Research progress of multi-target HDAC inhibitors blocking the BRD4-LIFR-JAK1-STAT3 signaling pathway in the treatment of cancer.

Histone deacetylase inhibitors (HDACis) show beneficial effects on different hematological malignancy subtypes. However, their impacts on treating solid tumors are still limited due to diverse resistance mechanisms. Recent studies have found that the feedback activation of BRD4-LIFR-JAK1-STAT3 pathway after HDACi incubation is a vital mechanism inducing resistance of specific solid tumor cells to HDACis. This review summarizes the recent development of multi-target HDACis that can concurrently block BRD4-LIFR-JAK1-STAT3 pathway. Moreover, our findings hope to shed novel lights on developing novel multi-target HDACis with reduced BRD4-LIFR-JAK1-STAT3-mediated drug resistance in some tumors.

Cycloastragenol: A Novel Senolytic Agent That Induces Senescent Cell Apoptosis and Restores Physical Function in TBI-Aged Mice.

Accumulating evidence indicates that the increased burden of senescent cells (SCs) in aged organisms plays an important role in many age-associated diseases. The pharmacological elimination of SCs with "senolytics" has been emerging as a new therapy for age-related diseases and extending the healthy lifespan. In the present study, we identified that cycloastragenol (CAG), a secondary metabolite isolated from Astragalus membrananceus, delays age-related symptoms in mice through its senolytic activity against SCs. By screening a series of compounds, we found that CAG selectively kills SCs by inducing SCs apoptosis and that this process is associated with the inhibition of Bcl-2 antiapoptotic family proteins and the PI3K/AKT/mTOR pathway. In addition, CAG treatment also suppressed the development of the senescence-associated secretory phenotype (SASP) in SCs, thereby inhibiting cell migration mediated by the SASP. Furthermore, the administration of CAG for 2 weeks to mice with irradiation-induced aging alleviated the burden of SCs and improved the animals' age-related physical dysfunction. Overall, our studies demonstrate that CAG is a novel senolytic agent with in vivo activity that has the potential to be used in the treatment of age-related diseases.

The Altered Functions of Shelterin Components in ALT Cells.

Telomeres are nucleoprotein complexes that cap the ends of eukaryotic linear chromosomes. Telomeric DNA is bound by shelterin protein complex to prevent telomeric chromosome ends from being recognized as damaged sites for abnormal repair. To overcome the end replication problem, cancer cells mostly preserve their telomeres by reactivating telomerase, but a minority (10-15%) of cancer cells use a homologous recombination-based pathway called alternative lengthening of telomeres (ALT). Recent studies have found that shelterin components play an important role in the ALT mechanism. The binding of TRF1, TRF2, and RAP1 to telomeres attenuates ALT activation, while the maintenance of ALT telomere requires TRF1 and TRF2. POT1 and TPP1 can also influence the occurrence of ALT. The elucidation of how shelterin regulates the initiation of ALT remains elusive. This review presents a comprehensive overview of the current findings on the regulation of ALT by shelterin components, aiming to enhance the insight into the altered functions of shelterin components in ALT cells and to identify potential targets for the treatment of ALT tumor cells.

Gain-of-Function p53N236S Mutation Drives the Bypassing of HRasV12-Induced Cellular Senescence via PGC-1α.

One of the key steps in tumorigenic transformation is immortalization in which cells bypass cancer-initiating barriers such as senescence. Senescence can be triggered by either telomere erosion or oncogenic stress (oncogene-induced senescence, OIS) and undergo p53- or Rb-dependent cell cycle arrest. The tumor suppressor p53 is mutated in 50% of human cancers. In this study, we generated p53N236S (p53S) mutant knock-in mice and observed that p53S heterozygous mouse embryonic fibroblasts (p53S/+) escaped HRasV12-induced senescence after subculture in vitro and formed tumors after subcutaneous injection into severe combined immune deficiency (SCID) mice. We found that p53S increased the level and nuclear translocation of PGC-1α in late-stage p53S/++Ras cells (LS cells, which bypassed the OIS). The increase in PGC-1α promoted the biosynthesis and function of mitochondria in LS cells by inhibiting senescence-associated reactive oxygen species (ROS) and ROS-induced autophagy. In addition, p53S regulated the interaction between PGC-1α and PPARγ and promoted lipid synthesis, which may indicate an auxiliary pathway for facilitating cell escape from aging. Our results illuminate the mechanisms underlying p53S mutant-regulated senescence bypass and demonstrate the role played by PGC-1α in this process.

