Decoding CLU (Clusterin): Conquering cancer treatment resistance and immunological barriers.

One major obstacle in the treatment of cancer is the presence of proteins resistant to cancer therapy, which can impede the effectiveness of traditional approaches such as radiation and chemotherapy. This resistance can lead to disease progression and cause treatment failure. Extensive research is currently focused on studying these proteins to create tailored treatments that can circumvent resistance mechanisms. CLU (Clusterin), a chaperone protein, has gained notoriety for its role in promoting resistance to a wide range of cancer treatments, including chemotherapy, radiation therapy, and targeted therapy. The protein has also been discovered to have a role in regulating the immunosuppressive environment within tumors. Its ability to influence oncogenic signaling and inhibit cell death bolster cancer cells resistant against treatments, which poses a significant challenge in the field of oncology. Researchers are actively investigating to the mechanisms by which CLU exerts its resistance-promoting effects, with the ultimate goal of developing strategies to circumvent its impact and enhance the effectiveness of cancer therapies. By exploring CLU's impact on cancer, resistance mechanisms, tumor microenvironment (TME), and therapeutic strategies, this review aims to contribute to the ongoing efforts to improve cancer treatment outcomes.

Neddylation-dependent LSD1 destabilization inhibits the stemness and chemoresistance of gastric cancer.

Histone lysine-specific demethylase 1 (LSD1) expression has been evaluated in multiple tumors, including gastric cancer (GC). However, the mechanisms underlying LSD1 dysregulation in GC remain largely unclear. In this study, neural precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) was identified to be conjugated to LSD1 at K63 by ubiquitin-conjugating enzyme E2 M (UBE2M), and this neddylated LSD1 could promote LSD1 ubiquitination and degradation, leading to a decrease of GC cell stemness and chemoresistance. Herein, our findings revealed a novel mechanism of LSD1 neddylation and its contribution to decreasing GC cell stemness and chemoresistance. Taken together, our findings may whistle about the future application of neddylation inhibitors.

Generation, secretion and degradation of cancer immunotherapy target PD-L1.

Cancer immunotherapy is a rapidly developing and effective method for the treatment of a variety of malignancies in recent years. As a significant immune checkpoint, programmed cell death 1 ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) play the most significant role in cancer immune escape and cancer immunotherapy. Though PD-L1 have become an important target for drug development and there have been various approved drugs and clinic trials targeting it, and various clinical response rate and adverse reactions prevent many patients from benefiting from it. In recent years, combination trials have become the main direction of PD-1/PD-L1 antibodies development. Here, we summarized PD-L1 biofunctions and key roles in various cancers along with the development of PD-L1 inhibitors. The regulators that are involved in controlling PD-L1 expression including post-translational modification, mRNA level regulation as well as degradation and exosome secretory pathway of PD-L1 were focused. This systematic summary may provide comprehensive understanding of different regulations on PD-L1 as well as a broad prospect for the search of the important regulator of PD-L1. The regulatory factors of PD-L1 can be potential targets for immunotherapy and increase strategies of immunotherapy in combination.

Detailed resume of RNA m6A demethylases.

N6-Methyladenosine (m6A) is the most abundant internal modification in eukaryotic mRNA, playing critical role in various bioprocesses. Like other epigenetic modifications, m6A modification can be catalyzed by the methyltransferase complex and erased dynamically to maintain cells homeostasis. Up to now, only two m6A demethylases have been reported, fat mass and obesity-associated protein (FTO) and alkylation protein AlkB homolog 5 (ALKBH5), involving in a wide range of mRNA biological progress, including mRNA shearing, export, metabolism and stability. Furthermore, they participate in many significantly biological signaling pathway, and contribute to the progress and development of cancer along with other diseases. In this review, we focus on the studies about structure, inhibitors development and biological function of FTO and ALKBH5.

Identification of the upstream regulators of KDM5B in gastric cancer.

