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Differences between normal tissues and invading tumors that allow tumor targeting while saving normal tissue are much sought after. Here we show that scarcity of VDAC2, and the consequent lack of Bak recruitment to mitochondria, renders hepatocyte mitochondria resistant to permeabilization by truncated Bid (tBid), a Bcl-2 Homology 3 (BH3)-only, Bcl-2 family protein. Increased VDAC2 and Bak is found in most human liver cancers and mitochondria from tumors and hepatic cancer cell lines exhibit VDAC2- and Bak-dependent tBid sensitivity. Exploring potential therapeutic targeting, we find that combinations of activators of the tBid pathway with inhibitors of the Bcl-2 family proteins that suppress Bak activation enhance VDAC2-dependent death of hepatocarcinoma cells with little effect on normal hepatocytes. Furthermore, in vivo, combination of S63845, a selective Mcl-1 inhibitor, with tumor-nectrosis factor-related, apoptosis-induncing ligand (TRAIL) peptide reduces tumor growth, but only in tumors expressing VDAC2. Thus, we describe mitochondrial molecular fingerprint that discriminates liver from hepatocarcinoma and allows sparing normal tissue while targeting tumors. In this study, the authors show that low levels of VDAC2 and Bak in hepatocyte mitochondria make them resistant to cell death induced by truncated Bid (tBid), while increased VDAC2 and Bak in liver cancer cells allow specific targeting by combinations of tBid activators and Mcl-1 inhibitors.

Bid-induced mitochondrial membrane permeabilization and cytochrome c release are central to apoptosis. It remains a mystery how tiny amounts of Bid synchronize the function of a large number of discrete organelles, particularly in mitochondria-rich cells. Looking at cell populations, the rate and lag time of the Bid-induced permeabilization are dose-dependent, but even very low doses lead eventually to complete cytochrome c release. By contrast, individual mitochondria display relatively rapid and uniform kinetics, indicating that the dose dependence seen in populations is due to a spreading of individual events in time. We report that Bid-induced permeabilization and cytochrome c release regularly demonstrate a wave-like pattern, propagating through a cell at a constant velocity without dissipation. Such waves do not depend on caspase activation or permeability transition pore opening. However, reactive oxygen species (ROS) scavengers suppressed the coordination of cytochrome c release and also inhibited Bid-induced cell death, whereas both superoxide and hydrogen peroxide sensitized mitochondria to Bid-induced permeabilization. Thus, Bid engages a ROS-dependent, local intermitochondrial potentiation mechanism that amplifies the apoptotic signal as a wave.

Humans exhibit considerable variation in how they value their own interest relative to the interests of others. Deciphering the neural codes representing potential rewards for self and others is crucial for understanding social decision-making. Here we integrate computational modeling with functional magnetic resonance imaging to investigate the neural representation of social value and the modulation by oxytocin, a nine-amino acid neuropeptide, in participants evaluating monetary allocations to self and other (self–other allocations). We found that an individual’s preferred self–other allocation serves as a reference point for computing the value of potential self–other allocations. In more prosocial participants, amygdala activity encoded a social-value-distance signal; that is, the value dissimilarity between potential and preferred allocations. Intranasal oxytocin administration amplified this amygdala representation and increased prosocial behavior in more individualistic participants but not in more prosocial ones. Our results reveal a neurocomputational mechanism underlying social-value representations and suggest that oxytocin may promote prosociality by modulating social-value representations in the amygdala.Using a behaviorally obtained reference point to compute social value, Ma et al. show that social-value distance is encoded by the amygdala in prosocials. Oxytocin amplifies this amygdala representation and increases prosociality in individualists.

Sarcopenia is defined as a progressive decrease in skeletal muscle mass and strength due to ageing, and is associated with adverse outcomes such as falls, fractures, and physical disability, leading to increased healthcare expenditures and mortality risks. Although sarcopenia has recently become a major challenge, there are currently no effective interventions or drugs marketed for sarcopenia. Therefore, new biomarkers for early diagnosis and targeted drugs for the treatment of sarcopenia are urgently needed. In the present research, transcriptomics and proteomics analyses were combined and experiments at the transcriptional and protein levels were conducted to identify key genes and molecular mechanisms underlying sarcopenia in senescence-accelerated mouse prone 8 (SAM-P8) mice, followed by molecular docking to predict targeted drugs. The combined omics analysis identified 8 key genes, while the experiments verified that only CD9 significantly decreased in sarcopenia. The gene set enrichment analysis (GSEA) results suggested that CD9 involved in ATP biosynthesis, mitochondrial biogenesis, and oxidative phosphorylation. Besides, dapoxetine, levomilnacipran, and milnacipran were predicted to target CD9 through molecular docking. Our study reported for the first time that CD9 is a novel potential biomarker of sarcopenia, and targeting CD9 may be a new idea for the development of therapeutic drugs for sarcopenia.

