Moracin D suppresses cell growth and induces apoptosis via targeting the XIAP/PARP1 axis in pancreatic cancer.

BACKGROUND: Pancreatic cancer, a tumor with a high metastasis rate and poor prognosis, is among the deadliest human malignancies. Investigating effective drugs for their treatment is imperative. Moracin D, a natural benzofuran compound isolated from Morus alba L., shows anti-inflammation and anti-breast cancer properties and is effective against Alzheimer's disease. However, the effect and mechanism of Moracin D action in pancreatic cancer remain obscure. PURPOSE: To investigate the function and molecular mechanism of Moracin D action in repressing the malignant progression of pancreatic cancer. METHODS: Pancreatic cancer cells were treated with Moracin D, and cell proliferation was evaluated by cell counting kit-8 (CCK-8) and immunofluorescence assays. The clonogenicity of pancreatic cancer cells was assessed based on plate colony formation and soft agar assay. Flow cytometry was used to detect cell apoptosis. The expression of proteins related to the apoptosis pathway was determined by Western blot analysis. Moracin D and XIAP were subjected to docking by auto-dock molecular docking analysis. Ubiquitination levels of XIAP and the interaction of XIAP and PARP1 were assessed by co-immunoprecipitation analysis. Moracin D's effects on tumorigenicity were assessed by a tumor xenograft assay. RESULTS: Moracin D inhibited cell proliferation, induced cell apoptosis, and regulated the protein expression of molecules involved in caspase-dependent apoptosis pathways. Moracin D suppressed clonogenicity and tumorigenesis of pancreatic cancer cells. Mechanistically, XIAP could interact with PARP1 and stabilize PARP1 by controlling its ubiquitination levels. Moracin D diminished the stability of XIAP and decreased the expression of XIAP by promoting proteasome-dependent XIAP degradation, further blocking the XIAP/PARP1 axis and repressing the progression of pancreatic cancer. Moracin D could dramatically improve the chemosensitivity of gemcitabine in pancreatic cancer cells. CONCLUSION: Moracin D repressed cell growth and tumorigenesis, induced cell apoptosis, and enhanced the chemosensitivity of gemcitabine through the XIAP/PARP1 axis in pancreatic cancer. Moracin D is a potential therapeutic agent or adjuvant for pancreatic cancer.

Three-Dimensional Multihierarchical Hexagonal/Cubic ZnIn2S4 S-Scheme Heterophase Junction for Superior Photocatalysis.

It is an important strategy to design composite materials with a special microstructure and a tunable electronic structure through structural compatibility. In this work, a novel hexagonal/cubic ZnIn2S4 polymorphic heterophase junction with a three-dimensional multihierarchical structure is successfully constructed by in situ growth of hexagonal ZnIn2S4 nanosheets on the surface of cubic ZnIn2S4 flower-like microspheres prepared by topological chemical synthesis. On the one hand, the multihierarchical architecture provides large specific surface area, abundant active sites, and excellent light trapping capability. On the other hand, the construction of a direct S-scheme heterophase junction enables the formation of a special charge-transfer channel under the force of a built-in electric field, which not only improves the separation efficiency of carriers but also ensures the stronger reaction activity of charges. The prepared ZnIn2S4 heterophase junction composite photocatalyst exhibits greatly boosted photocatalytic efficiency in rhodamine B degradation, hexavalent chromium reduction, and water splitting for hydrogen production, which are 12.3, 6.5, and 3.1 times higher than that of pure hexagonal ZnIn2S4 and 8.1, 5.1, and 2.3 times higher than that of pure cubic ZnIn2S4, respectively, demonstrating its significant potential for applications in energy and environmental fields.

PRMT1 promotes the proliferation and metastasis of gastric cancer cells by recruiting MLXIP for the transcriptional activation of the ß-catenin pathway.

