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PANoptosis, a new research hotspot at the moment, is a cell death pattern in which pyroptosis, apoptosis, and necroptosis all occur in the same cell population. In essence, PANoptosis is a highly coordinated and dynamically balanced programmed inflammatory cell death pathway that combines the main features of pyroptosis, apoptosis, and necroptosis. Many variables, such as infection, injury, or self-defect, may be involved in the occurrence of PANoptosis, with the assembly and activation of the PANoptosome being the most critical. PANoptosis has been linked to the development of multiple systemic diseases in the human body, including infectious diseases, cancer, neurodegenerative diseases, and inflammatory diseases. Therefore, it is necessary to clarify the process of occurrence, the regulatory mechanism of PANoptosis, and its relation to diseases. In this paper, we summarized the differences and relations between PANoptosis and the three types of programmed cell death, and emphatically expounded molecular mechanism and regulatory patterns of PANoptosis, with the expectation of facilitating the application of PANoptosis regulation in disease treatment.

Retinal angiogenesis drives both normal vascular development and sight-threatening retinal vascular diseases. While mitochondria are known to fuel this process, the roles of many specific mitochondrial proteins are poorly understood. Here we show that the mitochondrial protein RAB5 interacting factor (RAB5IF) as a critical pro-angiogenic regulator of physiological retinal vascular development in neonatal mice (sex-balanced) and pathological retinal angiogenesis in two models: oxygen-induced retinopathy mice (sex-balanced) and laser-induced choroidal neovascularization mice (sex-balanced). Proteomic sequencing identified SUMO2 as a critical downstream protein of RAB5IF. RAB5IF silencing impeded mitochondrial respiration and ribosome biogenesis, specifically suppressing SUMO2 mRNA translation initiation and consequently lowering SUMO2 protein levels in retinal microvascular endothelial cells. We also identify that SUMO2-mediated SUMOylation of Gαi1/3 is required for their roles in mediating VEGF signaling. Mutations at the SUMOylation sites of Gαi1/3 hindered VEGF-induced signaling and pro-angiogenic activity. Together, these findings delineate a RAB5IF-SUMO2-Gαi1/3 signaling axis essential for retinal angiogenesis, presenting new therapeutic targets for neovascular eye diseases. Endothelial RAB5IF is a critical proangiogenic regulator of both normal and pathological retinal angiogenesis. Here the authors show that RAB5IF-SUMO2-Gαi1/3 signaling axis drives this process, presenting new therapeutic targets for neovascular eye diseases.

Neuroligin-3 (NLGN3) is necessary and sufficient to promote glioma cell growth. The recruitment of Gαi1/3 to the ligand-activated receptor tyrosine kinases (RTKs) is essential for mediating oncogenic signaling. Various genetic strategies were utilized to examine the requirement of Gαi1/3 in NLGN3-driven glioma cell growth. NLGN3-induced Akt-mTORC1 and Erk activation was inhibited by decreasing Gαi1/3 expression. In contrast ectopic Gαi1/3 overexpression enhanced NLGN3-induced signaling. In glioma cells, NLGN3-induced cell growth, proliferation and migration were attenuated by Gαi1/3 depletion with shRNA, but facilitated with Gαi1/3 overexpression. Significantly, Gαi1/3 silencing inhibited orthotopic growth of patient-derived glioma xenografts in mouse brain, whereas forced Gαi1/3-overexpression in primary glioma xenografts significantly enhanced growth. The growth of brain-metastatic human lung cancer cells in mouse brain was largely inhibited with Gαi1/3 silencing. It was however expedited with ectopic Gαi1/3 overexpression. In human glioma Gαi3 upregulation was detected, correlating with poor prognosis. Gαi1/3 mediation of NLGN3-induced signaling is essential for neuronal-driven glioma growth

