Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation.

Liver metastasis is the major reason for most of colorectal cancer (CRC) related deaths. Accumulating evidence indicates that CRC patients with non-alcoholic fatty liver disease (NAFLD) are at a greater risk of developing liver metastasis. With the growing prevalence of NAFLD, a better understanding of the molecular mechanism in NAFLD-driven CRC liver metastasis is needed. In this study, we demonstrated that NAFLD facilitated CRC liver metastasis as a metabolic disorder and promoted the stemness of metastatic CRC cells for their colonization and outgrowth in hepatic niches. Metabolically, the lipid-rich microenvironment in NAFLD activated de novo palmitate biosynthesis in metastatic CRC cells via upregulating fatty acid synthase (FASN). Moreover, increased intracellular palmitate bioavailability promoted EGFR palmitoylation to enhance its protein stability and plasma membrane localization. Furthermore, we demonstrated that the FDA-approved FASN inhibitor orlistat could reduce NAFLD-activated endogenous palmitate production, thus inhibiting palmitoylation of EGFR to suppress CRC cell stemness and restrict liver metastasis in synergy with conventional chemotherapy. These findings reveal that the NAFLD metabolic microenvironment boosts endogenous palmitate biosynthesis in metastatic CRC cells and promotes cell stemness via EGFR palmitoylation, and FASN inhibitor orlistat could be a candidate adjuvant drug to suppress liver metastasis in CRC patients with NAFLD.

HILPDA-mediated lipidomic remodelling promotes radiotherapy resistance in nasopharyngeal carcinoma by accelerating mitophagy.

Radiotherapy resistance is a major obstacle to nasopharyngeal carcinoma (NPC) therapy and contributes to tumour recurrence and metastasis. Lipid metabolism is a key regulatory mechanism in cancer biology; however, its role in NPC radiotherapy resistance remains unclear. In this study, we identified hypoxia-inducible lipid droplet-associated protein (HILPDA) as a newly discovered regulator of radioresistance that induces not only lipid droplet (LD) formation but also intracellular lipid remodelling, notably changing mitochondrial cardiolipin (CL) levels. Additionally, we found that the upregulation of CL promotes mitophagy in response to irradiation exposure. Mechanistically, HILPDA inhibits PINK1-mediated CLS1 ubiquitination and degradation. The combination of a mitophagy inhibitor and irradiation significantly increases the radiosensitivity of NPC cells. Human cancer-derived data confirmed that the HILPDA-CLS1 pathway promotes NPC radioresistance. Collectively, these findings suggest that HILPDA plays a critical role in promoting NPC radioresistance and might be targeted to overcome radiotherapeutic resistance in NPC patients in the clinic.

Exploring the pharmacological mechanisms of Tripterygium wilfordii against diabetic kidney disease using network pharmacology and molecular docking.

Background: Tripterygium wilfordii (TW), when formulated in traditional Chinese medicine (TCM), can effectively treat diabetic kidney disease (DKD). However, the pharmacological mechanism associated with its success has not yet been elucidated. The current work adopted network pharmacology and molecular docking for exploring TW-related mechanisms in treating DKD. Methods: In the present work, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was employed to obtain the effective components and candidate targets of TW. Additionally, this work utilized the UniProt protein database for screening and standardizing human-derived targets for effective components. The Cytoscape software was utilized to construct an effective component-target network for TW. Targets for DKD were acquired in the GEO, DisGeNET, GeneCards, and OMIM databases. Additionally, a Venn diagram was also plotted to select the possible targets of TW for treating DKD. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted to explore the TW-related mechanism underlying DKD treatment. This work also built a protein-protein interaction (PPI) network based on the Cytoscape and String platform. Then, molecular docking was conducted in order to assess the affinity of key proteins for related compounds. Results: In total, 29 active components and 134 targets of TW were acquired, including 63 shared targets, which were identified as candidate therapeutic targets. Some key targets and important pathways were included in the effect of TW in treating DKD. Genes with higher degrees, including TNF and AKT1, were identified as hub genes of TW against DKD. Molecular docking showed that TNF and AKT1 bind well to the main components in TW (kaempferol, beta-sitosterol, triptolide, nobiletin, and stigmasterol). Conclusions: TW primarily treats DKD by acting on two targets (AKT1 and TNF) via the five active ingredients kaempferol, beta-sitosterol, triptolide, nobiletin, and stigmasterol.

Correlation of serum omentin-1 level with clinical features and major adverse cardiac and cerebral events in patients undergoing continuous ambulatory peritoneal dialysis.

