Pseudogenes are generally considered "junk" DNA or "genomic fossils" generated during the evolution process that lack biological activity. However, accumulating reports indicate that pseudogenes have biological functions critical for cancer development. Experiments from the current study showed marked overexpression of the cytidine monophospho-N-acetylneuraminic acid hydroxylase pseudogene (CMAHP) in gastric cancer, which was associated with poor overall survival. However, the mechanisms underlying the activity of CMAHP in tumor development are largely unknown. Gene Set Enrichment Analysis (GSEA) revealed that CMAHP-correlated genes are significantly involved in epithelial-mesenchymal transition (EMT) and angiogenesis. Functional studies further confirmed that CMAHP mediates metastasis and angiogenesis in vitro and in vivo. Furthermore, CMAHP promoted cancer cell migration, invasion, and metastasis through Snail overexpression, which decreased ubiquitination mediated by NF-κB signaling. Angiogenesis is known to be induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation. CMAHP increased GM-CSF transactivation via promoting direct binding of c-Jun to the -1981/-1975 region of the GM-CSF promoter. Notably, CMAHP interacts with Histone H1.4 promoting histone acetylation to enhance c-Jun and RelA (p65) expression. Our collective findings provide novel evidence that CMAHP contributes to tumor progression and modulates metastasis and angiogenesis in gastric cancer.

Sea cucumbers Apostichopus japonicus (3.54 ± 0.01 g of wet weight) were exposed to five concentrations of dietary hexavalent chromium (Cr6+) [0 (control), 100, 200, 400, and 800 mg Cr6+/kg dry weight] amended with K2Cr2O7 for 30 days. The bioaccumulation and immune responses [antioxidant enzymes: superoxide dismutase (SOD) and catalase (CAT); hydrolytic enzymes: acid phosphatase (ACP) and alkaline phosphatase (AKP)] of sea cucumbers were subsequently evaluated. This study found that the order of Cr accumulation in the experimental tissues was respiratory tree > intestine > body wall. Significantly lower SOD activities occurred in the 400 mg/kg group compared to that in the control group. Higher dietary Cr6+ exposure (400 and 800 mg Cr6+/kg dry weight) did not negatively alter the CAT activities, but significantly inhibited CAT activities in 100 mg/kg group, compared to control group. ACP activities in groups 200, 400 and 800 mg/kg were significantly lower than those in control group, while no significant differences occurred in AKP activities among groups. The present study provides important information into the bioaccumulation and immune responses of the sea cucumber A. japonicus in response to chronic dietary Cr6+ exposure.

Capsella bursa-pastoris (L.) Medic. (CBP) is a cruciferous plant valuable in reducing fever, improving eyesight and calming the liver. This herb was recorded in the Compendium of Materia Medica for cataract treatment.

Merkel cell carcinoma is an aggressive skin cancer frequently caused by the Merkel cell polyomavirus (MCPyV). Since proliferation of MCPyV-positive MCC tumor cells strictly depends on expression of the virus-encoded T antigens (TA), these proteins theoretically represent ideal targets for different kinds of therapeutic approaches. Here we developed a cell-based assay to identify compounds which specifically inhibit growth of MCC cells by repressing TA expression. Applying this technique we screened a kinase inhibitor library and identified six compounds targeting glycogen synthase kinase 3 (GSK3) such as CHIR99021 as suppressors of TA transcription in MCC cells. Involvement of GSK3α and -β in the regulation of TA-expression was confirmed by combining GSK3A knockout with inducible GSK3B shRNA knockdown since double knockouts could not be generated. Finally, we demonstrate that CHIR99021 exhibits in vivo antitumor activity in an MCC xenograft mouse model suggesting GSK3 inhibitors as potential therapeutics for the treatment of MCC in the future.

The present research was performed to assess N-heteroaryl acetic acid salts' anticancer activity against the breast cancer cell in order to introduce new inhibitory agents for histone deacetylase.

Hypericum perforatum L. is a traditional Chinese medicine used to sooth the liver, relieve depression, reduce body temperature, reduce sweating, and stimulate lactation. HP was extracted from Hypericum perforatum L.

The objective of the present study was to investigate the effect of melatonin and L-thyroxine (T4) on the expression of various receptors, and some metabolic, reproductive, and gonadotropic hormones in letrozole-induced polycystic ovary syndrome (PCOS) in rats.