Severe retinal ischemia causes persistent visual impairments in eye diseases. Retinal pigment epithelium (RPE) cells are located near the choroidal capillaries, and are easily affected by ischemic or hypoxia. Ginsenoside Rg-1 has shown significant neuroprotective effects. This study was performed to test the cytoprotective effect of ginsenoside Rg-1 in RPE cells against hypoxia and cobalt chloride (CoCl2) assaults, and to understand the underlying mechanisms. We found that Rg-1 pre-administration significantly inhibited CoCl2- and hypoxia-induced RPE cell death and apoptosis. Reactive oxygen specisis (ROS)-dependent p38 and c-Jun NH(2)-terminal kinases (JNK) MAPK activation was required for CoCl2-induced RPE cell death, and Rg-1 pre-treatment significantly inhibited ROS production and following p38/JNK activation. Further, CoCl2 suppressed pro-survival mTOR complex 1 (mTORC1) activation in RPE cells through activating of AMP-activated protein kinase (AMPK), while Rg-1 restored mTORC1 activity through inhibiting AMPK activation. CoCl2-induced AMPK activation was also dependent on ROS production, and anti-oxidant N-acetylcysteine (NAC) prevented AMPK activation and RPE cell death by CoCl2. Our results indicated that Rg-1 could be further investigated as a novel cell-protective agent for retinal ischemia.

IL-4 induces Akt activation in macrophages, required for full M2 (alternative) polarization. We examined the roles of Gαi1 and Gαi3 in M2 polarization using multiple genetic methods. In MEFs and primary murine BMDMs, Gαi1/3 shRNA, knockout or dominant negative mutations attenuated IL-4-induced IL4Rα endocytosis, Gab1 recruitment as well as Akt activation, leaving STAT6 signaling unaffected. Following IL-4 stimulation, Gαi1/3 proteins associated with the intracellular domain of IL-4Rα and the APPL1 adaptor, to mediate IL-4Rα endosomal traffic and Gab1-Akt activation in BMDMs. In contrast, gene silencing of Gαi1/3 with shRNA or knockout resulted in BMDMs that were refractory to IL-4-induced M2 polarization. Conversely, Gαi1/3-overexpressed BMDMs displayed preferred M2 response with IL-4 stimulation. In primary human macrophages IL-4-induced Akt activation and Th2 genes expression were inhibited with Gαi1/3 silencing, but augmented with Gαi1/3 overexpression. In Gαi1/3 double knockout (DKO) mice, M2 polarization, by injection of IL-4 complex or chitin, was potently inhibited. Moreover, in a murine model of asthma, ovalbumin-induced airway inflammation and hyperresponsiveness were largely impaired in Gαi1/3 DKO mice. These findings highlight novel and essential roles for Gαi1/3 in regulating IL-4-induced signaling, macrophage M2 polarization and allergic asthma response.

Background Individuals with chronic diseases are at higher risk of sarcopenia, and precise prediction is essential for its prevention. This study aims to develop a risk scoring model using longitudinal data to predict the probability of sarcopenia in this population over next 3–5 years, thereby enabling early warning and intervention. Methods Using data from a nationwide survey initiated in 2011, we selected patient data records from wave 1 (2011–2012) and follow-up data from wave 3 (2015–2016) as the study cohort. Retrospective data collection included demographic information, health conditions, and biochemical markers. After excluding records with missing values, a total of 2891 adults with chronic conditions were enrolled. Sarcopenia was assessed based on the Asian Working Group for Sarcopenia (AWGS) 2019 guidelines. A generalized linear mixed model (GLMM) with random effects and diverse machine learning models were utilized to explore feature contributions to sarcopenia risk. The Recursive Feature Elimination (RFE) algorithm was employed to optimize the full Multilayer Perceptron (MLP) model and develop an online application tool. Results Among total population, 580 (20.1%) individuals were diagnosed with sarcopenia in wave 1 (2011–2012), and 638 (22.1%) were diagnosed in wave 3 (2015–2016), while 2165 (74.9%) individuals were not diagnosed with sarcopenia across the study period. MLP model, performed better than other three classic machine learning models, demonstrated a ROC AUC of 0.912, a PR AUC of 0.401, a sensitivity of 0.875, a specificity of 0.844, a Kappa value of 0.376, and an F1 score of 0.44. According to MLP model-based SHapley Additive exPlanations (SHAP) scoring, weight, age, BMI, height, total cholesterol, PEF, and gender were identified as the most important features of chronic disease individuals for sarcopenia. Using the RFE algorithm, we selected six key variables—weight, age, BMI, height, total cholesterol, and gender—achieving an ROC AUC of about 0.9 for the online application tool. Conclusion We developed an MLP machine learning model that incorporates only six easily accessible variables, enabling the prediction of sarcopenia risk in individuals with chronic diseases. Additionally, we created a practical online application tool to assist in decision-making and streamline clinical assessments.