Protein arginine methyltransferase 1 (PRMT1), a type I PRMT, is overexpressed in gastric cancer (GC) cells. To elucidate the function of PRMT1 in GC, PRMT1 expression in HGC-27 and MKN-45 cells was knocked down by short hairpin RNA (shRNA) or inhibited by PRMT1 inhibitors (AMI-1 or DCLX069), which resulted in inhibition of GC cell proliferation, migration, invasion, and tumorigenesis in vitro and in vivo. MLX-interacting protein (MLXIP) and Kinectin 1 (KTN1) were identified as PRMT1-binding proteins. PRMT1 recruited MLXIP to the promoter of ß-catenin, which induced ß-catenin transcription and activated the ß-catenin signaling pathway, promoting GC cell migration and metastasis. Furthermore, KTN1 inhibited the K48-linked ubiquitination of PRMT1 by decreasing the interaction between TRIM48 and PRMT1. Collectively, our findings reveal a mechanism by which PRMT1 promotes cell proliferation and metastasis mediated by the ß-catenin signaling pathway.

Mycobacterium tuberculosis-macrophage interaction: Molecular updates.

Mycobacterium tuberculosis (Mtb), the causative agent of Tuberculosis (TB), remains a pathogen of great interest on a global scale. This airborne pathogen affects the lungs, where it interacts with macrophages. Acidic pH, oxidative and nitrosative stressors, and food restrictions make the macrophage's internal milieu unfriendly to foreign bodies. Mtb subverts the host immune system and causes infection due to its genetic arsenal and secreted effector proteins. In vivo and in vitro research have examined Mtb-host macrophage interaction. This interaction is a crucial stage in Mtb infection because lung macrophages are the first immune cells Mtb encounters in the host. This review summarizes Mtb effectors that interact with macrophages. It also examines how macrophages control and eliminate Mtb and how Mtb manipulates macrophage defense mechanisms for its own survival. Understanding these mechanisms is crucial for TB prevention, diagnosis, and treatment.

MESP2 binds competitively to TCF4 to suppress gastric cancer progression by regulating the SKP2/p27 axis.

Gastric cancer (GC) is a major cause of human deaths worldwide, and is notorious for its high incidence and mortality rates. Mesoderm Posterior Basic Helix-loop-helix (bHLH) transcription factor 2 (MESP2) acts as a transcription factor with a conserved bHLH domain. However, whether MESP2 contributes to tumorigenesis and its potential molecular mechanisms, remain unexplored. Noticeably, MESP2 expression levels are decreased in GC tissues and cell lines compared to those in normal tissue. Further, in vitro and in vivo experiments have confirmed that MESP2 overexpression suppresses GC cell growth, migration, and invasion, whereas MESP2 knockdown results in the exact opposite. Here, we present the first report that MESP2 binds to transcription factor 7-like 2 (TCF7L2/TCF4) to inhibit the activation of the TCF4/beta-catenin transcriptional complex, decrease the occupancy of the complex on the S-phase kinase Associated Protein 2 (SKP2) promoter, and promote p27 accumulation. MESP2 knockdown facilitated tumorigenesis, which was partially suppressed by SKP2 knockdown. Taken together, we conclude that MESP2 binds competitively to TCF4 to suppress GC progression by regulating the SKP2/p27 axis, thus offering a potential therapeutic strategy for future treatment.

Recent advances of the mammalian target of rapamycin signaling in mesenchymal stem cells.

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in a variety of cellular functions, such as cell proliferation, metabolism, autophagy, survival and cytoskeletal organization. Furthermore, mTOR is made up of three multisubunit complexes, mTOR complex 1, mTOR complex 2, and putative mTOR complex 3. In recent years, increasing evidence has suggested that mTOR plays important roles in the differentiation and immune responses of mesenchymal stem cells (MSCs). In addition, mTOR is a vital regulator of pivotal cellular and physiological functions, such as cell metabolism, survival and ageing, where it has emerged as a novel therapeutic target for ageing-related diseases. Therefore, the mTOR signaling may develop a large impact on the treatment of ageing-related diseases with MSCs. In this review, we discuss prospects for future research in this field.

