Proper network randomization is key to assessing social balance.

Social ties, either positive or negative, lead to signed network patterns, the subject of balance theory. For example, strong balance introduces cycles with even numbers of negative edges. The statistical significance of such patterns is routinely assessed by comparisons to null models. Yet, results in signed networks remain controversial. Here, we show that even if a network exhibits strong balance by construction, current null models can fail to identify it. Our results indicate that matching the signed degree preferences of the nodes is a critical step and so is the preservation of network topology in the null model. As a solution, we propose the STP null model, which integrates both constraints within a maximum entropy framework. STP randomization leads to qualitatively different results, with most social networks consistently demonstrating strong balance in three- and four-node patterns. On the basis our results, we present a potential wiring mechanism behind the observed signed patterns and outline further applications of STP randomization.

TransGCN: a semi-supervised graph convolution network-based framework to infer protein translocations in spatio-temporal proteomics.

Protein subcellular localization (PSL) is very important in order to understand its functions, and its movement between subcellular niches within cells plays fundamental roles in biological process regulation. Mass spectrometry-based spatio-temporal proteomics technologies can help provide new insights of protein translocation, but bring the challenge in identifying reliable protein translocation events due to the noise interference and insufficient data mining. We propose a semi-supervised graph convolution network (GCN)-based framework termed TransGCN that infers protein translocation events from spatio-temporal proteomics. Based on expanded multiple distance features and joint graph representations of proteins, TransGCN utilizes the semi-supervised GCN to enable effective knowledge transfer from proteins with known PSLs for predicting protein localization and translocation. Our results demonstrate that TransGCN outperforms current state-of-the-art methods in identifying protein translocations, especially in coping with batch effects. It also exhibited excellent predictive accuracy in PSL prediction. TransGCN is freely available on GitHub at https://github.com/XuejiangGuo/TransGCN.

Protein aggregation and biomolecular condensation in hypoxic environments (Review).

Due to molecular forces, biomacromolecules assemble into liquid condensates or solid aggregates, and their corresponding formation and dissolution processes are controlled. Protein homeostasis is disrupted by increasing age or environmental stress, leading to irreversible protein aggregation. Hypoxic pressure is an important factor in this process, and uncontrolled protein aggregation has been widely observed in hypoxia­related conditions such as neurodegenerative disease, cardiovascular disease, hypoxic brain injury and cancer. Biomolecular condensates are also high­order complexes assembled from macromolecules. Although they exist in different phase from protein aggregates, they are in dynamic balance under certain conditions, and their activation or assembly are considered as important regulatory processes in cell survival with hypoxic pressure. Therefore, a better understanding of the relationship between hypoxic stress, protein aggregation and biomolecular condensation will bring marked benefits in the clinical treatment of various diseases. The aim of the present review was to summarize the underlying mechanisms of aggregate assembly and dissolution induced by hypoxic conditions, and address recent breakthroughs in understanding the role of aggregates in hypoxic­related diseases, given the hypotheses that hypoxia induces macromolecular assemblage changes from a liquid to a solid phase, and that adenosine triphosphate depletion and ATP­driven inactivation of multiple protein chaperones play important roles among the process. Moreover, it is anticipated that an improved understanding of the adaptation in hypoxic environments could extend the overall survival of patients and provide new strategies for hypoxic­related diseases.

Multi-omics analysis revealed the mitochondrial-targeted drug combination to suppress the development of lung cancer.

