BOK Is a Non-canonical BCL-2 Family Effector of Apoptosis Regulated by ER-Associated Degradation.

The mitochondrial pathway of apoptosis is initiated by mitochondrial outer membrane permeabilization (MOMP). The BCL-2 family effectors BAX and BAK are thought to be absolutely required for this process. Here, we report that BCL-2 ovarian killer (BOK) is a bona fide yet unconventional effector of MOMP that can trigger apoptosis in the absence of both BAX and BAK. However, unlike the canonical effectors, BOK appears to be constitutively active and unresponsive to antagonistic effects of the antiapoptotic BCL-2 proteins. Rather, BOK is controlled at the level of protein stability by components of the endoplasmic reticulum (ER)-associated degradation pathway. BOK is ubiquitylated by the AMFR/gp78 E3 ubiquitin ligase complex and targeted for proteasomal degradation in a VCP/p97-dependent manner, which allows survival of the cell. When proteasome function, VCP, or gp78 activity is compromised, BOK is stabilized to induce MOMP and apoptosis independently of other BCL-2 proteins.

The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease.

Innate immunity is associated with Alzheimer's disease1, but the influence of immune activation on the production of amyloid-ß is unknown2,3. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-ß. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-ß. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces γ-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer's disease that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased.

Nanosensor-based monitoring of autophagy-associated lysosomal acidification in vivo.

Autophagy is a cellular process with important functions that drive neurodegenerative diseases and cancers. Lysosomal hyperacidification is a hallmark of autophagy. Lysosomal pH is currently measured by fluorescent probes in cell culture, but existing methods do not allow for quantitative, transient or in vivo measurements. In the present study, we developed near-infrared optical nanosensors using organic color centers (covalent sp3 defects on carbon nanotubes) to measure autophagy-mediated endolysosomal hyperacidification in live cells and in vivo. The nanosensors localize to the lysosomes, where the emission band shifts in response to local pH, enabling spatial, dynamic and quantitative mapping of subtle changes in lysosomal pH. Using the sensor, we observed cellular and intratumoral hyperacidification on administration of mTORC1 and V-ATPase modulators, revealing that lysosomal acidification mirrors the dynamics of S6K dephosphorylation and LC3B lipidation while diverging from p62 degradation. This sensor enables the transient and in vivo monitoring of the autophagy-lysosomal pathway.

HuM195 and its single-chain variable fragment increase Aß phagocytosis in microglia via elimination of CD33 inhibitory signaling.

CD33 is a transmembrane receptor expressed on cells of myeloid lineage and regulates innate immunity. CD33 is a risk factor for Alzheimer's disease (AD) and targeting CD33 has been a promising strategy drug development. However, the mechanism of CD33's action is poorly understood. Here we investigate the mechanism of anti-CD33 antibody HuM195 (Lintuzumab) and its single-chain variable fragment (scFv) and examine their therapeutic potential. Treatment with HuM195 full-length antibody or its scFv increased phagocytosis of ß-amyloid 42 (Aß42) in human microglia and monocytes. This activation of phagocytosis was driven by internalization and degradation of CD33, thereby downregulating its inhibitory signal. HumM195 transiently induced CD33 phosphorylation and its signaling via receptor dimerization. However, this signaling decayed with degradation of CD33. scFv binding to CD33 leads to a degradation of CD33 without detection of the CD33 dimerization and signaling. Moreover, we found that treatments with either HuM195 or scFv promotes the secretion of IL33, a cytokine implicated in microglia reprogramming. Importantly, recombinant IL33 potentiates the uptake of Aß42 in monocytes. Collectively, our findings provide unanticipated mechanistic insight into the role of CD33 signaling in both monocytes and microglia and define a molecular basis for the development of CD33-based therapy of AD.

The oxidized phospholipid PGPC impairs endothelial function by promoting endothelial cell ferroptosis via FABP3.