Poly(ADP-ribose) polymerases (PARP) act as DNA damage sensors that produce poly(ADP-ribose) (PAR) chains at double-strand breaks, facilitating the recruitment of repair factors. Cancers with homologous recombination defects are sensitive to small molecule PARP inhibitors. Despite PARP5B gene copy number changes in many cancers, the effects of this genetic alteration on tumor phenotype are largely unknown. To better understand this clinical finding, we characterized a PARP5B null mutation in a carcinogen-induced in vivo head and neck squamous cell carcinoma (SCC) model. Reduced PARP5B expression inhibited tumor growth, induced primary tumor differentiation and apoptosis, and inhibited cell proliferation and metastasis. Loss of PARP5B expression-induced ataxia telangiectasia and Rad3 related (ATR) activation and depleted the cancer stem cell fraction. PARP5B null tumor cells lacked 53BP1+ double-strand break foci, ATM activation, and p53 induction compared to PARP5B+/+ cancers. PARP5B null SCC expresses a multiprotein complex containing PML, pRPA, Rad50, Rad51, XRCC1, proliferating cell nuclear antigen (PCNA), and Mcm2, suggesting an HR-mediated repair mechanism at DNA replication foci. Low doses of etoposide combined with the PARP5B inhibitor XAV939 induced senescence and apoptosis in human SCC lines. NBS1 overexpression in these cells inhibited the effects of low-dose etoposide/XAV939 treatment. Our results indicate that PARP5B inhibition is new targeted cancer therapy.

Diabetic nephropathy (DN), is microvascular complication of diabetes causes to kidney dysfunction and renal fibrosis. It is known that hyperglycemia and advanced glycation end products (AGEs) produced by hyperglycemic condition induce myofibroblast differentiation and endothelial-to-mesenchymal transition (EndoMT), and exacerbate fibrosis in DN. Recently, we demonstrated that α2-antiplasmin (α2AP) is associated with inflammatory response and fibrosis progression.

Angiogenesis is the formation of new blood vessels from an existing vasculature through a series of processes such as activation, proliferation, and directed migration of endothelial cells. Angiogenesis is instrumental in the metastatic spread of tumors. Isopimpinellin, a furanocoumarin group of phytochemicals, is an anticarcinogenic agent. However, no studies have proven its antiangiogenic effects. The current study thus aimed to screen the antiangiogenic effect of isopimpinellin.

Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for lung adenocarcinoma (LUAD) harboring activating mutations, but patients ultimately develop acquired resistance. Circular RNAs are involved in EGFR-TKI resistance, while the role of hsa_circ_0005576 in the osimertinib resistance of LUAD remains unknown. In this study, we demonstrated that hsa_circ_0005576 could facilitate osimertinib-resistant LUAD cells. Briefly, knockdown of hsa_circ_0005576 not only suppressed the proliferation and promoted the apoptosis of resistant LUAD cells, but also increased their sensitivity to osimertinib. Mechanistically, hsa_circ_0005576, serving as an miRNA sponge, could directly interact with miR-512-5p and subsequently upregulate the miR-512-5p-targeted insulin-like growth factor 1 receptor. Rescue assays indicated that miR-512-5p inhibition could reverse the effects of hsa_circ_0005576 knockdown in LUAD cells resistant to osimertinib. Overall, our study revealed that hsa_circ_0005576 regulates proliferation and apoptosis through miR-512-5p/IGF1R signaling, which contributes further to the resistance of LUAD cells to osimertinib. In addition, this study provides a novel insight into the mechanisms underlying osimertinib resistance of LUAD.

Our previous data revealed that reduction of TASK-1 expression, as a consequence of exposure to 17β-estradiol, could participate in neuroprotective effects in N2A cells. However, it is unclear which estrogen receptor underlies these effects of 17β-estradiol.

Respiratory syncytial virus (RSV) is an important human pathogen that causes severe lower respiratory tract infections in young children, the elderly, and the immunocompromised, yet no effective treatments or vaccines are available. The precise mechanism underlying RSV-induced acute airway disease and associated sequelae are not fully understood; however, early lung inflammatory and immune events are thought to play a major role in the outcome of the disease. Moreover, oxidative stress responses in the airways play a key role in the pathogenesis of RSV. Oxidative stress has been shown to elevate cytosolic calcium (Ca2+) levels, which in turn activate Ca2+-dependent enzymes, including transglutaminase 2 (TG2). Transglutaminase 2 is a multifunctional cross-linking enzyme implicated in various physiological and pathological conditions; however, its involvement in respiratory virus-induced airway inflammation is largely unknown. In this study, we demonstrated that RSV-induced oxidative stress promotes enhanced activation and release of TG2 from human lung epithelial cells as a result of its translocation from the cytoplasm and subsequent release into the extracellular space, which was mediated by Toll-like receptor (TLR)-4 and NF-κB pathways. Antioxidant treatment significantly inhibited RSV-induced TG2 extracellular release and activation via blocking viral replication. Also, treatment of RSV-infected lung epithelial cells with TG2 inhibitor significantly reduced RSV-induced matrix metalloprotease activities. These results suggested that RSV-induced oxidative stress activates innate immune receptors in the airways, such as TLRs, that can activate TG2 via the NF-κB pathway to promote cross-linking of extracellular matrix proteins, resulting in enhanced inflammation.