PURPOSE: The incidence and mortality of lung cancer are continuously rising in recent years. Mitochondrial energy metabolism malfunction is found to be crucial in cancer proliferation and bioenergetic reprogramming, especially for lung cancer. In this study, we attempted to use mitochondrial-targeted drug therapy to change the energy metabolism pattern of cancer cells to inhibit the development of lung cancer, and investigated its mechanism of action and key targets through multi-omics studies. METHODS: In this study, we established the in vivo tumor mouse mode, treated mice with multiple mitochondrial-targeted drug combinations and DDP, severally. Then, we investigated the differences between the 7-drug group with the control group and the DDP treatment group by transcriptomics, proteomics and metabolomics to find the therapeutic targets. RESULTS: We found that mitochondria-targeting drug cocktail therapy, especially the 7-drug regimen, effectively improved mitochondrial metabolism, changed energy supply patterns in lung cancer cells, significantly increased NK cells in tumor tissues, and decreased tumor markers in plasma. Multi-omics analysis informed that the combination of 7-drug could up-regulate mitochondrial oxidative phosphorylation, ATP synthesis and autophagy related genes, and down-regulate proliferation and immune-related genes compared with the control group. By further mapping the protein interaction network, we identified a key target for 7-drug therapy to reverse tumor metabolic reprogramming and validated it in metabolomics. CONCLUSIONS: Mitochondrial-targeted drug cocktail therapy can effectively inhibit the occurrence and development of tumors, through the reprogramming of energy metabolism and the increase in immune cells in tumor tissues. Thus, we provide a novel approach for the treatment of lung cancer and present evidence-based clues for the combined use of targeted mitochondrial drugs.

A positive statistical benchmark to assess network agreement.

Current computational methods for validating experimental network datasets compare overlap, i.e., shared links, with a reference network using a negative benchmark. However, this fails to quantify the level of agreement between the two networks. To address this, we propose a positive statistical benchmark to determine the maximum possible overlap between networks. Our approach can efficiently generate this benchmark in a maximum entropy framework and provides a way to assess whether the observed overlap is significantly different from the best-case scenario. We introduce a normalized overlap score, Normlap, to enhance comparisons between experimental networks. As an application, we compare molecular and functional networks, resulting in an agreement network of human as well as yeast network datasets. The Normlap score can improve the comparison between experimental networks by providing a computational alternative to network thresholding and validation.

Mitochondria dysfunction in CD8+ T cells as an important contributing factor for cancer development and a potential target for cancer treatment: a review.

CD8+ T cells play a central role in anti-tumor immunity. Naïve CD8+ T cells are active upon tumor antigen stimulation, and then differentiate into functional cells and migrate towards the tumor sites. Activated CD8+ T cells can directly destroy tumor cells by releasing perforin and granzymes and inducing apoptosis mediated by the death ligand/death receptor. They also secrete cytokines to regulate the immune system against tumor cells. Mitochondria are the central hub of metabolism and signaling, required for polarization, and migration of CD8+ T cells. Many studies have demonstrated that mitochondrial dysfunction impairs the anti-tumor activity of CD8+ T cells through various pathways. Mitochondrial energy metabolism maladjustment will cause a cellular energy crisis in CD8+ T cells. Abnormally high levels of mitochondrial reactive oxygen species will damage the integrity and architecture of biofilms of CD8+ T cells. Disordered mitochondrial dynamics will affect the mitochondrial number and localization within cells, further affecting the function of CD8+ T cells. Increased mitochondria-mediated intrinsic apoptosis will decrease the lifespan and quantity of CD8+ T cells. Excessively low mitochondrial membrane potential will cause the release of cytochrome c and apoptosis of CD8+ T cells, while excessively high will exacerbate oxidative stress. Dysregulation of mitochondrial Ca2+ signaling will affect various physiological pathways in CD8+ T cells. To some extent, mitochondrial abnormality in CD8+ T cells contributes to cancer development. So far, targeting mitochondrial energy metabolism, mitochondrial dynamics, mitochondria-mediated cell apoptosis, and other mitochondrial physiological processes to rebuild the anti-tumor function of CD8+ T cells has proved effective in some cancer models. Thus, mitochondria in CD8+ T cells may be a potential and powerful target for cancer treatment in the future.

Berberine induces non-small cell lung cancer apoptosis via the activation of the ROS/ASK1/JNK pathway.