Omentin-1 shows a critical protective role of cardiovascular events in chronic kidney disease. This study aimed to further assess serum omentin-1 level and its relationship with clinical features and accumulating major adverse cardiac/cerebral events (MACCE) risk in end-stage renal disease patients undergoing continuous ambulatory peritoneal dialysis (CAPD-ESRD). Totally, 290 CAPD-ESRD patients and 50 healthy controls (HCs) were recruited, and their serum omentin-1 levels were measured by enzyme-linked immunosorbent assay. All CAPD-ESRD patients were followed up for 36 months to assess accumulating MACCE rate. Omentin-1 level in CAPD-ESRD patients was lower than that in HCs [median (interquartile range): 229.350 (153.575-355.550) vs. 449.800 (354.125-527.450) pg/mL] (p < 0.001). Moreover, omentin-1 level was inversely related to C-reactive protein (CRP) (p = 0.028), total cholesterol (p = 0.023), and low-density lipoprotein cholesterol (p = 0.005), while there was no correlation in omentin-1 level with other clinical features in CAPD-ESRD patients. The accumulating MACCE rate was 4.5%, 13.1%, and 15.5% in the first, second, and third years respectively, and it was lower in CAPD-ESRD patients with high level of omentin-1 than those with low level of omentin-1 (p = 0.004). Furthermore, omentin-1 (hazard ratio (HR)=0.422, p = 0.013) and high-density lipoprotein cholesterol (HR = 0.396, p = 0.010) were independently associated with reduced accumulating MACCE rate; while age (HR = 3.034, p = 0.006), peritoneal dialysis duration (HR = 2.741, p = 0.006), CRP (HR = 2.289, p = 0.026), serum uric acid (HR = 2.538, p = 0.008) were independently related to higher accumulating MACCE rate in CAPD-ESRD patients. In conclusion, serum high omentin-1 level is associated with decreased inflammation, lipid levels, and accumulating MACCE risk in CAPD-ESRD patients.

Screening of Therapeutic Targets for Pancreatic Cancer by Bioinformatics Methods.

Pancreatic cancer (PC) has the lowest survival rate and the highest mortality rate among all cancers due to lack of effective treatments. The objective of the current study was to identify potential therapeutic targets in PC. Three transcriptome datasets, namely GSE62452, GSE46234, and GSE101448, were analyzed for differentially expressed genes (DEGs) between cancer and normal samples. Several bioinformatics methods, including functional analysis, pathway enrichment, hub genes, and drugs were used to screen therapeutic targets for PC. Fisher's exact test was used to analyze functional enrichments. To screen DEGs, the paired t-test was employed. The statistical significance was considered at p <0.05. Overall, 60 DEGs were detected. Functional enrichment analysis revealed enrichment of the DEGs in "multicellular organismal process", "metabolic process", "cell communication", and "enzyme regulator activity". Pathway analysis demonstrated that the DEGs were primarily related to "Glycolipid metabolism", "ECM-receptor interaction", and "pathways in cancer". Five hub genes were examined using the protein-protein interaction (PPI) network. Among these hub genes, 10 known drugs targeted to the CPA1 gene and CLPS gene were found. Overall, CPA1 and CLPS genes, as well as candidate drugs, may be useful for PC in the future.

Ultrasound combined with nanobubbles promotes systemic anticancer immunity and augments anti-PD1 efficacy.

BACKGROUND: The poor immunogenicity of solid tumors limits the efficacy ofanti-programmed cell death protein 1 (anti-PD1)-based immune checkpoint blockade (ICB); thus, less than 30% of patients with cancer exhibit a response. Currently, there is still a lack of effective strategies for improving tumor immunogenicity. METHODS: The antitumor effect of ultrasound-stimulated nanobubbles (USNBs) alone and in combination with an anti-PD1 antibody was evaluated in RM1 (prostate cancer), MC38 (colon cancer) and B16 (melanoma) xenograft mouse models. The phenotypes of antigen-presenting cells and CD8+ T cells were evaluated by flow cytometry. Damage-associated molecular pattern (DAMP) release, antigen release and tumor cell necrosis were assessed via western blot, flow cytometry, transmission electron microscopy and confocal microscopy. RESULTS: USNB promoted the infiltration and antitumor activity of CD8+ T cells. The combination of USNB and anti-PD1 blockade improved systemic antitumor immunity and resulted in an abscopal effect and long-term immune memory protection after complete tumor remission. Mechanistically, tumor-targeting USNB induced tumor cell necrosis through an ultrasound-mediated cavitation effect, which significantly increased DAMP release and tumor antigen presentation, consequently sensitizing tumors to ICB treatment. CONCLUSION: The administration of USNB increased tumor immunogenicity by remodeling the tumor-immune microenvironment, providing a promising strategy for sensitizing poorly immunogenic solid tumors to immunotherapy in the clinic.