Antheraea pernyi Suppressor of Cytokine Signaling 2 Negatively Modulates the JAK/STAT Pathway to Attenuate Microbial Infection.

The Janus kinase (JAK) signal transducer and activator of transcription (STAT) pathway has been shown to govern various physiological processes, including immune responses, hematopoiesis, cell growth, and differentiation. Recent studies show that suppressors of cytokine signaling (SOCS) proteins attenuate JAK-STAT signaling in mammals; however, their functions are less clear in lepidopteran insects. Here, we report a full-length sequence of SOCS-2 from the Chinese oak silkworm Antheraea pernyi (designated as ApSOCS-2) and study its biological role in immune responses via the JAK-STAT pathway. ApSOCS-2 expression was high in the fat bodies and hemocytes of A. pernyi fifth instar larvae. After pathogen infection with nucleopolyhedrovirus, Beauveria bassiana, Escherichia coli, and Microccus luteus, ApSOCS-2 mRNA was strongly increased compared to the control group. To elucidate the possible involvement in innate immunity, we measured antimicrobial peptide genes expression profiles in the fat body of A. pernyi. In contrast, recombinant ApSOCS-2 protein administration significantly reduced the AMPs transcription, while the depletion of ApSOCS-2 by RNAi increased their expression. Furthermore, we observed higher antibacterial activity and lower bacterial replication in dsApSOCS-2-treated larvae. The ApSOCS-2 transcription level was reduced in STAT depleted A. pernyi larvae challenged by M. luteus. The ApSOCS-2 RNAi data sets were also subjected to transcriptomic analysis, which suggests that ApSOCS-2 is a key regulator of immune function. Taken together, our data suggest that ApSOCS-2 is required for the negative regulation of AMPs transcripts via the JAK-STAT pathway in the insect.

[Research progress on chemical constituents and pharmacological activities of Morus alba].

Morus alba, a traditional economic crop, is also a significant medicinal plant. The branches(Mori Ramulus), leaves(Mori Folium), roots and barks(Mori Cortex), and fruits(Mori Fructus) of M. alba are rich in chemical components, such as alkaloids, flavonoids, flavanols, anthocyanins, benzofurans, phenolic acids, and polysaccharides, and possess hypoglycemic, hypolipidemic, anti-inflammatory, anti-tumor, anti-microbial, liver protective, immunoregulatory, and other pharmacological activities. This study analyzed the sources, classification, and functions of the main chemical components in M. alba and systematically summarized the latest research results of essential active components in M. alba and their pharmacological effects to provide references for in-depth research and further development as well as utilization of active components in M. alba.

Nup54-induced CARM1 nuclear importation promotes gastric cancer cell proliferation and tumorigenesis through transcriptional activation and methylation of Notch2.

Gastric cancer (GC) has the fifth highest incidence globally, but its molecular mechanisms are not well understood. Here, we report that coactivator-associated arginine methyltransferase 1 (CARM1) is specifically highly expressed in gastric cancer and that its overexpression correlates with poor prognosis in patients with gastric cancer. Nucleoporin 54 (Nup54) was identified as a CARM1-interacting protein that promoted CARM1 nuclear importation. In the nucleus, CARM1 cooperates with transcriptional factor EB (TFEB) to activate Notch2 transcription by inducing H3R17me2 of the Notch2 promoter but not H3R26me2. Additionally, the Notch2 intracellular domain (N2ICD) was identified as a CARM1 substrate. Methylation of N2ICD at R1786, R1838, and R2047 by CARM1 enhanced the binding between N2ICD and mastermind-like protein 1 (MAML1) and increased gastric cancer cell proliferation in vitro and tumor formation in vivo. Our findings reveal a molecular mechanism linking CARM1-mediated transcriptional activation of the Notch2 signaling pathway to Notch2 methylation in gastric cancer progression.

