Automated exploitation of deep learning for cancer patient stratification across multiple types.

MOTIVATION: Recent frameworks based on deep learning have been developed to identify cancer subtypes from high-throughput gene expression profiles. Unfortunately, the performance of deep learning is highly dependent on its neural network architectures which are often hand-crafted with expertise in deep neural networks, meanwhile, the optimization and adjustment of the network are usually costly and time consuming. RESULTS: To address such limitations, we proposed a fully automated deep neural architecture search model for diagnosing consensus molecular subtypes from gene expression data (DNAS). The proposed model uses ant colony algorithm, one of the heuristic swarm intelligence algorithms, to search and optimize neural network architecture, and it can automatically find the optimal deep learning model architecture for cancer diagnosis in its search space. We validated DNAS on eight colorectal cancer datasets, achieving the average accuracy of 95.48%, the average specificity of 98.07%, and the average sensitivity of 96.24%, respectively. Without the loss of generality, we investigated the general applicability of DNAS further on other cancer types from different platforms including lung cancer and breast cancer, and DNAS achieved an area under the curve of 95% and 96%, respectively. In addition, we conducted gene ontology enrichment and pathological analysis to reveal interesting insights into cancer subtype identification and characterization across multiple cancer types. AVAILABILITY AND IMPLEMENTATION: The source code and data can be downloaded from https://github.com/userd113/DNAS-main. And the web server of DNAS is publicly accessible at 119.45.145.120:5001.

An ATG4B inhibitor blocks autophagy and sensitizes Sorafenib inhibition activities in HCC tumor cells.

Autophagy related 4B (ATG4B) which regulates autophagy by promoting the formation of autophagosome through reversible modification of LC3, is closely related to cancer cell growth and drug resistance, and therefore is an attractive therapeutic target. Recently, ATG4B inhibitors have been reported, yet with drawbacks including weak potency. To discover more promising ATG4B inhibitors, we developed a high-throughput screening (HTS) assay and identified a new ATG4B inhibitor named DC-ATG4in. DC-ATG4in directly binds to ATG4B and inhibits its enzyme activity with an IC50 of 3.08 ± 0.47 µM. We further confirmed that DC-ATG4in is an autophagy inhibitor and blocks autophagy induced by Sorafenib in Hepatocellular Carcinoma (HCC) cells. More importantly, combination of DC-ATG4in with Sorafenib synergized the cancer cell killing effect and proliferation inhibition activities on HCC cells. Our data suggested that inactivation of autophagy via ATG4B inhibition may be a viable strategy to sensitize existing targeted therapy such as Sorafenib in the future.

Biomineralized tetramethylpyrazine-loaded PCL/gelatin nanofibrous membrane promotes vascularization and bone regeneration of rat cranium defects.

Conventional electrospinning produces nanofibers with smooth surfaces that limit biomineralization ability. To overcome this disadvantage, we fabricated a tetramethylpyrazine (TMP)-loaded matrix-mimicking biomineralization in PCL/Gelatin composite electrospun membranes with bubble-shaped nanofibrous structures. PCL/Gelatin membranes (PG), PCL/Gelatin membranes containing biomineralized hydroxyapatite (HA) (PGH), and PCL/Gelatin membranes containing biomineralized HA and loaded TMP (PGHT) were tested. In vitro results indicated that the bubble-shaped nanofibrous surface increased the surface roughness of the nanofibers and promoted mineralization. Furthermore, sustained-release TMP had an excellent drug release efficiency. Initially released vigorously, it reached stabilization at day 7, and the slow-release rate stabilized at 61.0 ± 1.8% at 28 days. All membranes revealed an intact cytoskeleton, cell viability, and superior adhesion and proliferation when stained with Ghost Pen Cyclic Peptide, CCK-8, cell adhesion, and EdU. In PGHT membranes, the osteogenic and vascularized gene expression of BMSCs and human vascular endothelial cells was significantly upregulated compared with that in other groups, indicating the PGHT membranes exhibited an effective vascularization role. Subsequently, the membranes were implanted in a rat cranium defect model for 4 and 8 weeks. Micro-CT and histological analysis results showed that the PGHT membranes had better bone regenerative patterns. Additionally, the levels of CD31 and VEGF significantly increased in the PGHT membrane compared with those in other membranes. Thus, PGHT membranes could accelerate the repair of cranium defects in vivo via HA and TMP synergistic effects.