AIMS: Lysine-specific demethylase 5B (KDM5B) is an epigenetic regulator of chromatin that catalyzes the demethylation of histone 3 lysine 4. It is overexpressed in multiple cancer types and acts as a therapeutic target in cancer therapy. Nevertheless, its upstream regulatory pathway is not completely understood, prompting the search for the underlying biological factors driving KDM5B overexpression. MATERIALS AND METHODS: A comprehensive analysis was performed to examine the association between KDM5B overexpression and copy number variation (CNV), somatic mutation, mRNA expression, miRNA expression, and clinical characters from The Cancer Genome Atlas database. Coexpression and function enrichment analyses were performed with KDM5B-coexpressed genes. The gastric cancer (GC) cell line MKN45 was utilized to verify the regulation of KDM5B using the transcription factor (TF) Yin Yang 1 (YY1) and miR-29a-3p. KEY FINDINGS: KDM5B was overexpressed and associated with poor prognosis in GC. KDM5B upregulation was driven by CNV amplification and DNA hypomethylation rather than by KDM5B mutations. Enrichment analysis revealed that KDM5B-coexpressed genes were primarily related to the transmembrane transport function and the ubiquitin-mediated proteolysis signaling pathway. As a TF, YY1 might bind to the KDM5B promoter region to regulate KDM5B expression. In addition, miR-29a-3p might bind to and negatively regulate KDM5B expression. SIGNIFICANCE: Our results demonstrate that KDM5B expression is regulated via CNV amplification, DNA hypomethylation, and YY1 and miR-29a-3p; KDM5B expression regulation is associated with patient survival and tumor cell proliferation.

LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in gastric cancer.

BACKGROUND: Histone lysine-specific demethylase 1 (LSD1) expression has been shown to be significantly elevated in gastric cancer (GC) and may be associated with the proliferation and metastasis of GC. It has been reported that LSD1 repressed tumor immunity through programmed cell death 1 ligand 1 (PD-L1) in melanoma and breast cancer. The role of LSD1 in the immune microenvironment of GC is unknown. METHODS: Expression LSD1 and PD-L1 in GC patients was analyzed by immunohistochemical (IHC) and Western blotting. Exosomes were isolated from the culture medium of GC cells using an ultracentrifugation method and characterized by transmission electronic microscopy (TEM), nanoparticle tracking analysis (NTA), sucrose gradient centrifugation, and Western blotting. The role of exosomal PD-L1 in T-cell dysfunction was assessed by flow cytometry, T-cell killing and enzyme-linked immunosorbent assay (ELISA). RESULTS: Through in vivo exploration, mouse forestomach carcinoma (MFC) cells with LSD1 knockout (KO) showed significantly slow growth in 615 mice than T-cell-deficient BALB/c nude mice. Meanwhile, in GC specimens, expression of LSD1 was negatively correlated with that of CD8 and positively correlated with that of PD-L1. Further study showed that LSD1 inhibited the response of T cells in the microenvironment of GC by inducing the accumulation of PD-L1 in exosomes, while the membrane PD-L1 stayed constant in GC cells. Using exosomes as vehicles, LSD1 also obstructed T-cell response of other cancer cells while LSD1 deletion rescued T-cell function. It was found that while relying on the existence of LSD1 in donor cells, exosomes can regulate MFC cells proliferation with distinct roles depending on exosomal PD-L1-mediated T-cell immunity in vivo. CONCLUSION: LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in GC; this finding indicates a new mechanism with which LSD1 may regulate cancer immunity in GC and provides a new target for immunotherapy against GC.

Study on the spatial interaction between carbon emission intensity and shadow economy in China.

Both high carbon emission intensity (CEI) and large scale of shadow economy in China are the undesirable products of economic development with too fast growth rate. For the rapid and healthy development of the economy in China, the research on the relationship between the two should attract more attention, while the relevant literatures are very few at present. According to the panel data of 30 provinces in China from 2004 to 2016, this paper firstly examines the spatial correlation between CEI and the scale of shadow economic. Then verifies the interaction relationship between them with SPDM (spatial panel Dubin Model). Moreover, the robustness test is conducted with three different spatial weight matrices. As the interaction between CEI and shadow economy has been proved, providing new ideas for carbon emission reduction, environmental protection, and healthy economic development with rapid rate in the future. The specific conclusions are as follows: first, CEI and shadow economy both have significant positive spatial autocorrelation. Second, there is a spatial interaction between CEI and shadow economy, indicating provincial cooperation plays a very important role in both economic growth and environment protection. Third, the impacts from economic development on both CEI and shadow economy satisfy the EKC hypothesis. Also, the development of the tertiary industry plays a positive role in promoting the growth of CEI, while promotes and inhibits the expansion of shadow economic scale at the same time.

Lysine demethylase LSD1 delivered via small extracellular vesicles promotes gastric cancer cell stemness.