Fish scale-based biochar with defined pore size and ultrahigh specific surface area for highly efficient adsorption of ciprofloxacin.

A fish scale-based porous activated biochar with defined pore size (DPBC) was fabricated by a one-step calcination and activation method. The DPBC possessed an ultrahigh specific surface area of 3370 m2 g-1 and its pore diameter centered at 1.49 nm which fits into the ciprofloxacin (CIP) molecular dimension, making it an ideal adsorbent for CIP adsorption due to the molecular pore-filling effect. The maximum Langmuir monolayer adsorption capacity of DPBC for CIP was higher than 1000 mg g-1 and the equilibrium time was less than 4 h, superior to most adsorbents reported in literature. Thermodynamic analysis indicated the adsorption process was spontaneous and endothermic. Notably, fixed-bed experiments showed an encouraging adsorption performance towards CIP, with a high saturated dynamic adsorption capacity of 880.3 mg g-1. Both Thomas and Yoon-Nelson models predict the fixed-bed column adsorption performance well. Hydrophobic effect, π-π interaction, π-π EDA, cation exchange, hydrogen bonding formation, pore filling effect, electrostatic and cation-π interaction involved in the CIP adsorption on the DPBC.

Suppressor of cytokine signalling 6 is a potential regulator of antimicrobial peptides in the Chinese oak silkworm, Antheraea pernyi.

The SOCS/CIS is a family of intracellular proteins distributed widely among living organisms. The members of this family have extensively been studied in mammals and have been shown to regulate various physiological processes. In contrast, the functional roles of SOCS/CIS family proteins are unknown in most invertebrates, including insects. Here, we retrieved a full-length open reading frame (ORF) of SOCS-6 from Chines oak silkworm, Antheraea pernyi (Designated as ApSOCS-6), using the RNA-seq database. The predicted ApSOCS-6 amino acid sequence comprised an N-terminal SH2 domain and a C-terminal SOCS-box domain. It shared the highly conserved structures of the SOCS proteins with other lepidopteran species. ApSOCS-6 mRNA transcript was detected in all the tested tissues of the A. pernyi larvae; however, the highest mRNA levels were found in the larval hemocytes, fat bodies, and integuments. The mRNA transcript levels of ApSOCS-6 were increased in the A. pernyi larval hemocytes and fat bodies after a challenge by the Gram-positive bacteria, M. luteus, Gram-negative bacteria, Escherichia coli, Virus, ApNPV, and Fungus, B. bassiana. After the knockdown of ApSOCS-6, we found a significant increase in bacterial clearance and a decrease in the relative replication of bacteria. To evaluate the possible cause of enhanced antibacterial activity, we measured antimicrobial peptides expression in the fat body of A. pernyi larvae. The production of AMPs was strongly increased in the B. cereus infected larval fat bodies following silencing of ApSOCS-6. Our data indicate that ApSOCS-6 negatively regulates the expression of AMPs in immune tissues in response to the B. cereus challenge.

Integrin αvß3 Engagement Regulates Glucose Metabolism and Migration through Focal Adhesion Kinase (FAK) and Protein Arginine Methyltransferase 5 (PRMT5) in Glioblastoma Cells.

Metabolic reprogramming promotes glioblastoma cell migration and invasion. Integrin αvß3 is one of the major integrin family members in glioblastoma multiforme cell surface mediating interactions with extracellular matrix proteins that are important for glioblastoma progression. The role of αvß3 integrin in regulating metabolic reprogramming and its mechanism of action have not been determined in glioblastoma cells. Integrin αvß3 engagement with osteopontin promotes glucose uptake and aerobic glycolysis, while inhibiting mitochondrial oxidative phosphorylation. Blocking or downregulation of integrin αvß3 inhibits glucose uptake and aerobic glycolysis and promotes mitochondrial oxidative phosphorylation, resulting in decreased migration and growth in glioblastoma cells. Pharmacological inhibition of focal adhesion kinase (FAK) or downregulation of protein arginine methyltransferase 5 (PRMT5) blocks metabolic shift toward glycolysis and inhibits glioblastoma cell migration and invasion. These results support that integrin αvß3 and osteopontin engagement plays an important role in promoting the metabolic shift toward glycolysis and inhibiting mitochondria oxidative phosphorylation in glioblastoma cells. The metabolic shift in cell energy metabolism is coupled to changes in migration, invasion, and growth, which are mediated by downstream FAK and PRMT5 in glioblastoma cells.