Meta-analysis on the prevalence of bovine hydatid disease in China from 2000 to 2021.

Cystic Echinococcosis (hydatidosis) is caused by the larval stage of Echinococcus spp. It is an animal-borne zoonotic parasitic disease with local epidemic and natural foci, which is very common in northwest China. In recent years, a considerable attention has been paid to the epidemic investigation of hydatid disease in humans and sheep, but there are few large-scale epidemic investigation and data analysis of bovine hydatid disease. We systematically reviewed and analyzed the prevalence of bovine hydatid disease (2000-2021) in China for the first time. Several databases including CNKI, Wanfang, VIP Chinese periodical database, Baidu Library, PubMed and ScienceDirect were used to search 57 articles and 72 sets of valid data about bovine hydatid disease in China from 2000 to 2021. We used the random effect model in META package of R software, and PAS for rate conversion. The subgroup analysis and univariate meta regression analysis were used to reveal the factors leading to the heterogeneity of the study. The total prevalence rate of bovine hydatid disease in China from 2000 to 2021 is estimated to be 17.27% (10898/63113). According to the analysis of sampling years, the lowest positive rate since 2016 is 7.54% (1503/19929). The highest prevalence rate of bovine hydatid disease is 53.93% (4340/8048). The infection rate of bovine liver accounted for the highest proportion of the total infections, 45.2% (2040/4507). We also assessed the effects of different geographical and climatic factors on the prevalence of bovine hydatid disease. The results showed that the prevalence rate of hydatid disease was higher in cold and humid areas. Although the infection rate of bovine hydatid disease has declined in recent years, it is still necessary to carry out long-term surveillance and control of hydatid disease, cut off the infection route and reduce the risk of infection in high-risk areas.

P300/CBP inhibition sensitizes mantle cell lymphoma to PI3Kδ inhibitor idelalisib.

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder lacking reliable therapies. PI3K pathway contributes to the pathogenesis of MCL, serving as a potential target. However, idelalisib, an FDA-approved drug targeting PI3Kδ, has shown intrinsic resistance in MCL treatment. Here we report that a p300/CBP inhibitor, A-485, could overcome resistance to idelalisib in MCL cells in vitro and in vivo. A-485 was discovered in a combinational drug screening from an epigenetic compound library containing 45 small molecule modulators. We found that A-485, the highly selective catalytic inhibitor of p300 and CBP, was the most potent compound that enhanced the sensitivity of MCL cell line Z-138 to idelalisib. Combination of A-485 and idelalisib remarkably decreased the viability of three MCL cell lines tested. Co-treatment with A-485 and idelalisib in Maver-1 and Z-138 MCL cell xenograft mice for 3 weeks dramatically suppressed the tumor growth by reversing the unsustained inhibition in PI3K downstream signaling. We further demonstrated that p300/CBP inhibition decreased histone acetylation at RTKs gene promoters and reduced transcriptional upregulation of RTKs, thereby inhibiting the downstream persistent activation of MAPK/ERK signaling, which also contributed to the pathogenesis of MCL. Therefore, additional inhibition of p300/CBP blocked MAPK/ERK signaling, which rendered maintaining activation to PI3K-mTOR downstream signals p-S6 and p-4E-BP1, thus leading to suppression of cell growth and tumor progression and eliminating the intrinsic resistance to idelalisib ultimately. Our results provide a promising combination therapy for MCL and highlight the potential use of epigenetic inhibitors targeting p300/CBP to reverse drug resistance in tumor.

Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that is increasingly prevalent worldwide. Liver inflammation is an important contributor to disease progression from nonalcoholic fatty liver (NAFL) to NASH, but there is a lack of efficient therapies. In the current study we evaluated the therapeutic potential of givinostat, a histone deacetylase (HDAC) inhibitor, in the treatment of NASH in vivo and in vitro. Liver inflammation was induced in mice by feeding a methionine- and choline-deficient diet (MCD) or a fructose, palmitate, cholesterol diet (FPC). The mice were treated with givoinostat (10 mg·kg-1·d-1, ip) for 8 or 10 weeks. At the end of the experiment, the livers were harvested for analysis. We showed that givoinostat administration significantly alleviated inflammation and attenuated hepatic fibrosis in MCD-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed that givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In human hepatocellular carcinoma cell line HepG2 and human derived fetal hepatocyte cell line L02, givinostat significantly decreased palmitic acid-induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in FPC-induced NASH mice. Givinostat administration significantly attenuated hepatic steatosis, inflammation as well as liver injury in this mouse model. In conclusion, givinostat is efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for the treatment of human NASH.

CDK1 Promotes Epithelial-Mesenchymal Transition and Migration of Head and Neck Squamous Carcinoma Cells by Repressing ∆Np63α-Mediated Transcriptional Regulation.

∆Np63α is a key transcription factor overexpressed in types of squamous cell carcinomas (SCCs), which represses epithelial-mesenchymal transition (EMT) and cell migration. In this study, we found that CDK1 phosphorylates ∆Np63α at the T123 site, impairing its affinity to the target promoters of its downstream genes and its regulation of them in turn. Database analysis revealed that CDK1 is overexpressed in head and neck squamous cell carcinomas (HNSCCs), especially the metastatic HNSCCs, and is negatively correlated with overall survival. We further found that CDK1 promotes the EMT and migration of HNSCC cells by inhibiting ∆Np63α. Altogether, our study identified CDK1 as a novel regulator of ΔNp63α, which can modulate EMT and cell migration in HNSCCs. Our findings will help to elucidate the migration mechanism of HNSCC cells.

Cyclin-dependent kinase inhibitor roscovitine attenuates liver inflammation and fibrosis by influencing initiating steps of liver injury.

Liver diseases present a significant public health burden worldwide. Although the mechanisms of liver diseases are complex, it is generally accepted that inflammation is commonly involved in the pathogenesis. Ongoing inflammatory responses exacerbate liver injury, or even result in fibrosis and cirrhosis. Here we report that roscovitine, a cyclin-dependent kinase (CDK) inhibitor, exerts beneficial effects on acute and chronic liver inflammation as well as fibrosis. Animal models of lipopolysaccharide (LPS)/d-galactosamine- and acute or chronic CCl4-induced liver injury showed that roscovitine administration markedly attenuated liver injury, inflammation and histological damage in LPS/d-galactosamine- and CCl4-induced acute liver injury models, which is consistent with the results in vitro. RNA sequencing (RNA-seq) analysis showed that roscovitine treatment repressed the transcription of a broad set of pro-inflammatory genes involved in many aspects of inflammation, including cytokine production and immune cell proliferation and migration, and inhibited the TGF-ß signaling pathway and the biological process of tissue remodeling. For further validation, the beneficial effect of roscovitine against inflammation was evaluated in chronic CCl4-challenged mice. The anti-inflammation effect of roscovitine was observed in this model, accompanied with reduced liver fibrosis. The anti-fibrotic mechanism involved inhibition of profibrotic genes and blocking of hepatic stellate cell (HSC) activation. Our data show that roscovitine administration protects against liver diseases through inhibition of macrophage inflammatory actions and HSC activation at the onset of liver injury.

Ultraviolet B irradiation up-regulates MM1 and induces photoageing of the epidermis.