The Complement System, Aging, and Aging-Related Diseases.

The complement system is a part of the immune system and consists of multiple complement components with biological functions such as defense against pathogens and immunomodulation. The complement system has three activation pathways: the classical pathway, the lectin pathway, and the alternative pathway. Increasing evidence indicates that the complement system plays a role in aging. Complement plays a role in inflammatory processes, metabolism, apoptosis, mitochondrial function, and Wnt signaling pathways. In addition, the complement system plays a significant role in aging-related diseases, including Alzheimer's disease, age-related macular degeneration, and osteoarthritis. However, the effect of complement on aging and aging-related diseases is still unclear. Thus, a better understanding of the potential relationship between complement, aging, and aging-related diseases will provide molecular targets for treating aging, while focusing on the balance of complement in during treatment. Inhibition of a single component does not result in a good outcome. In this review, we discussed the research progress and effects of complement in aging and aging-related diseases.

Gain of function in the mouse model of a recurrent mutation p53N236S promotes the formation of double minute chromosomes and the oncogenic potential of p19ARF.

The mutation p53N236S (p53S) has been identified as one of the recurrent mutations in human cancers by TCGA database. Our in vitro data revealed the oncogenic gain of function of p53S. To understand the function of p53S in vivo, we generated the p53S knock-in mouse. The p53S/S mice manifested highly invasive lymphomas and metastatic sarcomas with dramatically increased double minute chromosomes. The survival curve, the incidence of tumors and the tumor spectrum of p53S/S mice is very similar to the p53R172H mouse model. The p53S/+ mice showed delayed onset of tumorigenesis and a high metastasis rate (40%) and low loss of heterozygosity rate (2/16). The activation of CDKN2A pathway in p53S/S MEF and tumors, and the accumulation of p19ARF protein in tumor tissues suggested p19ARF might contribute to the accumulation of mutant p53S protein in the tumor and promote tumorigenesis. The high expression of p19ARF correlated with mutant p53 accumulation and tumor progression, suggesting a dual role of p19ARF in tumor promotion or suppression that might depend on the p53 mutation status in tumor cells. The oncogenic gain of function of this recurrent mutation p53S prompts the reconsideration of p53 mutations function that occurs at a low frequency.

An Isoquinolin-1(2H)-Imine Derivative Induces Cell Death via Generation of Reactive Oxygen Species and Activation of JNK in Human A549 Cancer Cells.

Compound 11-benzoyl-10-chloro-7,9-difluoro-6-imino-2,3,4,6-tetrahydro-1H-pyrimido[1,2-b]isoquinoline-8-carbonitrile (HC6h) is a novel polyhalo 1,3-diazaheterocycle fused isoquinolin-1(2H)-imines derivative, which displays good anticancer activity and low toxicity in vivo. However, the underlying anticancer mechanisms have not previously been identified. The proliferation of A549 was assessed by MTT assay. The reactive oxygen species (ROS) level was assessed in A549 with a H2 DCFDA probe. Mitochondrial membrane potential was measured using the JC-1 staining. Apoptosis were measured by annexin-V/PI assay and autophagy by acridine orange staining and GFP-LC3 fluorescence assay. The expression of autophagic and apoptotic proteins was determined by Western blot. The compound HC6h increased accumulation of vesicles, acridine orange-stained cells and LC3-II in A549 cells. Inhibition of compound HC6h-induced autophagy by bafilomycin A1 increased apoptosis. Compound HC6h enhanced activation of caspase-3, caspase-9 and PARP cleavage in A549 cells. Compound HC6h leads to the rapid generation of intracellular ROS. Moreover, compound HC6h induced phosphorylation of JNK and was conferred by the increased ROS levels. Furthermore, down-regulation of JNK attenuated autophagic and apoptotic effect in response to HC6h. The induction of ROS upon HC6h treatment leads to the activation of JNK that mediates autophagy and apoptosis in human A549 cancer cells. J. Cell. Biochem. 118: 4394-4403, 2017. © 2017 Wiley Periodicals, Inc.