Excessive UV radiation and reactive oxygen species (ROS) cause retinal pigment epithelium (RPE) cell injuries. Nrf2 regulates transcriptional activation of many anti-oxidant genes. Here, we tested the potential role of 3H-1,2-dithiole-3-thione (D3T) against UV or ROS damages in cultured RPE cells (both primary cells and ARPE-19 line). We showed that D3T significantly inhibited UV-/H 2 O 2 -induced RPE cell death and apoptosis. UV-stimulated ROS production was dramatically inhibited by D3T pretreatment. D3T induced Nrf2 phosphorylation in cultured RPE cells, causing Nrf2 disassociation with KEAP1 and its subsequent nuclear accumulation. This led to expression of antioxidant response elements (ARE)-dependent gene heme oxygenase-1 (HO-1). Nrf2-HO-1 activation was required for D3T-mediated cytoprotective effect. Nrf2 shRNA knockdown or S40T dominant negative mutation as well as the HO-1 inhibitor Zinc protoporphyrin (ZnPP) largely inhibited D3T’s RPE cytoprotective effects against UV radiation. Yet, exogenous overexpression Nrf2 enhanced D3T’s activity in RPE cells. Further studies showed that D3T activated Akt/mTORC1 in cultured RPE cells. Akt-mTORC1 inhibitors, or Akt1 knockdown by shRNA, not only inhibited D3T-induced Nrf2-HO-1 activation, but also abolished the RPE cytoprotective effects. In vivo , D3T intravitreal injection protected from light-induced retinal dysfunctions in mice. Thus, D3T protects RPE cells from UV-induced damages via activation of Akt-mTORC1-Nrf2-HO-1 signaling axis.

Rapid urbanization is forcing the need to build urban environments that promote healthy and sustainable human settlements with a view to reducing the risks of various diseases. Previous studies have demonstrated that green rooftop spaces may stimulate restorative benefits and enhance their livability. However, this potential remains without empirical research support. To investigate the restoration of green rooftop spaces on human well-being, we conducted a field experiment using psychophysiology measurements. With the help of physiological indicators (SBP, DBP, HR, HRV) and psychological indicators (PRS, BPOMS), the changes of indicators in the experiment were analyzed. We recruited a total of 35 college students who were randomly assigned to one of four rooftop spaces for a field experiment. Physiological and psychological indicators were measured before and after recovery to analyze the effects of rooftop spaces on restorative benefits. Paired sample t-test results revealed that although there were differences in the physiological and psychological measurements related to environmental restorative benefits, both confirmed that green rooftop spaces exhibited stress-reduction effects on participants. Notably, all four rooftop spaces had psychophysiological restoration to varying degrees, with spaces featuring a higher degree of naturalness demonstrating better restoration. Furthermore, a grassy environment had effects on positive psychophysiological responses. Correlation analysis indicated that subjective perception evaluations of green rooftop spaces had positive effects on psychophysiological restoration. The results of the study are conducive to increasing awareness of the restorative value and potential of green rooftop spaces, which can be constructed by designers, thereby contributing to sustainable urban development.

The brittleness prediction of shale formations is of interest to researchers nowadays. Conventional methods of brittleness prediction are usually based on isotropic models while shale is anisotropic. In order to obtain a better prediction of shale brittleness, our study firstly proposed a novel brittleness index equation based on the Voigt–Reuss–Hill average, which combines two classical isotropic methods. The proposed method introduces upper and lower brittleness bounds, which take the uncertainty of brittleness prediction into consideration. In addition, this method can give us acceptable predictions by using limited input values. Secondly, an anisotropic rock physics model was constructed. Two parameters were introduced into our model, which can be used to simulate the lamination of clay minerals and the dip angle of formation. In addition, rock physics templates have been built to analyze the sensitivity of brittleness parameters. Finally, the effects of kerogen, pore structure, clay lamination and shale formation dip have been investigated in terms of anisotropy. The prediction shows that the vertical/horizontal Young’s modulus is always below one while the vertical/horizontal Poisson’s ratio (PR) can be either greater or less than 1. Our study finds different degrees of shale lamination may be the explanation for the random distribution of V ani (the ratio of vertical PR to horizontal PR).