Background Proteolysis targeting chimera (PROTAC), a novel drug discovery strategy, utilizes the ubiquitin–proteasome system to degrade target proteins in cells. While Western blotting, mass spectrometry, and Lumit Immunoassay have been instrumental in determining protein levels, the rapid screening of PROTACs continues to pose challenges, necessitating the development of alternative methodologies. Results We herein reported an alternative high-throughput method for screening PROTACs using a dual-reporter system expressing a Renilla luciferase (RLUC)-fused target protein and enhanced green fluorescent protein (EGFP). EGFP served as an internal reference and RLUC as an indicated target protein degradation. Rapid measurement of EGFP or RLUC light signals was achieved using a fluorescence/luminescence plate-based reader in the endpoint mode. The feasibility of the screening model was tested using ARV110, a clinical trial-stage PROTAC targeting the androgen receptor (AR). In EGFP/RLUC-tAR-expressing modal cells treated with varying concentrations of ARV110, normalized RLUC luminescence decreased dose-dependently, as confirmed via western blotting detection of AR expression. Then the platform was used to practically screen Sirtuin 2 (SIRT2) degraders from a small group of PROTACs that we built. Normalized RLUC luminescence changes in model cells expressing EGFP/RLUC-SIRT2 reflected the degradation efficiencies of PROTACs. Compounds 128 and 129 exhibited the highest degradation efficacies, leading to dose-dependent degradation of endogenous SIRT2 protein in the MCF-7 cell line and inducing cell growth arrest. Conclusions The dual-reporter system using both fluorescence and chemiluminescence was successfully constructed. Using this method, we identified effective candidate PROTACs against SIRT2. The dual-reporter system may accelerate drug discovery during PROTAC development.

Intermittent fasting (IF) has emerged as a potential cancer treatment modality, although its tumor-suppressive effects are limited. Glioblastoma (GBM) can be classified into CDKN2A subtype and TP53 subtype. Here, we discover that the efficacy of IF is correlated with tumor subtypes of GBM. IF significantly inhibite GBM progression in mice with the Tp53 GBM model, whereas its inhibitory effect is not significant in the Cdkn2a GBM model. Multi-omics sequencing is performed in the IF-responsive Tp53 GBM mouse model, delineating a comprehensive molecular profiling of IF that including the spatial transcriptome, spatial metabolome, single-cell transcriptome, single-cell RNA methylation, metabolome, and microbiome. Through systematic biological analysis and rescue experiments conducted in IF-responsive Tp53 GBM mice model, we demonstrate that the efficacy of IF is primarily mediated by alterations in the gut microbiota, which subsequently modulate the production of the microbial metabolite methionine sulfoxide. Methionine sulfoxide, by regulating m 6 A modification, inhibits the TGF-β signaling pathway, resulting in suppressing GBM progression. This study proposes a genotype-based hypothesis for the therapeutic effects of IF on tumors, and elucidates the potential RNA modification-related molecular mechanisms underlying the effective suppression of GBM by IF. Intermittent fasting (IF) has been recognized as a potential cancer therapeutic approach but its effect on tumor growth is limited. This study demonstrates that response to IF varies between glioblastoma subtypes, with IF specifically inhibiting Tp53-driven glioblastoma due to a reshaping of the gut microbiota and subsequent altered methionine metabolism suppressing TGF- β signaling.

To examine chemokine expression in children with Respiratory Syncytial Virus (RSV) bronchiolitis and evaluate its clinical utility for early warning and prognosis. Five hospitalised RSV bronchiolitis children and five matched controls were studied. To validate findings, 50 RSV infants and 30 controls were assessed for recurrent wheezing after 1 year. Blood leukocyte RNA-seq identified RSV-associated hub genes via GO/KEGG analysis, with flow cytometry confirming chemokine expression. Twelve hub genes were identified, with 712 differentially expressed genes (292 upregulated, 420 downregulated). RSV patients showed elevated CXCL2, CXCL12, CXCL13, CCL13, and CCL24 ( P  < 0.05). CXCL12 was higher in moderate-to-severe cases (Area Under the Curve, AUC = 0.835, 95% CI 0.714–0.956, P  < 0.05), while CXCL13 was elevated in recurrent wheezers (AUC = 0.851, 95% CI 0.711–0.991, P  < 0.05). CXCL12 predicted severity, and CXCL13 predicted recurrence (ROC-confirmed, P  < 0.05). CXCL12 and CXCL13 may serve as biomarkers for assessing RSV bronchiolitis severity and predicting recurrence, aiding early clinical evaluation and prognosis.