A review: factors affecting excess sludge anaerobic digestion for volatile fatty acids production.

This paper presents a review of methods that improve the production of volatile fatty acids (VFA) from excess sludge during the anaerobic digestion process. These methods are mainly divided into two approaches. The first approach is located in the pre-treatment methods, which change the properties of the substrates, such as thermal pre-treatment, alkaline pre-treatment, microwave pre-treatment and ultrasonic pre-treatment. The other approach is found in the fermentation process control methods, which influence the environment of anaerobic digestion for the production of VFA, such as pH, temperature, mixing, additives and solids retention time control. In the text recent research studies of each method are listed and analyzed in detail. Comparably, microwave and ultrasonic pre-treatment methods are considered emerging and promising technologies due to their efficiency and environmentally friendly characteristics. However, the microwave pre-treatment has high electricity demand, which might make the process economically unfeasible. In order to calculate optimal operation, further studies still need to be done.

[Synthetic lethal genes to mutant p53].

Targeted therapy has become a powerful approach for cancer treatment. Better understanding of oncogenes as well as synthetic lethal interactions with oncogenes will lead to new strategies for tumor-specific treatment. It is well known that mutant p53 plays an important role in tumorigenesis and tumor development. Thus, understanding the synthetic lethal relationship between p53 mutations and interacting genes in tumor is critical for the personalized treatments of p53 mutant tumors. Synthetic lethal genes to mutant p53 can be divided into cell cycle regulators and non-cell cycle regulators. This paper review show these two types of target genes contribute to synthetic lethal interactions with p53 mutations and potential applications of these interactions in anticancer therapy.

Discovery of potent and novel dual NAMPT/BRD4 inhibitors for efficient treatment of hepatocellular carcinoma.

The NAPRT-induced increase in NAD+ levels was proposed as a mechanism contributing to hepatocellular carcinoma (HCC) resistance to NAMPT inhibitors. Thus, concurrently targeting NAMPT and NAPRT could be considered to overcome drug resistance. A BRD4 inhibitor downregulates the expression of NAPRT in HCC, and the combination of NAMPT inhibitors with BRD4 inhibitors simultaneously blocks NAD+ generation via salvage and the PH synthesis pathway. Moreover, the combination of the two agents significantly downregulated the expression of tumor-promoting genes and strongly promoted apoptosis. The present work identified various NAMPT/BRD4 dual inhibitors based on the multitargeted drug rationale. Among them, compound A2, which demonstrated the strongest effect, exhibited potent inhibition of NAMPT and BRD4 (IC50 = 35 and 58 nM, respectively). It significantly suppressed the growth and migration of HCC cells and facilitated their apoptosis. Furthermore, compound A2 also manifested a robust anticancer effect in HCCLM3 xenograft mouse models, with no apparent toxic effects. Our findings in this study provide an effective approach to target NAD+ metabolism for HCC treatment.

Preparation and characterization of aspirin-fucoidan complex and its admirable antitumor activity on human non-small cell lung cancer cells.

The purpose of this work is to prepare a novel acetylated derivative of Undaria pinnatifida fucoidan (UPFUC) with admirable antitumor activity. Fucoidan was first acetylated by acetylsalicylic acid (aspirin, ASA) to form the ASA-UPFUC complex. The antitumor efficacy results stated that ASA-UPFUC inhibited the proliferation of human non-small cell lung cancer A549 cells in a dose-dependent manner, with an IC50 value of 49.09 µg/mL, 50.20 % lower than that of UPFUC. Importantly, the acetylation process had no adverse effects on the backbone structure of UPFUC. Simultaneously, ASA-UPFUC demonstrated a larger charge density than UPFUC, leading to enhanced solubility, improved surface charge effects, and a greater potential for exerting biological activity. Consequently, ASA-UPFUC increased the formation of alkyl and hydrogen bonds with tumor necrosis factor related apoptosis-inducing ligand receptors DR4 and DR5, thereby effectively stimulating the generation of cellular reactive oxygen species, diminishing mitochondrial membrane potential, suppressing nuclear factor κB (NFκB) p65 phosphorylation, enhancing the contents of Bax and cleaved caspase 3, and reducing the level of Bcl-2. The collective effects ultimately triggered the mitochondrial apoptotic pathway, leading to apoptosis in A549 cells. The findings support the potential utilization of ASA-UPFUC as a novel dietary additive for human lung cancer chemoprevention.