ABHD5 inhibits YAP-induced c-Met overexpression and colon cancer cell stemness via suppressing YAP methylation.

Cancer stemness represents a major source of development and progression of colorectal cancer (CRC). c-Met critically contributes to CRC stemness, but how c-Met is activated in CRC remains elusive. We previously identified the lipolytic factor ABHD5 as an important tumour suppressor gene in CRC. Here, we show that loss of ABHD5 promotes c-Met activation to sustain CRC stemness in a non-canonical manner. Mechanistically, we demonstrate that ABHD5 interacts in the cytoplasm with the core subunit of the SET1A methyltransferase complex, DPY30, thereby inhibiting the nuclear translocation of DPY30 and activity of SET1A. In the absence of ABHD5, DPY30 translocates to the nucleus and supports SET1A-mediated methylation of YAP and histone H3, which sequesters YAP in the nucleus and increases chromatin accessibility to synergistically promote YAP-induced transcription of c-Met, thus promoting the stemness of CRC cells. This study reveals a novel role of ABHD5 in regulating histone/non-histone methylation and CRC stemness.

The coevolutionary process of restaurant CSR in the time of mega disruption.

This study investigates how US foodservice conglomerates have embarked on corporate social responsibility (CSR) measures to circumvent dire situations during the COVID-19 pandemic. It explores the evolution of CSR practices from restaurant enterprises to rescue and salvage their stakeholders. By analyzing press releases from ten restaurant chains in three different crisis phases (incubation, acceleration, and climax) through corpus linguistics, we identify a CSR progression mechanism that coevolves with the aftermath of the crisis among their stakeholders. This study improvises the CSR- as-process view to highlight the time-variant dynamic nature of CSR development over the course of major disruption.

ABHD5 blunts the sensitivity of colorectal cancer to fluorouracil via promoting autophagic uracil yield.

The efficacy of Fluorouracil (FU) in the treatment of colorectal cancer (CRC) is greatly limited by drug resistance. Autophagy has been implicated in chemoresistance, but the role of selective autophagic degradation in regulating chemoresistance remains unknown. In this study, we revealed a critical role of ABHD5 in charging CRC sensitivity to FU via regulating autophagic uracil yield. We demonstrated that ABHD5 localizes to lysosome and interacts with PDIA5 to prevent PDIA5 from interacting with RNASET2 and inactivating RNASET2. ABHD5 deficiency releases PDIA5 to directly interact with RNASET2 and leave RNASET2 in an inactivate state, which impairs RNASET2-mediated autophagic uracil yield and promotes CRC cells to uptake FU as an exogenous uracil, thus increasing their sensitivity to FU. Our findings for the first time reveal a novel role of ABHD5 in regulating lysosome function, highlighting the significance of ABHD5 as a compelling biomarker predicting the sensitivity of CRCs to FU-based chemotherapy.

Identification of a fluorescent small-molecule enhancer for therapeutic autophagy in colorectal cancer by targeting mitochondrial protein translocase TIM44.

OBJECTIVE: As the modulation of autophagic processes can be therapeutically beneficial to cancer treatment, the identification of novel autophagic enhancers is highly anticipated. However, current autophagy-inducing anticancer agents exert undesired side effects owing to their non-specific biodistribution in off-target tissues. This study aims to develop a multifunctional agent to integrate cancer targeting, imaging and therapy and to investigate its mechanism. DESIGN: A series of mitochondria-targeting near-infrared (NIR) fluorophores were synthesised, screened and identified for their autophagy-enhancing activity. The optical properties and biological effects were tested both in vitro and in vivo. The underlying mechanism was investigated using inhibitors, small interfering RNA (siRNA), RNA sequencing, mass spectrometry and human samples. RESULTS: We have screened and identified a new NIR autophagy-enhancer, IR-58, which exhibits significant tumour-selective killing effects. IR-58 preferentially accumulates in the mitochondria of colorectal cancer (CRC) cells and xenografts, a process that is glycolysis-dependent and organic anion transporter polypeptide-dependent. IR-58 kills tumour cells and induces apoptosis via inducing excessive autophagy, which is mediated through the reactive oxygen species (ROS)-Akt-mammalian target of rapamycin (mTOR) pathway. RNA sequencing, mass spectrometry and siRNA interference studies demonstrate that translocase of inner mitochondrial membrane 44 (TIM44)-superoxide dismutase 2 (SOD2) pathway inhibition is responsible for the excessive ROS, autophagy and apoptosis induced by IR-58. TIM44 expression correlates positively with CRC development and poor prognosis in patients. CONCLUSIONS: A novel NIR small-molecule autophagy-enhancer, IR-58, with mitochondria-targeted imaging and therapy capabilities was developed for CRC treatment. Additionally, TIM44 was identified for the first time as a potential oncogene, which plays an important role in autophagy through the TIM44-SOD2-ROS-mTOR pathway.