Background: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Berberine (BBR), an isoquinoline alkaloid, is commonly used in traditional Chinese medicine. Previous studies have shown that BBR has a potential anti-tumor effect. However, the mechanisms of BBR on mitochondrial function in anti-lung cancer remain unknown. The aim of this study was to explore mitochondrial function in anti-tumor mechanisms of BBR in NSCLC. Methods: The NSCLCs were cultured and treated with various doses (40, 80, 120 µg/mL) of BBR for 24 and 48 h. Cell viability was evaluated using Cell Counting Kit-8 (CCK-8). Cell apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. Relative protein expression was examined by western blot and immunohistochemical (IHC) analysis. Results: BBR potently suppressed NSCLC cells growth by inducing apoptosis in a dose-and time-dependent manner. BBR induced apoptosis in NSCLC cells as evidenced by caspase-3 cleavage, cytochrome c release, and mitochondrial membrane depolarization. BBR-induced, dose-dependent induction of apoptosis was accompanied by sustained phosphorylation of c-jun-NH2-kinase (JNK) and the JNK inhibitor (SP600125) significantly suppressed BBR-induced apoptosis, N-acetyl cysteine (NAC), a ROS scavenger, was sufficient to both suppress apoptosis signal-regulating kinase 1 (ASK1) and JNK activation and disrupt apoptotic induction. Conclusions: The results suggest that BBR induces apoptosis of NSCLC cells via ROS-mediated ASK1/JNK activation and the mitochondrial pathway.

Melatonin enhances radiofrequency-induced NK antitumor immunity, causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development.

Surgery is the common treatment for early lung cancer with multiple pulmonary nodules, but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas. In this study, we found that a combined treatment of local radiofrequency ablation (RFA) and melatonin (MLT) greatly improved clinical outcomes for early lung cancer patients with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas. Mechanically, as demonstrated in an associated mouse lung tumor model, RFA not only effectively remove treated tumors but also stimulate antitumor immunity, which could inhibit tumor growth in non-ablated areas. MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA. Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment, which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT. Analysis of residual tumor further revealed the depressed activity of MAPK, NF-kappa B, Wnt, and Hedgehog pathways and upregulated P53 pathway in tumors, which was in line with the inhibited tumor growth. Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy. These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules. Trial registration: www.chictr.org.cn , identifier ChiCTR2100042695, http://www.chictr.org.cn/showproj.aspx?proj=120931 .

Melatonin inhibits lung cancer development by reversing the Warburg effect via stimulating the SIRT3/PDH axis.

Recently, the morbidity and mortality from lung cancer have continued to increase. Mitochondrial dysfunction plays a key role in apoptosis, proliferation, and the bioenergetic reprogramming of cancer cells, especially for energy metabolism. Herein, we investigated the ability of melatonin (MLT) to influence lung cancer growth and explored the association between mitochondrial functions and the progression of lung tumors. The deacetylase, sirtuin 3 (Sirt3), is a pivotal player in maintenance of mitochondrial function, among participating in ATP production by regulating the acetylone and pyruvate dehydrogenase complex (PDH). We initially found that MLT inhibited lung cancer growth in the Lewis mouse model. Similarly, we observed that MLT inhibited the proliferation of lung cancer cells (A549, PC9, and LLC cells), and the underlying mechanism of MLT was related to reprogramming cancer cell metabolism, accompanied by a shift from cytosolic aerobic glycolysis to oxidative phosphorylation (OXPHOS). These changes were accompanied by higher ATP production, an elevated ATP production-coupled oxygen consumption rate (QCR), higher ROS levels, higher mito-ROS levels, and lower lactic acid secretion. Additionally, we observed that MLT improved mitochondrial membrane potential and the activities of complexes Ⅰ and Ⅳ in the electron transport chain. Importantly, we also found and verified that the foregoing changes resulted from activation of Sirt3 and PDH. As a result of these changes, MLT significantly enhanced mitochondrial energy metabolism to reverse the Warburg effect via increasing PDH activity with stimulation of Sirt3. Collectively, these findings suggest the potential use of melatonin as an anti-lung cancer therapy and provide a mechanistic basis for this proposal.