BACKGROUND: ΔNp63α and c-Myc are key transcription factors controlling proliferation and senescence in epithelial cells. We previously reported that the c-Myc modulator MM1 and its E3 ligase, HERC3, together with the transcription factor ΔNp63α, compose a feedback loop, which regulates proliferative senescence in MCF-10A mammary epithelial cells. However, it is unknown whether this loop is involved in skin ageing. On the other hand, ultraviolet B (UVB) rays are assumed to be the main culprits for photoageing of the epidermis, but the underlying mechanisms are obscure. AIMS: To investigate whether MM1/ΔNp63α axis is involved in UVB-induced photoageing of the epidermis. MATERIALS AND METHODS: HaCaT human immortalized keratinocytes overexpressed with MM1, knocked down with c-Myc or irradiated with UVB, were subjected to MTT assays to measure cell proliferation, as well as RT-qPCR or immunoblot to detect the members of MM1/ΔNp63α loop and the cellular senescence markers. Meanwhile, primary normal human keratinocytes (NHKs) or mice were irradiated with UVB, followed by immunoblot analysis, SA-ß-gal, haematoxylin-eosin or immunohistochemistry staining. RESULTS: Overexpression of MM1 down-regulated ΔNp63α and induced proliferative senescence in the HaCaT cells. In the HaCaT cells, NHKs and the mouse epidermis, UVB irradiation increased MM1 mRNA level and led to a down-regulation of ΔNp63α, HERC3 and c-Myc, concomitant with cellular senescence or photoageing. Additionally, knock-down of c-Myc induced proliferative senescence in the HaCaT cells and abrogated UVB-induced cellular senescence. CONCLUSIONS: UVB up-regulates MM1 and consequently modulates ΔNp63α and c-Myc, which may account for the proliferative senescence of keratinocytes and photoageing of the epidermis.

Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein.

The autophagic ubiquitin-like protein LC3 functions through interactions with LC3-interaction regions (LIRs) of other autophagy proteins, including autophagy receptors, which stands out as a promising protein-protein interaction (PPI) target for the intervention of autophagy. Post-translational modifications like acetylation of Lys49 on the LIR-interacting surface could disrupt the interaction, offering an opportunity to design covalent small molecules interfering with the interface. Through screening covalent compounds, we discovered a small molecule modulator of LC3A/B that covalently modifies LC3A/B protein at Lys49. Activity-based protein profiling (ABPP) based evaluations reveal that a derivative molecule DC-LC3in-D5 exhibits a potent covalent reactivity and selectivity to LC3A/B in HeLa cells. DC-LC3in-D5 compromises LC3B lipidation in vitro and in HeLa cells, leading to deficiency in the formation of autophagic structures and autophagic substrate degradation. DC-LC3in-D5 could serve as a powerful tool for autophagy research as well as for therapeutic interventions.

Prefoldin subunit MM1 promotes cell migration via facilitating filopodia formation.

c-Myc modulator 1 (MM1), also known as PFDN5, is the fifth subunit of prefoldin. It was previously reported that MM1-based prefoldin promotes folding of actin during assembly of cytoskeleton, which plays key roles in cell migration. However, no evidence supports that MM1 affects cell migration. In the present study, we found that MM1 promotes cell migration in multiple cell lines. Further study revealed that MM1 promotes polymerization of ß-actin into filamentous form and increases both density and length of filopodia. Effects of MM1 on filopodia formation and cell migration depend on its prefoldin activity. Though c-Myc is repressed by MM1, simultaneous knock-down of c-Myc fails to rescue migration inhibition induced by MM1 ablation. Taken together, we here, for the first time, report that prefoldin subunit MM1 is involved in cell migration; this involvement of MM1 in cell migration is due to its prefoldin activity to boost polymerization of ß-actin during filopodia formation. Our findings may be helpful to elucidate the mechanism of cell migration and cancer metastasis.

A double dealing tale of p63: an oncogene or a tumor suppressor.

As a member of tumor suppressor p53 family, p63, a gene encoding versatile protein variant, has been documented to correlate with cancer formation and progression, though it is rarely mutated in cancer patients. However, it has long been controversial on whether p63 is an oncogene or a tumor suppressor. Here, we comprehensively reviewed reports on roles of p63 in development, tumorigenesis and tumor progression. According to data from molecular cell biology, genetic models and clinic research, we conclude that p63 may act as either an oncogene or a tumor suppressor gene in different scenarios: TA isoforms of p63 gene are generally tumor-suppressive through repressing cell proliferation, survival and metastasis; ΔN isoforms, however, may initiate tumorigenesis via promoting cell proliferation and survival, but inhibit tumor metastasis and progression; effects of p63 on tumor formation and progression depend on the context of the whole p53 family, and either amplification or loss of p63 gene locus can break the balance to cause tumorigenesis.