The Kinase mTORC1 Promotes the Generation and Suppressive Function of Follicular Regulatory T Cells.

Follicular regulatory T (Tfr) cells differentiate from conventional regulatory T (Treg) cells and suppress excessive germinal center (GC) responses by acting on both GC B cells and T follicular helper (Tfh) cells. Here, we examined the impact of mTOR, a serine/threonine protein kinase that senses and integrates diverse environmental cues, on the differentiation and functional competency of Tfr cells in response to protein immunization or viral infection. By genetically deleting Rptor or Rictor, essential components for mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), respectively, we found that mTORC1 but not mTORC2 is essential for Tfr differentiation. Mechanistically, mTORC1-mediated phosphorylation of the transcription factor STAT3 induced the expression of the transcription factor TCF-1 by promoting STAT3 binding to the Tcf7 5'-regulatory region. Subsequently, TCF-1 bound to the Bcl6 promoter to induce Bcl6 expression, which launched the Tfr cell differentiation program. Thus, mTORC1 initiates Tfr cell differentiation by activating the TCF-1-Bcl-6 axis during immunization or infection.

Melatonin regulates PARP1 to control the senescence-associated secretory phenotype (SASP) in human fetal lung fibroblast cells.

Cellular senescence is an important tumor-suppressive mechanism. However, acquisition of a senescence-associated secretory phenotype (SASP) in senescent cells has deleterious effects on the tissue microenvironment and, paradoxically, promotes tumor progression. In a drug screen, we identified melatonin as a novel SASP suppressor in human cells. Strikingly, melatonin blunts global SASP gene expression upon oncogene-induced senescence (OIS). Moreover, poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, was identified as a new melatonin-dependent regulator of SASP gene induction upon OIS. Here, we report two different but potentially coherent epigenetic strategies for melatonin regulation of SASP. The interaction between the telomeric repeat-containing RNA (TERRA) and PARP-1 stimulates the SASP, which was attenuated by 67.9% (illustrated by the case of IL8) by treatment with melatonin. Through binding to macroH2A1.1, PARP-1 recruits CREB-binding protein (CBP) to mediate acetylation of H2BK120, which positively regulates the expression of target SASP genes, and this process is interrupted by melatonin. Consequently, the findings provide novel insight into melatonin's epigenetic role via modulating PARP-1 in suppression of SASP gene expression in OIS-induced senescent cells. Our studies identify melatonin as a novel anti-SASP molecule, define PARP-1 as a new target by which melatonin regulates SASP, and establish a new epigenetic paradigm for a pharmacological mechanism by which melatonin interrupts PARP-1 interaction with the telomeric long noncoding RNA(lncRNA) or chromatin.

TERT Genetic Mutations as Prognostic Marker in Glioma.

Telomerase reverse transcriptase (TERT) encodes the catalytic subunit of telomerase. The role of TERT in gliomagenesis has been extensively investigated. Since the influence of district, population, sample size, and experimental technology, our analysis, based on published articles, was aimed to obtain an accurate estimation of the relationship between TERT mutations and prognosis of glioma patients. PubMed, Web of science and Google Scholar databases were searched for potential articles. Finally, six studies with 2111 patients were included in the meta-analysis. Heterogeneity was evaluated by I2 statistics and P value. I2 > 50 % and P < 0.05 indicated significant heterogeneity between included studies and random-effects model was used; otherwise, fixed-effects model was used for analysis. The results of meta-analysis was expressed as hazard ratio (HR) and 95 % confidence interval (CI). The pooled results calculated by fixed-effects model suggested that TERT mutations were associated with poor prognosis of glioma patients (HR 1.68, 95 % CI 1.43-1.97). In conclusion, TERT mutations may be associated with shorter survival of glioma patients.

ABHD5 interacts with BECN1 to regulate autophagy and tumorigenesis of colon cancer independent of PNPLA2.