Several studies have examined the functions of nucleic acids in small extracellular vesicles (sEVs). However, much less is known about the protein cargos of sEVs and their functions in recipient cells. This study demonstrates the presence of lysine-specific demethylase 1 (LSD1), which is the first identified histone demethylase, in the culture medium of gastric cancer cells. We show that sEVs derived from gastric cancer cells and the plasma of patients with gastric cancer harbor LSD1. The shuttling of LSD1-containing sEVs from donor cells to recipient gastric cancer cells promotes cancer cell stemness by positively regulating the expression of Nanog, OCT4, SOX2, and CD44. Additionally, sEV-delivered LSD1 suppresses oxaliplatin response of recipient cells in vitro and in vivo, whereas LSD1-depleted sEVs do not. Taken together, we demonstrate that LSD1-loaded sEVs can promote stemness and chemoresistance to oxaliplatin. These findings suggest that the LSD1 content of sEV could serve as a biomarker to predict oxaliplatin response in gastric cancer patients.

Study on the long-term impact of economic globalization and population aging on CO2 emissions in OECD countries.

Both economic globalization and population aging have given rise to changes in environmental quality, but the research that integrates these two crucial factors into the same environment policy framework is still a blank. Therefore, using panel data of the Organization for Economic Cooperation and Development (OECD) over the period 1971-2016, this study examines the long-term impact of economic globalization and population aging on CO2 emissions. First, second-generation panel regression approaches are employed to verify the panel data, including unit root tests, cointegration tests and causality tests. Next, Fully Modified Ordinary Least Squares (FMOLS) and Dynamic Ordinary Least Squares (DOLS) are respectively used for empirical analysis of the long-term impact between variables. The augmented mean group (AMG) is also applied to ascertain the robustness results of the estimation coefficients. Finally, using Dumitrescu and Hurlin non-causality test to examine the causal associations between variables to avoid the contingency of the results. The overall results show that economic globalization and population aging decrease the long-term CO2 emissions. The inverted U-shaped relationship between economic growth and environmental pollution confirms the effectiveness of the Environmental Kuznets Curve (EKC) in OECD countries. In addition, unidirectional causal relationships have been found from economic globalization and population aging to CO2 emissions in this study. Policy suggestions in response to these findings are discussed.

Convergence analysis of regional marginal abatement cost of carbon dioxide in China based on spatial panel data models.

China has announced to launch a national emission trading system (ETS). The heterogeneity of marginal abatement cost (MAC) is prerequisite for trading, and the knowledge about the evolutionary characteristics of MAC is particularly necessary. However, the ß convergence theory has been proved to be suitable yet rarely applied to the study of MAC of CO2. To fill this gap, this paper connects them creatively, and the convergence of MAC during 2001-2015 and the influential factors are explored by spatial panel data models. Results show that China's MAC converges during the study period whether the spatial effect is considered or not. When evaluating the convergence of MAC, the spatial effect should not be ignored, because it will improve the explanatory power of models and promote the convergence. The size of labor force, emission level, coal consumption, foreign direct investment, and industrial structure significantly affect the growth rate of MAC. Low-carbon policies could be formulated fully considering the factors and their spillover effects. Those findings are certainly significant in imposing carbon reduction targets and adopting policy instruments. In addition, a national ETS is more applicable to China's reality at this stage and suggested to introduce carbon tax in due course in the future.

The effect of indirect household energy consumption on PM 2.5 emission in China: An analysis based on CLA method.

PM 2.5 emissions caused by household activities are considered to be important drivers of haze formation, and indirect activities closely related to industrial structure account for a large proportion of them. This article quantifies the indirect effects on energy usage and PM 2.5 emissions of urban and rural residents' lifestyles in China during 2005-2015 according to the application of consumer lifestyle analysis. The results show that during this period, the degree of indirect impact on energy consumption of residents' living was 2.44-2.71 times as of direct impact, and there are large regional differences between those two impacts. PM 2.5 emissions from energy consumption per unit of households in North, Northeast and Northwest China are higher than that in other regions, while energy consumption in South China is relatively environmentally friendly. Residential, clothing and transportation are the most energy-intensive and PM 2.5-intensive activities among all indirect energy consumption activities. This is the first time that the CLA method has been used to analyze and calculate PM2.5 emissions caused by household energy consumption in a wide area of China through data collection over a longer period. The calculation results are more accurate than previous studies using other methods. Also, it provides factual evidence for key policies of energy saving and environmental protection, as well as pointing out the main sectors of household energy consumption that caused high PM 2.5 emissions for specific regions. The above contributions can provide a theoretical basis and accurate reference data for governments to more purposefully guide the transformation of energy-intensive industries represented by residence and other industries and improve technology to reduce their emissions.

Interaction between shadow economy and pollution: empirical analysis based on panel data of northeast China.