Ferroptosis is a novel cell death mechanism that is mediated by iron-dependent lipid peroxidation. It may be involved in atherosclerosis development. Products of phospholipid oxidation play a key role in atherosclerosis. 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) is a phospholipid oxidation product present in atherosclerotic lesions. It remains unclear whether PGPC causes atherosclerosis by inducing endothelial cell ferroptosis. In this study, human umbilical vein endothelial cells (HUVECs) were treated with PGPC. Intracellular levels of ferrous iron, lipid peroxidation, superoxide anions (O2•-), and glutathione were detected, and expression of fatty acid binding protein-3 (FABP3), glutathione peroxidase 4 (GPX4), and CD36 were measured. Additionally, the mitochondrial membrane potential (MMP) was determined. Aortas from C57BL6 mice were isolated for vasodilation testing. Results showed that PGPC increased ferrous iron levels, the production of lipid peroxidation and O2•-, and FABP3 expression. However, PGPC inhibited the expression of GPX4 and glutathione production and destroyed normal MMP. These effects were also blocked by ferrostatin-1, an inhibitor of ferroptosis. FABP3 silencing significantly reversed the effect of PGPC. Furthermore, PGPC stimulated CD36 expression. Conversely, CD36 silencing reversed the effects of PGPC, including PGPC-induced FABP3 expression. Importantly, E06, a direct inhibitor of the oxidized 1-palmitoyl-2-arachidonoyl-phosphatidylcholine IgM natural antibody, inhibited the effects of PGPC. Finally, PGPC impaired endothelium-dependent vasodilation, ferrostatin-1 or FABP3 inhibitors inhibited this impairment. Our data demonstrate that PGPC impairs endothelial function by inducing endothelial cell ferroptosis through the CD36 receptor to increase FABP3 expression. Our findings provide new insights into the mechanisms of atherosclerosis and a therapeutic target for atherosclerosis.

Activation of the PI3K/AKT signaling pathway by ARNTL2 enhances cellular glycolysis and sensitizes pancreatic adenocarcinoma to erlotinib.

BACKGROUND: Pancreatic adenocarcinoma (PC) is an aggressive malignancy with limited treatment options. The poor prognosis primarily stems from late-stage diagnosis and when the disease has become therapeutically challenging. There is an urgent need to identify specific biomarkers for cancer subtyping and early detection to enhance both morbidity and mortality outcomes. The addition of the EGFR tyrosine kinase inhibitor (TKI), erlotinib, to gemcitabine chemotherapy for the first-line treatment of patients with advanced pancreatic cancer slightly improved outcomes. However, restricted clinical benefits may be linked to the absence of well-characterized criteria for stratification and dependable biomarkers for the prediction of treatment effectiveness. METHODS AND RESULTS: We examined the levels of various cancer hallmarks and identified glycolysis as the primary risk factor for overall survival in PC. Subsequently, we developed a glycolysis-related score (GRS) model to accurately distinguish PC patients with high GRS. Through in silico screening of 4398 compounds, we discovered that erlotinib had the strongest therapeutic benefits for high-GRS PC patients. Furthermore, we identified ARNTL2 as a novel prognostic biomarker and a predictive factor for erlotinib treatment responsiveness in patients with PC. Inhibition of ARNTL2 expression reduced the therapeutic efficacy, whereas increased expression of ARNTL2 improved PC cell sensitivity to erlotinib. Validation in vivo using patient-derived xenografts (PDX-PC) with varying ARNTL2 expression levels demonstrated that erlotinib monotherapy effectively halted tumor progression in PDX-PC models with high ARNTL2 expression. In contrast, PDX-PC models lacking ARNTL2 did not respond favorably to erlotinib treatment. Mechanistically, we demonstrated that the ARNTL2/E2F1 axis-mediated cellular glycolysis sensitizes PC cells to erlotinib treatment by activating the PI3K/AKT signaling pathway. CONCLUSIONS: Our investigations have identified ARNTL2 as a novel prognostic biomarker and predictive indicator of sensitivity. These results will help to identify erlotinib-responsive cases of PC and improve treatment outcomes. These findings contribute to the advancement of precision oncology, enabling more accurate and targeted therapeutic interventions.

Advancing the frontiers of colorectal cancer treatment: harnessing ferroptosis regulation.

In recent years, colorectal cancer incidence and mortality have increased significantly due to poor lifestyle choices. Despite the development of various treatments, their effectiveness against advanced/metastatic colorectal cancer remains unsatisfactory due to drug resistance. However, ferroptosis, a novel iron-dependent cell death process induced by lipid peroxidation and elevated reactive oxygen species (ROS) levels along with reduced activity of the glutathione peroxidase 4 (GPX4) antioxidant enzyme system, shows promise as a therapeutic target for colorectal cancer. This review aims to delve into the regulatory mechanisms of ferroptosis in colorectal cancer, providing valuable insights into potential therapeutic approaches. By targeting ferroptosis, new avenues can be explored for innovative therapies to combat colorectal cancer more effectively. In addition, understanding the molecular pathways involved in ferroptosis may help identify biomarkers for prognosis and treatment response, paving the way for personalized medicine approaches. Furthermore, exploring the interplay between ferroptosis and other cellular processes can uncover combination therapies that enhance treatment efficacy. Investigating the tumor microenvironment's role in regulating ferroptosis may offer strategies to sensitize cancer cells to cell death induction, leading to improved outcomes. Overall, ferroptosis presents a promising avenue for advancing the treatment of colorectal cancer and improving patient outcomes.