Autophagy critically contributes to metabolic reprogramming and chromosomal stability. It has been reported that monoallelic loss of the essential autophagy gene BECN1 (encoding BECN1/Beclin 1) promotes cancer development and progression. However, the mechanism by which BECN1 is inactivated in malignancy remains largely elusive. We have previously reported a tumor suppressor role of ABHD5 (abhydrolase domain containing 5), a co-activator of PNPLA2 (patatin like phospholipase domain containing 2) in colorectal carcinoma (CRC). Here we report a noncanonical role of ABHD5 in regulating autophagy and CRC tumorigenesis. ABHD5 directly competes with CASP3 for binding to the cleavage sites of BECN1, and consequently prevents BECN1 from being cleaved by CASP3. ABHD5 deficiency provides CASP3 an advantage to cleave and inactivate BECN1, thus impairing BECN1-induced autophagic flux and augmenting genomic instability, which subsequently promotes tumorigenesis. Notably, clinical data also confirm that ABHD5 proficiency is significantly correlated with the expression levels of BECN1, LC3-II and CASP3 in human CRC tissues. Our findings suggest that ABHD5 possesses a PNPLA2-independent function in regulating autophagy and tumorigenesis, further establishing the tumor suppressor role of ABHD5, and offering an opportunity to develop new approaches aimed at preventing CRC carcinogenesis.

Follicular CXCR5- expressing CD8(+) T cells curtail chronic viral infection.

During chronic viral infection, virus-specific CD8(+) T cells become exhausted, exhibit poor effector function and lose memory potential. However, exhausted CD8(+) T cells can still contain viral replication in chronic infections, although the mechanism of this containment is largely unknown. Here we show that a subset of exhausted CD8(+) T cells expressing the chemokine receptor CXCR5 has a critical role in the control of viral replication in mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). These CXCR5(+) CD8(+) T cells were able to migrate into B-cell follicles, expressed lower levels of inhibitory receptors and exhibited more potent cytotoxicity than the CXCR5(-) [corrected] subset. Furthermore, we identified the Id2-E2A signalling axis as an important regulator of the generation of this subset. In patients with HIV, we also identified a virus-specific CXCR5(+) CD8(+) T-cell subset, and its number was inversely correlated with viral load. The CXCR5(+) subset showed greater therapeutic potential than the CXCR5(-) [corrected] subset when adoptively transferred to chronically infected mice, and exhibited synergistic reduction of viral load when combined with anti-PD-L1 treatment. This study defines a unique subset of exhausted CD8(+) T cells that has a pivotal role in the control of viral replication during chronic viral infection.

Macrophages induce resistance to 5-fluorouracil chemotherapy in colorectal cancer through the release of putrescine.

The development of chemoresistance to 5-fluorouracil (5-FU) is a major obstacle for sustained effective treatment of colorectal cancer (CRC), with the mechanisms being not fully understood. Here we demonstrated that tumor associated macrophages (TAMs) became activated during treatment with 5-FU and secreted factors that protected the CRC cells against chemotherapy with 5-FU. By performing metabolomics analysis, we identified putrescine, a member of polyamines, inducing resistance to 5-FU-triggered CRC apoptosis and tumor suppression via JNK-caspase-3 pathway. Noteworthily, either pharmacological or genetic blockage of ornithine decarboxylase (ODC) prevented TAMs-induced chemoresistance to 5-FU in vitro and in vivo. Our findings show that TAMs are potent mediators of resistance to 5-FU chemotherapy and uncover potential targets to enhance chemotherapy sensitivity in patients with CRC.

Macrophage ABHD5 promotes colorectal cancer growth by suppressing spermidine production by SRM.

Metabolic reprogramming in stromal cells plays an essential role in regulating tumour growth. The metabolic activities of tumour-associated macrophages (TAMs) in colorectal cancer (CRC) are incompletely characterized. Here, we identify TAM-derived factors and their roles in the development of CRC. We demonstrate that ABHD5, a lipolytic co-activator, is ectopically expressed in CRC-associated macrophages. We demonstrate in vitro and in mouse models that macrophage ABHD5 potentiates growth of CRC cells. Mechanistically, ABHD5 suppresses spermidine synthase (SRM)-dependent spermidine production in macrophages by inhibiting the reactive oxygen species-dependent expression of C/EBPɛ, which activates transcription of the srm gene. Notably, macrophage-specific ABHD5 transgene-induced CRC growth in mice can be prevented by an additional SRM transgene in macrophages. Altogether, our results show that the lipolytic factor ABHD5 suppresses SRM-dependent spermidine production in TAMs and potentiates the growth of CRC. The ABHD5/SRM/spermidine axis in TAMs might represent a potential target for therapy.