Alleviation of Reverse Salt Leakage across Nanofiber Supported Thin-Film Composite Forward Osmosis Membrane via Heat-Curing in Hot Water.

Electrospun nanofiber with interconnected porous structure has been studied as a promising support layer of polyamide (PA) thin-film composite (TFC) forward osmosis (FO) membrane. However, its rough surface with irregular pores is prone to the formation of a defective PA active layer after interfacial polymerization, which shows high reverse salt leakage in FO desalination. Heat-curing is beneficial for crosslinking and stabilization of the PA layer. In this work, a nanofiber-supported PA TFC membrane was conceived to be cured on a hot water surface with preserved phase interface for potential "defect repair", which could be realized by supplementary interfacial polymerization of residual monomers during heat-curing. The resultant hot-water-curing FO membrane with a more uniform superhydrophilic and highly crosslinked PA layer exhibited much lower reverse salt flux (FO: 0.3 gMH, PRO: 0.8 gMH) than that of oven-curing FO membrane (FO: 2.3 gMH, PRO: 2.2 gMH) and achieved ∼4 times higher separation efficiency. It showed superior stability owing to mitigated reverse salt leakage and osmotic pressure loss, with its water flux decline lower than a quarter that of the oven-curing membrane. This study could provide new insight into the fine-tuning of nanofiber-supported TFC FO membrane for high-quality desalination via a proper selection of heat-curing methods.

Niemann-Pick type C1 regulates cholesterol transport and metamorphosis in silkworm, Bombyx mori (Dazao).

NPC1 is a large glycoprotein with 13 transmembrane-spanning domains, which plays a crucial biological role in cholesterol transport and metamorphosis of animals. However, the physiological functions of this gene have rarely been elucidated in insects. Here, we isolated the NPC1 gene from Bombyx mori (BmNPC1), sequenced and evaluated its physiological functions. BmNPC1 comprised of 3702 bp open reading frame, encoding a protein of 1233 amino acid residues. The recombinant protein was expressed, and anti-BmNPC1 antibodies were synthesized. Immunofluorescence assay revealed that BmNPC1 protein localized in the cytoplasm of the cells. The qRT-PCR analysis showed that BmNPC1 expression was most significant in the testis, followed by the malpighian tubules, hemocytes, and ovary. The knockdown of BmNPC1 by double-stranded RNA caused the accumulation of cholesterol in the cells. Furthermore, suppression of this gene influenced the expression of ecdysone-responsive genes and also prevented the molting in B. mori (Dazao) larvae. Overall, BmNPC1 may have different biological roles in the physiology of silkworm, B. mori (Dazao), since it regulates the cholesterol transport and molting process.

WDR5-Myc axis promotes the progression of glioblastoma and neuroblastoma by transcriptional activating CARM1.

The WD repeat domain 5 (WDR5), also known as SWD3 and BIG-3, is often overexpressed in cancers, however its molecular function in cancer remains to be elucidated. In this study, we found that WDR5 promoted the proliferation and self-renewal of glioblastoma and neuroblastoma cells. The data from databases and Western blot assay showed that CARM1 is a downstream gene of WDR5-Myc axis. In addition, we observed that WDR5 promoted the binding of Myc to CARM1 promoter by interacting with Myc and inducing histone 3 lysine 4 trimethylation (H3K4me3). Dual luciferase reporter system indicated that Myc binds to the upstream region (-520 to -515) before transcription start site (TSS) of CARM1 promoter. These findings suggest a novel regulatory model for the proliferation and tumorigenesis of glioblastoma and neuroblastoma by WDR5-Myc axis.