Nucleic acid therapeutics have been attracting attention as novel drug discovery modalities for intractable diseases, including amyotrophic lateral sclerosis. This review provides an overview of the current status and prospects of antisense oligonucleotide treatment for amyotrophic lateral sclerosis. Recently, the results of a phase I/II study using the antisense oligonucleotides Tofersen to treat familial amyotrophic lateral sclerosis with superoxide dismutase 1 mutation have been reported. Intrathecal Tofersen administration resulted in a 36% reduction in superoxide dismutase 1 level in the cerebrospinal fluid. Another report described 2 patients with mutant superoxide dismutase 1 treated with an adeno-associated virus encoding a microRNA targeting superoxide dismutase 1. The first patient, who possessed the fast progressive mutant A5V, received a single intrathecal infusion. Although the patient died of respiratory arrest 16 months after treatment, autopsy findings showed a reduction of >90% in superoxide dismutase 1 level in the spinal cord. Clinical trials on antisense oligonucleotide therapies targeting other major amyotrophic lateral sclerosis-causative genes, fused in sarcoma and chromosome 9 open reading frame 72, are ongoing. To attenuate the pathology of TDP-43, strategies targeting regulators of TDP-43 (ataxin 2) and proteins downstream of TDP-43 (stathmin 2) by antisense oligonucleotides are being developed. The advent of nucleic acid therapeutics has enabled to specifically attack the molecules in the amyotrophic lateral sclerosis pathological cascade, expanding the options for therapeutic targets. ANN NEUROL 2022;91:13-20.

Irinotecan (CPT-11) is one of the main agents used to treat colorectal cancer; unfortunately, it is associated with increased intestinal mucositis developing. Luteolin has been shown to prevent damage induced by this chemotherapeutic in mice; thus, in this research, we have investigated luteolin's action mechanism in human intestinal epithelial cells. The potential of luteolin in reducing inflammation and oxidative stress induced by irinotecan in Caco-2 cells was evaluated by PCR through mRNA expression of inflammatory and oxidative genes and by ELISA at the protein level. To assess whether luteolin's ability to control irinotecan-induced damage occurs in a PPARγ dependent manner, experiments were performed on PPARγ downregulated cells. Irinotecan downregulated PPARγ expression and upregulated inflammatory and oxidative genes, while luteolin upregulated PPARγ, HO-1, SOD and decreased expression of IL-1β and iNOS. Interestingly, when the cells were co-stimulated with luteolin and irinotecan, the flavonoid reversed the inflammation and oxidative imbalance evoked by the chemotherapeutic. However, when these experiments were performed in cells downregulated for PPARγ, luteolin lost the capacity to increase PPARγ and reverse the effect of irinotecan in all tested genes, except by IL-1β. The present study showed that the protective effect of luteolin against irinotecan is PPARγ dependent.

Docosahexaenoyl difluorodeoxycytidine (DHA-dFdC) is an amide with potent, broad-spectrum antitumor activity. In the present study, DHA-dFdC's ability to induce immunogenic cell death (ICD) was tested using CT26 mouse colorectal cancer cells, an established cell line commonly used for identifying ICD inducers, as well as Panc-02 mouse pancreatic cancer cells.

Rearrangements of Janus kinase 2 (JAK2r) form a subtype of acute lymphoblastic leukaemia (ALL) associated with poor patient outcomes. We present a high-risk case of B-cell ALL (B-ALL) where retrospective mRNA sequencing identified a novel GOLGA4-JAK2 fusion gene. Expression of GOLGA4-JAK2 in murine pro-B cells promoted factor-independent growth, implicating GOLGA4-JAK2 as an oncogenic driver. Cells expressing GOLGA4-JAK2 demonstrated constitutive activation of JAK/STAT signalling and were sensitive to JAK inhibitors. This study contributes to the diverse collection of JAK2 fusion genes identified in B-ALL and supports the incorporation of JAK inhibitors into treatment strategies to improve outcomes for this subtype.