Selenomethionine protects the liver from dietary deoxynivalenol exposure via Nrf2/PPARγ-GPX4-ferroptosis pathway in mice.

Deoxynivalenol (DON) is a significant Fusarium toxin that has gained global attention due to its high frequency of contamination in food and feed. It was reported to have hepatotoxicity, immunotoxicity, and reproduction toxicity in organs. On the other hand, Selenomethionine (SeMet) was proven to have anti-oxidation, tissue repairing, immunity improvement, and antifungal mycotoxin infection functions. However, the molecular mechanism by which SeMet alleviates DON damage is not yet clear. C57BL/6 mice were randomly divided into three groups, Se-A and Se-A+DON were fed with a diet containing 0.2 mg/kg Se whereas Se-S+DON were fed with a diet of 1.0 mg/kg Se. After feeding for four weeks, the mice were gavaged for 21 days with DON (2.0 mg/kg BW) or ultrapure water once per day. In the present study, we showed that SeMet significantly decreased the lipid peroxidation product malondialdehyde, and increased activities of antioxidant enzymes superoxide dismutase and total antioxidant capacity after DON exposure. In addition, our investigation revealed that SeMet regulated pathways related to lipid synthesis and metabolisms, and effectively mitigated DON-induced liver damage. Moreover, we have discovered that SeMet downregulation of N-acylethanolamine and HexCer accumulation induced hepatic lipotoxicity. Further study showed that SeMet supplementation increased protein levels of glutathione peroxidase 4 (GPX4), peroxisome proliferator-activated receptor γ (PPARγ), nuclear erythroid 2-related factor 2 (Nrf2), and upregulated target proteins, indicating suppression of oxidative stress in the liver. Meanwhile, we found that SeMet significantly reduced the DON-induced protein abundances of Bcl2, Beclin1, LC3B and proteins related to ferroptosis (Lpcat3, and Slc3a2), and downregulation of Slc7a11. In conclusion, SeMet protected the liver from damage by enhancing the Nrf2/PPARγ-GPX4-ferroptosis pathway, inhibiting lipid accumulation and hepatic lipotoxicity. The findings of this study indicated that SeMet has a positive impact on liver health by improving antioxidant capacity and relieving lipotoxicity in toxin pollution.

Structure-Based Design and Discovery of a Potent and Cell-Active LC3A/B Covalent Inhibitor.

Autophagy is a highly conserved cellular homeostasis maintenance mechanism in eukaryotes. Microtubule-associated protein light chain 3 (LC3) plays a crucial role in autophagy. It has multiple pairs of protein-protein interactions (PPIs) with other proteins, and these PPIs have an effect on the regulation of autophagosome formation and the recruitment of autophagic substrates. In our previous work, a small molecule covalent inhibitor DC-LC3in-D5 which could inhibit LC3A/B PPIs was identified, but a detailed study of structure-activity relationships (SARs) was lacking. Herein, a new molecule LC3in-C42 was discovered utilizing the hybridization of advantageous fragments, whose potency (IC50 = 7.6 nM) had been greatly improved compared with that of DC-LC3in-D5. LC3in-C42 inhibits autophagy at the cellular level and its efficacy far exceeds that of DC-LC3in-D5. Thus far, LC3in-C42 stands as the most potent LC3A/B small molecule inhibitor. LC3in-C42 could serve as a powerful tool for LC3A/B protein and autophagy research.

Biomimetic Hydroxyapatite on 3D-Printed Nanoattapulgite/Polycaprolactone Scaffolds for Bone Regeneration of Rat Cranium Defects.

Nanoattapulgite (nano-ATP), a magnesium-aluminum silicate clay, can absorb substances and is a suitable material for bone repair and regeneration. In this study, using three-dimensional printing technology, a nano-ATP/polycaprolactone (PCL) scaffold was fabricated and modified using NaOH to form a rough surface. Biomimetic hydroxyapatite (HA) on nano-ATP/PCL scaffolds was fabricated using a biomineralized approach. The scaffold provided structural support through PCL and was modified with ATP and HA to improve hydrophilicity and promote the delivery of nutrients. The biocompatibility and osteogenic induction of scaffolds were assessed in vitro using mouse bone marrow mesenchymal stem cells. According to the in vitro study results, the nano-ATP/PCL/HA composite scaffold significantly boosted the expression levels of genes related to osteogenesis (p < 0.05), attributed to its superior alkaline phosphatase activity and calcium deposition capabilities. The outcomes of in vivo experimentation demonstrated an augmentation in bone growth at the rat cranial defect site when treated with the ATP/PCL/HA composite scaffold. It can be inferred from the results that the implementation of ATP and HA for the bone tissue engineering repair material displays encouraging prospects.

