresh-cut lotuses are still unclear. In this study, fresh-cut lotus root slices were treated with melatonin, the physical signs of browning were tested, and then the selected samples (0 d, 6 d, 12 d) were used in multiomics analysis. Fresh-cut lotus root slices with a thickness of 4 mm were soaked in a 40 mmol/L melatonin solution for 10 min; then, the slices were packed in pallets and packages and stored at 10 ± 1 °C. The results show that the 40 mmol/L melatonin selected for repressing the browning of lotus roots significantly delayed the decrease in water, total soluble solid content, and Vitamin C, decreased the growth of microorganisms, enhanced total phenolic content, improved total antioxidant capacity, and decreased ·OH, H2O2, and O2-· contents. Moreover, this treatment enhanced phenylalanine ammonialyase, polyphenol oxidase, superoxide dismutase, and catalase activities and reduced peroxidase activities and soluble quinones. NnSOD (104590242), NnCAT (104609297), and some NnPOD genes showed a similar transcript accumulation pattern with enzyme activity. It can be seen from these results that exogenous melatonin accelerated an enhancement in the antioxidant system and AsA-GSH cycle system by regulating ROS-metabolism-related genes, thereby improving the capacity to withstand browning and the quality of lotus root slices. The microbiome also showed that melatonin suppressed the fertility of spoilage organisms, such as Pseudomonas, Tolumonas, Acinetobacter, Stenotrophomonas, and Proteobacteria. Metabonomics data uncovered that the metabolites of flavonoid biosynthesis, phenylpropanoid biosynthesis, tyrosine metabolism, and phenylalanine metabolism were involved in the process.

The oxidoreductases POR and CYB5R1 catalyze lipid peroxidation to execute ferroptosis.

Our recent study showed that two oxidoreductases - NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1) - transfer electrons to oxygen to generate hydrogen peroxide (H2O2). H2O2 then reacts with ferrous iron, generating hydroxyl radicals that cause peroxidation of polyunsaturated-fatty-acid chains of membrane phospholipids, resulting in plasma membrane rupture and ferroptosis.

Assessing POR and CYB5R1 oxidoreductase-mediated oxidative rupture of PUFA in liposomes.

Lipid peroxidation of polyunsaturated fatty acid (PUFA) phospholipids induces necrotic cell death through compromised cell membrane integrity during ferroptosis. We established assays to investigate oxidoreductase-mediated oxidative rupture, specifically via NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1), of PUFA phospholipids in artificially generated protein-free liposomes. Liposome breakage was detected via Tb3+ liposome release and electron microscopy liposome morphology imaging. This protocol was also applied to other oxidoreductases with analogous functions and investigation of ferroptotic membrane damage in cell-free systems. For complete details on the use and execution of this protocol, please refer to Yan et al. (2020).

Membrane Damage during Ferroptosis Is Caused by Oxidation of Phospholipids Catalyzed by the Oxidoreductases POR and CYB5R1.

Ferroptosis is a form of necrotic cell death caused by iron-dependent peroxidation of polyunsaturated phospholipids on cell membranes and is actively suppressed by the cellular antioxidant systems. We report here that oxidoreductases, including NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1), transfer electrons from NAD(P)H to oxygen to generate hydrogen peroxide, which subsequently reacts with iron to generate reactive hydroxyl radicals for the peroxidation of the polyunsaturated fatty acid (PUFA) chains of membrane phospholipids, thereby disrupting membrane integrity during ferroptosis. Genetic knockout of POR and CYB5R1 decreases cellular hydrogen peroxide generation, preventing lipid peroxidation and ferroptosis. Moreover, POR knockdown in mouse liver prevents ConA-induced liver damage. Ferroptosis, therefore, is a result of incidental electron transfer carried out by POR/CYB5R1 oxidoreductase and thus needs to be constitutively countered by the antioxidant systems.

Casein kinase 1G2 suppresses necroptosis-promoted testis aging by inhibiting receptor-interacting kinase 3.

Casein kinases are a large family of intracellular serine/threonine kinases that control a variety of cellular signaling functions. Here we report that a member of casein kinase 1 family, casein kinase 1G2, CSNK1G2, binds and inhibits the activation of receptor-interacting kinase 3, RIPK3, thereby attenuating RIPK3-mediated necroptosis. The binding of CSNK1G2 to RIPK3 is triggered by auto-phosphorylation at serine 211/threonine 215 sites in its C-terminal domain. CSNK1G2-knockout mice showed significantly enhanced necroptosis response and premature aging of their testis, a phenotype that was rescued by either double knockout of the Ripk3 gene or feeding the animal with a RIPK1 kinase inhibitor-containing diet. Moreover, CSNK1G2 is also co-expressed with RIPK3 in human testis, and the necroptosis activation marker phospho-MLKL was observed in the testis of old (>80) but not young men, indicating that the testis-aging program carried out by the RIPK3-mediated and CSNK1G2-attenuated necroptosis is evolutionarily conserved between mice and men.

An alkaloid initiates phosphodiesterase 3A-schlafen 12 dependent apoptosis without affecting the phosphodiesterase activity.

The promotion of apoptosis in tumor cells is a popular strategy for developing anti-cancer drugs. Here, we demonstrate that the plant indole alkaloid natural product nauclefine induces apoptosis of diverse cancer cells via a PDE3A-SLFN12 dependent death pathway. Nauclefine binds PDE3A but does not inhibit the PDE3A's phosphodiesterase activity, thus representing a previously unknown type of PDE3A modulator that can initiate apoptosis without affecting PDE3A's canonical function. We demonstrate that PDE3A's H840, Q975, Q1001, and F1004 residues-as well as I105 in SLFN12-are essential for nauclefine-induced PDE3A-SLFN12 interaction and cell death. Extending these molecular insights, we show in vivo that nauclefine inhibits tumor xenograft growth, doing so in a PDE3A- and SLFN12-dependent manner. Thus, beyond demonstrating potent cytotoxic effects of an alkaloid natural product, our study illustrates a potentially side-effect-reducing strategy for targeting PDE3A for anti-cancer therapeutics without affecting its phosphodiesterase activity.