Gold/SH-functionalized nanographene oxide/polyamidamine/poly(ethylene glycol) nanocomposites for enhanced non-enzymatic hydrogen peroxide detection.

Hydrogen peroxide (H2O2) is an important mediator in biological medicine, disease diagnosis and environmental analyses and therefore it is essential to develop a detection approach for H2O2 in physical environments. Herein, we designed and prepared a series of AuNP-containing nanocomposites (AuNPs@NGO-PEG, AuNPs@G1-PAMAM-NGO-PEG and AuNPs@G3-PAMAM-NGO-PEG) for enhanced non-enzymatic H2O2 detection. We firstly demonstrated functionalized nanographene oxide (NGO) based materials, which combined advantages of biocompatible poly(ethylene glycol) (PEG), hyperbranched polyamidamine (PAMAM) dendrimer and thiol active site, as compatible platforms. Gold nanoparticles (AuNPs) were then aptly in situ grown on these functionalized NGO based materials via the reduction of HAuCl4 under mild conditions, i.e. AuNPs@NGO-PEG, AuNPs@G1-PAMAM-NGO-PEG and AuNPs@G3-PAMAM-NGO-PEG nanocomposites, which possess stable and uniform AuNPs standing on the functionalized NGO sheets. For H2O2 detection, these nanocomposites were cast on a glassy carbon electrode (GCE) conveniently, i.e. GCE/AuNPs@NGO-PEG, GCE/AuNPs@G1-PAMAM-NGO-PEG and GCE/AuNPs@G3-PAMAM-NGO-PEG. It is evident that these GCEs could be applied as efficient non-enzymatic H2O2 detectors resulting from the corresponding cyclic voltammetric curves and typical ready-state amperometric curves. GCE/AuNPs@G1-PAMAM-NGO-PEG exhibited the fastest electron transfer rate among these modified GCEs. We envisage that these GCEs could provide efficient sensors for H2O2 detection and a new strategy for sensor design.

Delivery of Oridonin and Methotrexate via PEGylated Graphene Oxide.

Graphene oxide (GO) possessing plenty of hydroxyls and carboxyls is often used in the field of biomedicine. To improve its water solubility and biocompatibility, 6-armed poly(ethylene glycol) (PEG) was bonded on the surface of GO sheets via a facile amidation process to form the universal drug delivery platform (GO-PEG10K-6arm) with a 200 nm size in favor of the enhanced permeability and retention effect. Herein, we prepared the stable and biocompatible platform of GO-PEG10K-6arm under mild conditions and characterized the chemical structure and micromorphology via thermogravimetric analysis and atomic force microscopy. This nanosized GO-PEG10K-6arm was found to be of very low toxicity to human normal cells of 293T and tumor cells of CAL27, MG63, and HepG2. Moreover, oridonin and methotrexate (MTX), widely used hydrophobic cancer chemotherapy drugs, were compounded with GO-PEG10K-6arm via π-π stacking and hydrophobic interactions so as to afford nanocomplexes of oridonin@GO-PEG10K-6arm and MTX@GO-PEG10K-6arm, respectively. Both nanocomplexes could quickly enter into tumor cells, which was evidenced by inverted fluorescence microscopy using fluorescein isothiocyanate as a probe, and they both showed remarkably high cytotoxicity to the tumor cells of CAL27, MG63, and HepG2 within a broad range of concentration in comparison with free drugs. This kind of nanoscale drug delivery system based on GO-PEG10K-6arm may have potential applications in biomedicine, and GO-PEG10K-6arm would be a universal and available carrier for extensive hydrophobic anticarcinogens.

Hepatoprotective and antiviral properties of isochlorogenic acid A from Laggera alata against hepatitis B virus infection.