Air quality and health benefits for different heating decarbonization pathways in China.

The urgent need for decarbonization in China's heating system, comprised of approximately one hundred thousand boilers, is imperative to meet climate and clean air objectives. To formulate national and regional strategies, we developed an integrated model framework that combines a facility-level emission inventory, the Community Multiscale Air Quality (CMAQ) model, and the Global Exposure Mortality Model (GEMM). We then explore the air quality and health benefits of alternative heating decarbonization pathways, including the retirement of coal-fired industrial boilers (CFIBs) for replacement with grid-bound heat supply systems, coal-to-gas conversion, and coal-to-biomass conversion. The gas replacement pathway shows the greatest potential for reducing PM2.5 concentration by 2.8 (2.3-3.4) µg/m3 by 2060, avoiding 23,100 (19,600-26,500) premature deaths. In comparison, the biomass replacement pathway offers slightly lower environmental and health benefits, but is likely to reduce costs by approximately two-thirds. Provincially, optimal pathways vary - Xinjiang, Sichuan, and Chongqing favor coal-to-gas conversion, while Shandong, Henan, Hebei, Inner Mongolia, and Shanxi show promise in CFIBs retirement. Henan leads in environmental and health benefits. Liaoning, Heilongjiang, and Jilin, rich in biomass resources, present opportunities for coal-to-biomass conversion.

The Cross Talk between Cellular Senescence and Melanoma: From Molecular Pathogenesis to Target Therapies.

Melanoma is a malignant skin tumor that originates from melanocytes. The pathogenesis of melanoma involves a complex interaction that occurs between environmental factors, ultraviolet (UV)-light damage, and genetic alterations. UV light is the primary driver of the skin aging process and development of melanoma, which can induce reactive oxygen species (ROS) production and the presence of DNA damage in the cells, and results in cell senescence. As cellular senescence plays an important role in the relationship that exists between the skin aging process and the development of melanoma, the present study provides insight into the literature concerning the topic at present and discusses the relationship between skin aging and melanoma, including the mechanisms of cellular senescence that drive melanoma progression, the microenvironment in relation to skin aging and melanoma factors, and the therapeutics concerning melanoma. This review focuses on defining the role of cellular senescence in the process of melanoma carcinogenesis and discusses the targeting of senescent cells through therapeutic approaches, highlighting the areas that require more extensive research in the field.

Modified iPOND revealed the role of mutant p53 in promoting helicase function and telomere maintenance.

The G-rich DNA, such as telomere, tends to form G-quadruplex (G4) structure, which slows down the replication fork progression, induces replication stress, and becomes the chromosome fragile sites. Here we described a molecular strategy that cells developed to overcome the DNA replication stress via DNA helicase regulation. The p53N236S (p53S) mutation has been found in the Werner syndrome mouse embryo fibroblast (MEFs) escaped from senescence, could be the driving force for cell escaping senescence. We revealed that the p53S could transcriptionally up-regulate DNA helicases expression, including Wrn, Blm, Timeless, Ddx, Mcm, Gins, Fanc, as well as telomere specific proteins Terf1, Pot1, through which p53S promoted the unwinding of G4 structures, and protected the cells from DNA replication stress induced by G4 stabilizer. By modified iPOND (isolation of proteins on nascent DNA) assay and telomere assay, we demonstrated that the p53S could promote the recruitment of those helicases to the DNA replication forks, facilitated the maintenance of telomere, and prevent the telomere dysfunction induced by G4 stabilizer. Interestingly, we did not observe the function of promoting G4 resolving and facilitating telomere lengthening in the cells with Li-Fraumeni Syndrome mutation-p53R172H (p53H), which suggests that this is the specific gain of function for p53S. Together our data suggest that the p53S could gain the new function of releasing the replication stress via regulating the helicase function and G4 structure, which benefits telomere lengthening. This strategy could be applied to the treatment of diseases caused by telomere replication stress.