3D-Printed Biomimetic Hydroxyapatite Composite Scaffold Loaded with Curculigoside for Rat Cranial Defect Repair.

The treatment of various large bone defects has remained a challenge for orthopedic surgeons for a long time. Recent research indicates that curculigoside (CUR) extracted from the curculigo plant exerts a positive influence on bone formation, contributing to fracture healing. In this study, we employed emulsification/solvent evaporation techniques to successfully fabricate poly(ε-caprolactone) nanoparticles loaded with curculigoside (CUR@PM). Subsequently, using three-dimensional (3D) printing technology, we successfully developed a bioinspired composite scaffold named HA/GEL/SA/CUR@PM (HGSC), chemically cross-linked with calcium chloride, to ensure scaffold stability. Further characterization of the scaffold's physical and chemical properties revealed uniform pore size, good hydrophilicity, and appropriate mechanical properties while achieving sustained drug release for up to 12 days. In vitro experiments demonstrated the nontoxicity, good biocompatibility, and cell proliferative properties of HGSC. Through alkaline phosphatase (ALP) staining, Alizarin Red S (ARS) staining, cell migration assays, tube formation assays, and detection of angiogenic and osteogenic gene proteins, we confirmed the HGSC composite scaffold's significant angiogenic and osteoinductive capabilities. Eight weeks postimplantation in rat cranial defects, Micro-computed tomography (CT) and histological observations revealed pronounced angiogenesis and new bone growth in areas treated with the HGSC composite scaffold. These findings underscore the scaffold's exceptional angiogenic and osteogenic properties, providing a solid theoretical basis for clinical bone repair and demonstrating its potential in promoting vascularization and bone regeneration.

Podocyte OTUD5 alleviates diabetic kidney disease through deubiquitinating TAK1 and reducing podocyte inflammation and injury.

Recent studies have shown the crucial role of podocyte injury in the development of diabetic kidney disease (DKD). Deubiquitinating modification of proteins is widely involved in the occurrence and development of diseases. Here, we explore the role and regulating mechanism of a deubiquitinating enzyme, OTUD5, in podocyte injury and DKD. RNA-seq analysis indicates a significantly decreased expression of OTUD5 in HG/PA-stimulated podocytes. Podocyte-specific Otud5 knockout exacerbates podocyte injury and DKD in both type 1 and type 2 diabetic mice. Furthermore, AVV9-mediated OTUD5 overexpression in podocytes shows a therapeutic effect against DKD. Mass spectrometry and co-immunoprecipitation experiments reveal an inflammation-regulating protein, TAK1, as the substrate of OTUD5 in podocytes. Mechanistically, OTUD5 deubiquitinates K63-linked TAK1 at the K158 site through its active site C224, which subsequently prevents the phosphorylation of TAK1 and reduces downstream inflammatory responses in podocytes. Our findings show an OTUD5-TAK1 axis in podocyte inflammation and injury and highlight the potential of OTUD5 as a promising therapeutic target for DKD.

Regulation of the immune microenvironment by pioglitazone-loaded polylactic glycolic acid nanosphere composite scaffolds to promote vascularization and bone regeneration.