ETHNOPHARMACOLOGICAL RELEVANCE: The aim of this study was to determine the anti-hepatitis B effect of isochlorogenic acid A isolated from Laggera alata (Asteraceae), a traditional Chinese herbal medicine. MATERIALS AND METHODS: The anti-hepatitis B activity of isochlorogenic acid A was evaluated by the D-galactosamine (D-GalN)-induced HL-7702 hepatocyte damage model and the HBV-transfected HepG2.2.15 cells. RESULTS: Isochlorogenic acid A significantly improved HL-7702 hepatocyte viability and markedly inhibited the productions of HBsAg and HBeAg. The inhibitory rates of isochlorogenic acid A on the HBsAg and HBeAg expressions were 86.9% and 72.9%, respectively. In addition, isochlorogenic acid A declined markedly the content of hepatitis B virus covalently closed circular DNA (HBV cccDNA) and induced significantly the heme oxygenase-1 (HO-1) expression in HepG2.2.15 cells. CONCLUSIONS: Isochlorogenic acid A was verified to possess the potent anti-hepatitis B activity. The anti-HBV target of isochlorogenic acid A is probably associated with blocking the translation step of the HBV replication. Overexpression of HO-1 may contribute to the anti-HBV activity of isochlorogenic acid A by reducing the stability of the HBV core protein and thus blocking the refill of nuclear HBV cccDNA. Additionally, the hepatoprotective effect of isochlorogenic acid A could be achieved by its antioxidative property and induction of HO-1.

Protective Properties of Laggera alata Extract and its Principle Components Against d-Galactosamine-Injured Hepatocytes.

Laggera alata extract (LAE) was quantitatively analyzed, and its principle components isochlorogenic acids were isolated and authenticated. Protective properties of LAE were studied using a d-galactosamine (d-GalN)-induced injury model in neonatal rat hepatocytes and a d-GalN-induced acute liver damage model in mice. Meanwhile, the effect of isochlorogenic acids derived from LAE on d-GalN-induced hepatocyte injury were also measured in vitro. LAE at concentrations of 10-100 µg/ml significantly reduced cellular leakage of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and improved cell viability. The isochlorogenic acids (4,5-O-dicaffeoylquinic acid, 3,5-O-dicaffeoylquinic acid and 3,4-O-dicaffeoylquinic acid) at concentrations of 1-100 µg/ml also remarkably improved viability of hepatocytes. The oral treatment of LAE at doses of 50, 100 and 200 mg/kg markedly reduced the serum AST and ALT activity of mice and resulted in significant recovery of hepatocytes in liver sections.

Anti-hepatitis B virus effect and possible mechanism of action of 3,4-o-dicaffeoylquinic Acid in vitro and in vivo.

The anti-hepatitis B activity of 3,4-O-dicaffeoylquinic acid isolated from Laggera alata was studied using the D-galactosamine- (D-GalN-) induced hepatocyte damage model, HepG2.2.15 cells, and with HBV transgenic mice. In vitro results showed that 3,4-O-dicaffeoylquinic acid improved HL-7702 hepatocyte viability and markedly inhibited the production of HBsAg and HBeAg. At a concentration of 100 µg/mL, its inhibitory rates on the expression levels of HBsAg and HBeAg were 89.96% and 81.01%, respectively. The content of hepatitis B virus covalently closed circular DNA (HBV cccDNA) in HepG2.2.15 cells was significantly decreased after the cells were treated with the test compound. In addition, 3,4-O-dicaffeoylquinic acid significantly increased the expression of heme oxygenase-1 (HO-1) in HepG2.2.15 cells. In vivo results indicated that the test compound at concentrations of 100 µg/mL significantly inhibited HBsAg production and increased HO-1 expression in HBV transgenic mice. In conclusion, this study verifies the anti-hepatitis B activity of 3,4-O-dicaffeoylquinic acid. The upregulation of HO-1 may contribute to the anti-HBV effect of this compound by reducing the stability of the HBV core protein, which blocks the refill of nuclear HBV cccDNA. Furthermore, the hepatoprotective effect of this compound may be mediated through its antioxidative/anti-inflammatory properties and by the induction of HO-1 expression.