Oxygen vacancies in MnOx regulating reaction kinetics for aqueous zinc-ion batteries.

MnO2 cathode materials have presented challenges due to their poor conductivity, unstable structure, and sluggish diffusion kinetics for aqueous zinc-ion batteries (AZIBs). In this study, a nanostructured MnOx cathode material was synthesized using an acid etching method, Which introduced abundant Mn(III) sites, resulting in the formation of numerous oxygen vacancies. Comprehensive characterizations revealed that these oxygen vacancies facilitated the reversible adsorption/desorption of Zn2+ ions and promoted efficient electron transfer. In addition, the designed mesoporous structure offered ample active sites and shortened the diffusion path for Zn2+ and H+ ions. Consequently, the nanosized MnOx cathode exhibited enhanced reaction kinetics, achieving a considerable reversible specific capacity of 388.7 mAh/g at 0.1 A/g and superior durability with 72.0% capacity retention over 2000 cycles at 3.0 A/g. The material delivered a maximum energy density of 639.7 Wh kg-1 at 159.94 W kg-1. Furthermore, a systematic analysis of the zinc storage mechanism was performed. This work demonstrates that engineering oxygen vacancies with nanostructure regulation provides valuable insights into optimizing MnO2 cathode materials for AZIBs.

A rationally designed fluorescence probe achieves highly specific and long-term detection of senescence in vitro and in vivo.

Senescent cells (SnCs) are implicated in aging and various age-related pathologies. Targeting SnCs can treat age-related diseases and extend health span. However, precisely tracking and visualizing of SnCs is still challenging, especially in in vivo environments. Here, we developed a near-infrared (NIR) fluorescent probe (XZ1208) that targets ß-galactosidase (ß-Gal), a well-accepted biomarker for cellular senescence. XZ1208 can be cleaved rapidly by ß-Gal and produces a strong fluorescence signal in SnCs. We demonstrated the high specificity and sensitivity of XZ1208 in labeling SnCs in naturally aged, total body irradiated (TBI), and progeroid mouse models. XZ1208 achieved a long-term duration of over 6 days in labeling senescence without causing significant toxicities and accurately detected the senolytic effects of ABT263 on eliminating SnCs. Furthermore, XZ1208 was applied to monitor SnCs accumulated in fibrotic diseases and skin wound healing models. Overall, we developed a tissue-infiltrating NIR probe and demonstrated its excellent performance in labeling SnCs in aging and senescence-associated disease models, indicating great potential for application in aging studies and diagnosis of senescence-associated diseases.

p53 codon 72 polymorphism and endometriosis: a meta-analysis.

BACKGROUND: p53 tumour suppressor gene Arg72Pro polymorphism has been associated with endometriosis. However, the current available data were inconsistent. We performed this meta-analysis to estimate the association between p53 Arg72Pro polymorphism and endometriosis. METHODS: Electronic screening of PubMed library was conducted to select studies. Studies containing available genotype frequencies of Arg72Pro were chosen, and pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the association. RESULTS: Six published studies, including 749 endometriosis and 857 controls were identified. The overall results suggested that the variant genotypes were not associated with the endometriosis risk (Pro/Pro + Arg/Pro vs. Arg/Arg: OR = 1.552, 95% CI 0.916-2.632, p = 0.103). In the stratified analysis, individuals carried the Pro allele in a dominant model had increased risk of endometriosis (OR = 2.595, 95% CI 1.005-6.702, p = 0.049) in Asian subjects. The symmetric funnel plot, the Egger's test (p = 0.602), and the Begg's test (p = 0.167) were all suggestive of the lack of publication bias. However, the association was not significant between this polymorphism and endometriosis in Caucasian (OR = 1.005, 95% CI 0.755-1.337, p = 0.972). CONCLUSION: This meta-analysis suggests that p53 codon 72 Pro/Pro + Arg/Pro genotypes are associated with increased risk of endometriosis in Asian. To validate the association between p53 codon 72 polymorphism and endometriosis, further studies with larger participants worldwide are needed.