Side issues of economy development break out in China during recent decades, like environmental pollution or the widely ignored one, shadow economy. Using annual data for the three provinces at northeast China over the period 2000 to 2016, this paper examines the size of the shadow economy by MIMIC model first and then adopts the dynamic panel analysis to study the direct relationship between the shadow economy and pollution level. The major innovation point of this paper is the pioneering study of the impact from the pollution level on the size of shadow economy. We also employ various pollution descriptions from terrestrial, aquatic, and atmospheric ecosystems as the robustness check to make our following conclusions more comprehensive and credible: (1) shadow economy is a direct quality factor to the increase of the pollution level. (2) A positive effect from pollution to shadow economy also exists: the higher the pollution level is, the larger the size of shadow economy will be. In the end, this paper proposes several valuable information and suggestions to the government in economy development and pollution abatement.

Do driving restrictions improve air quality: Take Beijing-Tianjin for example?

To manage air quality, Tianjin introduced driving restriction (DR) in 2014 and new driving restriction (NDR) in 2018. Ever since February 22th, 2018, private cars that belong to Beijing have been treated equally as local cars of Tianjin. However, existing studies rarely compare the effects of driving restrictions in different cities. In this paper, using the regression discontinuity design (RDD) model and urban air quality monitoring data from Beijing and Tianjin during the period 2014 to 2018, we explore whether driving restriction policies can improve air quality in Beijing and Tianjin. The main results are as follows. (1) Our results of regression discontinuity design revealed that the DR had no obvious improvement in the air quality in Tianjin. Furthermore, the effect of the DR decreases along with its implementation. (2) The implementation of the DR in Tianjin had slight improvement in air quality in Beijing, which mainly reduced emissions from cars. In other words, the DR brought about weak externality. (3) We found that the effect of NDR on the air pollution was limited in both Tianjin and Beijing. To sum up, we compared the NDR with DR and found out that the DR was more effective in the short run, while the NDR could work well in the long term.

USP7: Novel Drug Target in Cancer Therapy.

Ubiquitin specific protease 7 (USP7) is one of the deubiquitinating enzymes (DUB) that erases ubiquitin and protects substrate protein from degradation. Full activity of USP7 requires the C-terminal Ub-like domains fold back onto the catalytic domain, allowing the remodeling of the active site to a catalytically competent state by the C-terminal peptide. Until now, numerous proteins have been identified as substrates of USP7, which play a key role in cell cycle, DNA repair, chromatin remodeling, and epigenetic regulation. Aberrant activation or overexpression of USP7 may promote oncogenesis and viral disease, making it a target for therapeutic intervention. Currently, several synthetic small molecules have been identified as inhibitors of USP7, and applied in the treatment of diverse diseases. Hence, USP7 may be a promising therapeutic target for the treatment of cancer.

Sanggenon O induced apoptosis of A549 cells is counterbalanced by protective autophagy.

Sanggenon O (SO) is a Diels-Alder type adduct extracted fromMorus alba, which has been used for its anti-inflammatory action in the Oriental medicine. However, whether it has regulatory effect on human cancer cell proliferation and what the underlying mechanism remains unknown. Here, we found that SO could significantly inhibit the growth and proliferation of A549 cells and induce its pro-apoptotic action through a caspase-dependent pathway. It could also impair the mitochondria which can be reflected by mitochondrial membrane permeabilization. Besides, SQSTM1 up-regulation and autophagic flux measurement demonstrated that exposure to SO led to autophagosome accumulation, which plays a protective role in SO-treated cells. In addition, knocking down of LC3B increased SO triggered apoptotic cell rates. These results indicated that SO has great potential as a promising candidate combined with autophagy inhibitor for the treatment of NSCLC. In conclusion, our results identified a novel mechanism by which SO exerts potent anticancer activity.

Lysine demethylase 5B (KDM5B): A potential anti-cancer drug target.

Lysine demethylase 5B (KDM5B) is a histone demethylase identified in 2007, which is responsible for erasing H3K4me2/3 activation marker. It participates in multiple repressive transcriptional complexes around target gene promoters and performs wide regulatory effects on chromatin structure. Until now, there is growing evidence for the oncogenic function of KDM5B. As the H3K4me2/3 residue represents the transcription initiation site of the active transcription gene, and demethylation of H3K4 is associated with transcriptional repression, making it a potential participant in inhibiting the expression of tumor suppressors. Therefore, KDM5B is considered as a promising drug target for cancer therapy, and many medicinal chemists are trying to design and synthesize potent and selective KDM5B inhibitors with the aid of high-throughput screening, structure based drug design, and structure activity relationship studies. This review focuses on the basic biochemical and physiological function of KDM5B and its involved mechanisms in cancers, a comprehensive overview of KDM5B inhibitors is also introduced.