Osteogenesis is caused by multiple factors, and the inflammatory response, osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), regeneration of blood vessels, and other factors must be considered in bone tissue engineering. To effectively repair bone defect, it is important to decrease excessive inflammation, enhance the differentiation of mesenchymal stem cells into osteoblasts, and stimulate angiogenesis. Herein, nano-attapulgite (ATP), polyvinyl alcohol (PVA), and gelatin (GEL) scaffolds were produced using 3D printing technology and pioglitazone (PIO)-containing polylactic acid-glycolic acid (PLGA) nanospheres were added. In both in vitro and in vivo studies, material scaffolds with PIO-loaded polylactic acid-glycolic acid nanospheres could reduce the inflammatory response by encouraging macrophage polarization from M1 to M2 and promoting the osteogenic differentiation of BMSCs by activating the BMP2/Smad/RUNX2 signal pathway to repair bone defects. The vascularization of human umbilical vein endothelial cells (HUVECs) through the PI3K/AKT/HIF1-/VEGF pathway was also encouraged. In vivo research using PIO-containing PLGA nanospheres revealed massive collagen deposition in skin models. These findings indicate a potentially effective scaffold for bone healing, when PLGA nanospheres-which contain the drug PIO-are combined with ATP/PVA/GEL scaffolds.

Selenium maintains intestinal epithelial cells to activate M2 macrophages against deoxynivalenol injury.

Selenium (Se) is indispensable in alleviating various types of intestinal injuries. Here, we thoroughly investigated the protective effect of Se on the regulation of the epithelial cell-M2 macrophages pathway in deoxynivalenol (DON)-induced intestinal damage. In the present study, Se has positive impacts on gut health by improving gut barrier function and reducing the levels of serum DON in vivo. Furthermore, our study revealed that Se supplementation increased the abundances of GPX4, p-PI3K, and AKT, decreased the levels of 4-HNE and inhibited ferroptosis. Moreover, when mice were treated with DON and Fer-1(ferroptosis inhibitor), ferroptosis was suppressed and PI3K/AKT pathway was activated. These results indicated that GPX4-PI3K/AKT-ferroptosis was a predominant pathway in DON-induced intestinal inflammation. Interestingly, we discovered that both the number of M2 anti-inflammatory macrophages and the levels of CSF-1 decreased while the pro-inflammatory cytokine IL-6 increased in the intestine and MODE-K cells supernatant. Therefore, Se supplementation activated the CSF-1-M2 macrophages axis, resulting in a decrease in IL-6 expression and an enhancement of the intestinal anti-inflammatory capacity. This study provides novel insights into how intestinal epithelial cells regulate the CSF-1-M2 macrophage pathway, which is essential in maintaining intestinal homeostasis confer to environmental hazardous stimuli.

PRMT1 Inhibition Activates the Interferon Pathway to Potentiate Antitumor Immunity and Enhance Checkpoint Blockade Efficacy in Melanoma.

Despite the immense success of immune checkpoint blockade (ICB) in cancer treatment, many tumors, including melanoma, exhibit innate or adaptive resistance. Tumor-intrinsic T-cell deficiency and T-cell dysfunction have been identified as essential factors in the emergence of ICB resistance. Here, we found that protein arginine methyltransferase 1 (PRMT1) expression was inversely correlated with the number and activity of CD8+ T cells within melanoma specimen. PRMT1 deficiency or inhibition with DCPT1061 significantly restrained refractory melanoma growth and increased intratumoral CD8+ T cells in vivo. Moreover, PRMT1 deletion in melanoma cells facilitated formation of double-stranded RNA derived from endogenous retroviral elements (ERV) and stimulated an intracellular interferon response. Mechanistically, PRMT1 deficiency repressed the expression of DNA methyltransferase 1 (DNMT1) by attenuating modification of H4R3me2a and H3K27ac at enhancer regions of Dnmt1, and DNMT1 downregulation consequently activated ERV transcription and the interferon signaling. Importantly, PRMT1 inhibition with DCPT1061 synergized with PD-1 blockade to suppress tumor progression and increase the proportion of CD8+ T cells as well as IFNγ+CD8+ T cells in vivo. Together, these results reveal an unrecognized role and mechanism of PRMT1 in regulating antitumor T-cell immunity, suggesting PRMT1 inhibition as a potent strategy to increase the efficacy of ICB. SIGNIFICANCE: Targeting PRMT1 stimulates interferon signaling by increasing expression of endogenous retroviral elements and double-stranded RNA through repression of DNMT1, which induces antitumor immunity and synergizes with immunotherapy to suppress tumor progression.