The associations of serum folate and vitamin B12 levels with cardiovascular outcomes among patients with type 2 diabetes (T2D) remain unclear. To investigate the associations of serum folate and vitamin B12 levels with risk of cardiovascular disease (CVD) mortality among individuals with T2D. This prospective cohort study included 8067 patients with T2D who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 through 2014 and NHANES III (1988-1994). American Diabetes Association criteria were used to define T2D. Data were analyzed between October 1, 2020, and April 1, 2021. Serum folate and vitamin B12 levels. Multivariable Cox proportional hazards regression models were used to compute hazard ratios and 95% CIs for the associations of serum folate and vitamin B12 levels with risks of CVD and all-cause mortality. Two multivariable models were constructed. Restricted cubic spline analyses were used to examine the nonlinear association of serum folate levels and vitamin B12 levels with CVD mortality, and nonlinearity was assessed using the likelihood ratio test. This cohort study included data from 7700 participants in the folate analysis (mean [SE] age, 57.8 [0.3] years; 3882 men [weighted, 50.5%]; median serum folate level, 12.1 ng/mL [IQR, 7.1-19.5 ng/mL]) and 4860 participants for the vitamin B12 analysis (mean [SE] age, 57.8 [0.3] years; 2390 men [weighted, 50.7%]; median serum vitamin B12 level, 506.1 pg/mL [IQR, 369.1-703.5 pg/mL]). During 72 031 person-years of follow-up, 799 CVD deaths were documented for the folate analysis, and during 43 855 person-years of follow-up, 467 CVD deaths were reported for the vitamin B12 analysis. Nonlinear associations were observed for serum levels of folate (P = .04 for nonlinearity) and vitamin B12 (P = .04 for nonlinearity) with risk of CVD mortality among patients with T2D. Compared with participants in the second quartile of serum folate levels (7.1-12.1 ng/mL), the hazard ratios for CVD mortality were 1.43 (95% CI, 1.04-1.98) for participants in the lowest serum folate level quartile (<7.1 ng/mL) and 1.03 (95% CI, 0.74-1.44) for participants in the highest quartile (≥19.5 ng/mL). In addition, compared with participants in the second quartile of serum vitamin B12 levels (369.1-506.0 pg/mL), the hazard ratios for CVD mortality were 1.74 (95% CI, 1.20-2.52) for participants in the lowest quartile (<369.1 pg/mL) and 2.32 (95% CI, 1.60-3.35) for participants in the highest quartile (≥703.5 pg/mL). Similar patterns of association were observed for all-cause mortality (nonlinearity: P = .01 for folate and P = .02 for vitamin B12). This cohort study found that both low and high serum levels of vitamin B12 as well as low serum levels of folate were significantly associated with higher risk of CVD mortality among individuals with T2D.

Background Consumption of leafy vegetables is a primary route of cadmium (Cd) exposure in the human body. Salicylic acid (SA) is a major stress signaling molecule that alleviates Cd toxicity in various plants. Our study aimed to investigate the effects of different SA concentrations on spinach growth, cadmium accumulation, and stress resistance physiology under cadmium stress (50 µmol/L). Results Cd stress significantly markedly decreased spinach growth and biomass, reduced its photosynthetic efficiency, increased activities of antioxidative enzymes, and upregulated the relative expression of several genes involved in cadmium absorption and transport compared to the control. The exogenous application of SA mitigated the harmful effects of Cd in spinach. 0.8 and 1.6 mmol/L SA significantly increased spinach root length, plant height, and biomass and decreased the Cd content in shoots by 30.03 and 17.35% compared to the Cd-treated group. Moreover, SA alleviated the yellowing of leaves caused by Cd stress. Exogenous SA ameliorated Cd toxicity in spinach by reducing reactive oxygen species, malondialdehyde, proline, and soluble protein levels. Exogenous SA application reduced Cd absorption in spinach leaves by downregulating the expression of genes involved in Cd transport, such as SoHMA4-like , SoNramp3.1-like , SoNramp6-like , and SoNramp7.2-like . Principal component analysis and correlation analysis showed that exogenous SA application under Cd stress was correlated with plant Cd content, photosynthetic pigment content, and relative expression of Cd absorption and transportation-related genes. Conclusions To summarize, these findings indicate that SA mitigates Cd toxicity in spinach by reversing the adverse effects of Cd stress on plant growth and reducing Cd accumulation in the shoots.

Combination of the prodrug technique with an albumin nano drug-loaded system is a novel promising approach for cancer treatment. However, the long-lasting and far-reaching challenge for the treatment of cancers lies in how to construct the albumin nanometer drug delivery system with lead compounds and their derivatives. In this study, we reported the preparation of injectable albumin nanoparticles (NPs) with a high and quantitative drug loading system based on the Nab TM technology of paclitaxel palmitate (PTX-PA). Our experimental study on drug tissue distribution in vivo demonstrated that the paclitaxel palmitate albumin nanoparticles (Nab-PTX-PA) remained in the tumor for a longer time post-injection. Compared with saline and paclitaxel albumin nanoparticles (Abraxane ® ), intravenous injection of Nab-PTX-PA not only reduced the toxicity of the drug in normal organs, and increased the body weight of the animals but maintained sustained release of paclitaxel (PTX) in the tumor, thereby displaying an excellent antitumor activity. Blood routine analysis showed that Nab-PTX-PA had fewer adverse effects or less toxicity to the normal organs, and it inhibited tumor cell proliferation more effectively as compared with commercial paclitaxel albumin nanoparticles. This carrier strategy for small molecule drugs is based on naturally evolved interactions between long-chain fatty acids (LCFAs) and Human Serum Albumin (HSA), demonstrated here for PTX. Nab-PTX-PA shows higher antitumor efficacy in vivo in breast cancer models. On the whole, this novel injectable Nab-PTX-PA has great potential as an effective drug delivery system in the treatment of breast cancer.