Carbon-Coated MOF-Derived Porous SnPS3 Core-Shell Structure as Superior Anode for Sodium-Ion Batteries.

Metal thiophosphites have recently emerged as a hot electrode material system for sodium-ion batteries because of their large theoretical capacity. Nevertheless, the sluggish electrochemical reaction kinetics and drastic volume expansion induced by the low conductivity and inherent conversion-alloying reaction mechanism, require urgent resolution. Herein, a distinctive porous core-shell structure, denoted as SnPS3@C, is controllably synthesized by synchronously phosphor-sulfurizing resorcinol-formaldehyde-coated tin metal-organic framework cubes. Thanks to the 3D porous structure, the ion diffusion kinetics are accelerated. In addition, SnPS3@C features a tough protective carbon layer, which improves the electrochemical activity and reduces the polarization. As expected, the as-prepared SnPS3@C electrode exhibits superior electrochemical performance compared to pure SnPS3, including excellent rate capability (1342.4 and 731.1 mAh g-1 at 0.1 and 4 A g-1, respectively), and impressive long-term cycling stability (97.9% capacity retention after 1000 cycles at 1 A g-1). Moreover, the sodium storage mechanism is thoroughly studied by in-situ and ex-situ characterizations. This work offers an innovative approach to enhance the energy storage performance of metal thiophosphite materials through meticulous structural design, including the introduction of porous characteristics and core-shell structures.

Investigating the role of killer cell immunoglobulin-like receptors and human leukocyte antigen genetic variants in hepatitis C virus infection.

The genetic diversity of killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) genes influences the host's immune response to viral pathogens. This study aims to explore the impact of five single nucleotide polymorphisms (SNPs) in KIR3DL2 and HLA-A genes on hepatitis C virus (HCV) infection. A total of 2251 individuals were included in the case-control study. SNPs including KIR3DL2 rs11672983, rs3745902, rs1654644, and HLA-A rs3869062, rs12202296 were genotyped. By controlling various confounding factors using a modified logistic regression model, as well as incorporating stratified analysis, joint effects analysis, and multidimensional bioinformatics analysis, we analyzed the relationship between SNPs and HCV infection. The logistic regression analysis showed a correlation between KIR3DL2 rs11672983 AA, KIR3DL2 rs3745902 TT, and increased HCV susceptibility (p < 0.01). Stratified analysis indicated that KIR3DL2 rs1654644 and HLA-A rs3869062 also heightened HCV susceptibility in certain subgroups. A linear trend of rising HCV infection rates was observed when combining KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT (ptrend = 0.007). Bioinformatics analysis suggested these SNPs' regulatory potential and their role in altering messenger RNA secondary structure, implying their functional relevance in HCV susceptibility. Our findings indicate that KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT are significantly associated with increased susceptibility to HCV infection.

Growing-Season Precipitation Is a Key Driver of Plant Leaf Area to Sapwood Area Ratio at the Global Scale.

Leaf area to sapwood area ratio (AL/AS) influences carbon sequestration, community composition, and ecosystem functioning in terrestrial vegetation and is closely related to leaf economics and hydraulics. However, critical predictors of AL/AS are not well understood. We compiled an AL/AS data set with 1612 species-site combinations (1137 species from 285 sites worldwide) from our field experiments and published literature. We found the global mean AL/AS to be 0.63 m2 cm-2, with its variation largely driven by growing-season precipitation (Pgs), which accounted for 18% of the variation in AL/AS. Species in tropical rainforests exhibited the highest AL/AS (0.82 m2 cm-2), whereas desert species showed the lowest AL/AS (0.16 m2 cm-2). Soil factors such as soil nitrogen and soil organic carbon exhibited positive effects on AL/AS, whereas soil pH was negatively correlated with AL/AS. Tree density accounted for 7% of the variation in AL/AS. All biotic and abiotic predictors collectively explained up to 45% of the variation in AL/AS. Additionally, AL/AS was positively correlated to the net primary productivity (NPP) of the ecosystem. Our study provides insights into the driving factors of AL/AS at the global scale and highlights the importance of AL/AS in ecosystem productivity. Given that Pgs is the most critical driver of AL/AS, alterations in global precipitation belts, particularly seasonal precipitation, may induce changes in plant leaf area on the branches.