Regulation of Replication Stress in Alternative Lengthening of Telomeres by Fanconi Anaemia Protein.

Fanconi anaemia (FA)-related proteins function in interstrand crosslink (ICL) repair pathways and multiple damage repair pathways. Recent studies have found that FA proteins are involved in the regulation of replication stress (RS) in alternative lengthening of telomeres (ALT). Since ALT cells often exhibit high-frequency ATRX mutations and high levels of telomeric secondary structure, high levels of DNA damage and replicative stress exist in ALT cells. Persistent replication stress is required to maintain the activity of ALT mechanistically, while excessive replication stress causes ALT cell death. FA proteins such as FANCD2 and FANCM are involved in the regulation of this balance by resolving or inhibiting the formation of telomere secondary structures to stabilize stalled replication forks and promote break-induced repair (BIR) to maintain the survival of ALT tumour cells. Therefore, we review the role of FA proteins in replication stress in ALT cells, providing a rationale and direction for the targeted treatment of ALT tumours.

Alternative Lengthening of Telomeres and Mediated Telomere Synthesis.

Telomeres are DNA-protein complexes that protect eukaryotic chromosome ends from being erroneously repaired by the DNA damage repair system, and the length of telomeres indicates the replicative potential of the cell. Telomeres shorten during each division of the cell, resulting in telomeric damage and replicative senescence. Tumor cells tend to ensure cell proliferation potential and genomic stability by activating telomere maintenance mechanisms (TMMs) for telomere lengthening. The alternative lengthening of telomeres (ALT) pathway is the most frequently activated TMM in tumors of mesenchymal and neuroepithelial origin, and ALT also frequently occurs during experimental cellular immortalization of mesenchymal cells. ALT is a process that relies on homologous recombination (HR) to elongate telomeres. However, some processes in the ALT mechanism remain poorly understood. Here, we review the most recent understanding of ALT mechanisms and processes, which may help us to better understand how the ALT pathway is activated in cancer cells and determine the potential therapeutic targets in ALT pathway-stabilized tumors.

Elucidating the anti-aging mechanism of Si Jun Zi Tang by integrating network pharmacology and experimental validation in vivo.

Si Jun Zi Tang (SJZT) is a classic Traditional Chinese Medicine (TCM) prescription used to treat aging-related diseases. However, the potential molecular mechanisms of the anti-aging effects of the bioactive compounds and their targets remain elusive. In this study, we combined network pharmacology and molecular docking with in vivo experiments to elucidate the anti-aging molecular mechanism of SJZT. A series of network pharmacology strategies were used to predict potential targets and therapeutic mechanisms of SJZT, including compound screening, pathway enrichment analysis and molecular docking studies. Based on the network pharmacology predictions and observation of outward signs of aging, the expression levels of selected genes and proteins and possible key targets were subsequently validated and analysed using qRT-PCR and immunoblotting. Using a data mining approach, 235 effective targets of SJZT and aging were obtained. AKT1, STAT3, JUN, MAPK3, TP53, MAPK1, TNF, RELA, MAPK14 and IL6 were identified as core genes in the Protein-Protein Interaction Networks (PPI) analysis. The results of the effective target Gene Ontology (Go) functional enrichment analysis suggested that SJZT may be involved aging and antiapoptotic biological processes. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that the anti-aging mechanism of SJZT may be associated with the PI3K-AKT and P38 MAPK signalling pathways. Molecular docking analysis suggested that kaempferol and quercetin could fit in the binding pockets of the core targets. In addition, SJZT alleviated the aging symptoms of mice such as osteoporosis and hair loss. In conclusion, the anti-aging effect of SJZT was associated with the inhibition of the PI3K-AKT and P38 MAPK signalling pathways, and these findings were consistent with the network pharmacology prediction.