The Roles of Sirtuin Family Proteins in Cancer Progression.

Sirtuin family members are characterized by either mono-ADP-ribosyltransferase or deacylase activity and are linked to various cancer-related biological pathways as regulators of transcriptional progression. Sirtuins play fundamental roles in carcinogenesis and maintenance of the malignant phenotype, mainly participating in cancer cell viability, apoptosis, metastasis, and tumorigenesis. Although sirtuin family members have a high degree of homology, they may play different roles in various kinds of cancer. This review highlights their fundamental roles in tumorigenesis and cancer development and provides a critical discussion of their dual roles in cancer, namely, as tumor promoters or tumor suppressors.

G9a promotes cell proliferation and suppresses autophagy in gastric cancer by directly activating mTOR.

As an important methyltransferase, G9a has been reported to be abnormally expressed in various human cancers and plays essential roles in tumorigenesis. However, the biologic functions and molecular mechanisms of G9a in gastric cancer (GC) remain unclear. GC is the fifth most frequent cancer around the world and seriously threatens human health, especially in developing countries. Here, our results showed that high expression of G9a was intensively correlated with poor prognosis and more advanced stages of GCs. Knockdown of G9a or treatment with its inhibitor, BIX01294, significantly reduced cell growth by cell cycle arrest and autophagy. In addition, the mechanistic target of rapamycin (mTOR) was evidently decreased after G9a silencing or inhibition, and mTOR activation partially rescued the effects of cell proliferation inhibition and autophagy induced by G9a knockdown or inhibition. Down-regulation of G9a effectively inhibited mTOR expression and tumor growth in the xenograft tumor model of GC cells. We also showed that G9a regulates mTOR and cell proliferation and autophagy depending on its histone methylase activity. Using chromatin immunoprecipitation analysis, we found that mTOR expression was associated with promoter methylation and an enrichment for mono- and dimethylated histone 3 lys 9 (H3K9). G9a knockdown revealed an apparent decrease in H3K9 monomethylation levels, but no apparent change in H3K9 dimethylation levels at the mTOR promoter. These results indicate that G9a is a novel and promising therapeutic target for GC treatment.-Yin, C., Ke, X., Zhang, R., Hou, J., Dong, Z., Wang, F., Zhang, K., Zhong, X., Yang, L., Cui, H. G9a promotes cell proliferation and suppresses autophagy in gastric cancer by directly activating mTOR.

Correction: Inhibition of H3K9 Methyltransferase G9a Repressed Cell Proliferation and Induced Autophagy in Neuroblastoma Cells.

[This corrects the article DOI: 10.1371/journal.pone.0106962.].

The roles of sirtuins family in cell metabolism during tumor development.

Altering energy metabolism to meet the uncontrolled proliferation and metastasis has emerged as one of the most significant hallmarks in tumors. However, the detailed molecular mechanisms and regulatory actions underlying have not been fully elucidated. As a family of NAD+ dependent protein modifying enzymes, sirtuins (SIRT1-SIRT7) have multiple catalytic functions such as deacetylase, desuccinylase, demalonylase, demyristoylase, depalmitoylase, and/or mono-ADP-ribosyltransferase. They play important roles in regulating cell metabolism, especially in glucose and lipid metabolism, thereby exerting complex functions in either increasing or decreasing malignant characteristics in tumors. This review highlights the major function and its mechanisms of sirtuins in cellular metabolic reprogramming, such as glucose metabolism including aerobic glycolysis (the Warburg effect), oxidative phosphorylation (OXPHOS)/tricarboxylic acid (TCA) cycle and glutamine metabolism; lipometabolism including fatty acid metabolism, cholesterol metabolism, ketone body metabolism and acetate metabolism; as well as leucine metabolism and the urea cycle in tumorigenesis and cancer development.