Pseudomonas aeruginosa forms surface-attached communities that persist in the face of antimicrobial agents and environmental perturbation. Published work has found that extracellular polysaccharide (EPS) production, regulation of motility, and induction of stress response pathways contribute to biofilm tolerance during such insults. However, little is known regarding the mechanism(s) whereby biofilm maintenance is regulated when exposed to such environmental challenges. Here, we provide evidence that the diguanylate cyclase YfiN is important for the regulation of biofilm maintenance when exposed to peroxide. We find that compared to the wild type (WT), static biofilms of the ΔyfiN mutant exhibit a maintenance defect, which can be further exacerbated by exposure to peroxide (H2O2); this defect can be rescued through genetic complementation. Additionally, we found that the ΔyfiN mutant biofilms produce less c-di-GMP than WT and that H2O2 treatment enhanced motility of surface-associated bacteria and increased cell death for the ΔyfiN mutant grown as a biofilm compared to WT biofilms. These data provide evidence that YfiN is required for biofilm maintenance by P. aeruginosa, via c-di-GMP signaling, to limit motility and protect viability in response to peroxide stress. These findings add to the growing recognition that biofilm maintenance by P. aeruginosa is an actively regulated process that is controlled, at least in part, by the wide array of c-di-GMP metabolizing enzymes found in this microbe. IMPORTANCE We build on previous findings that suggest that Pseudomonas aeruginosa utilizes c-di-GMP metabolizing enzymes to actively maintain a mature biofilm. Here, we explore how the diguanylate cyclase YfiN contributes to the regulation of biofilm maintenance during peroxide exposure. We find that mature P. aeruginosa biofilms require YfiN to synthesize c-di-GMP, regulate motility, and ensure viability during peroxide stress. These findings provide further evidence that the modulation of c-di-GMP in response to environmental signals is an important mechanism by which biofilms are maintained.

DNA topoisomerases regulate the topological state of DNA, relaxing DNA supercoils and resolving catenanes and knots that result from biologic processes, such as transcription and replication. DNA topoisomerase II (TOP2) enzymes achieve this by binding DNA and introducing an enzyme-bridged DNA double-strand break (DSB) where each protomer of the dimeric enzyme is covalently attached to the 5' end of the cleaved DNA via an active site tyrosine phosphodiester linkage. The enzyme then passes a second DNA duplex through the DNA break, before religation and release of the enzyme. However, this activity is potentially hazardous to the cell, as failure to complete religation leads to persistent TOP2 protein-DNA covalent complexes, which are cytotoxic. Indeed, this property of topoisomerase has been exploited in cancer therapy in the form of topoisomerase poisons which block the religation stage of the reaction cycle, leading to an accumulation of topoisomerase-DNA adducts. A number of parallel cellular processes have been identified that lead to removal of these covalent TOP2-DNA complexes, facilitating repair of the resulting protein-free DSB by standard DNA repair pathways. These pathways presumably arose to repair spontaneous stalled or poisoned TOP2-DNA complexes, but understanding their mechanisms also has implications for cancer therapy, particularly resistance to anti-cancer TOP2 poisons and the genotoxic side effects of these drugs. Here, we review recent progress in the understanding of the processing of TOP2 DNA covalent complexes, the basic components and mechanisms, as well as the additional layer of complexity posed by the post-translational modifications that modulate these pathways. SIGNIFICANCE STATEMENT: Multiple pathways have been reported for removal and repair of TOP2-DNA covalent complexes to ensure the timely and efficient repair of TOP2-DNA covalent adducts to protect the genome. Post-translational modifications, such as ubiquitination and SUMOylation, are involved in the regulation of TOP2-DNA complex repair. Small molecule inhibitors of these post-translational modifications may help to improve outcomes of TOP2 poison chemotherapy, for example by increasing TOP2 poison cytotoxicity and reducing genotoxicity, but this remains to be determined.

Phosphatidylinositol 3-kinase (PI3K) δ-specific inhibitors have been approved for the therapy of certain types of B cell lymphoma (BCL). However, their clinical use is limited by the substantial toxicity and lack of efficacy in other types of BCL. Emerging evidence indicates that PI3Kα plays important roles in the progression of B cell lymphoma. In this study, we revealed that PI3Kα was important for the PI3K signaling and proliferation in BCL cells. A novel clinical PI3Kα-selective inhibitor CYH33 possessed superior activity against BCL compared to the marketed PI3Kα-selective inhibitor Alpelisib and PI3Kδ-selective inhibitor Idelalisib. Though CYH33 was able to inhibit PI3K/AKT signaling in tested BCL cells, differential activity against proliferation was observed. Transcriptome profiling revealed that CYH33 down-regulated "MYC-targets" gene set in sensitive but not resistant cells. CYH33 inhibited c-MYC transcription in sensitive cells, which was attributed to a decrease in acetylated H3 bound to the promoter and super-enhancer region of c-MYC. Accordingly, CYH33 treatment resulted in phosphorylation and proteasomal degradation of the histone acetyltransferase p300. An unbiased screening with drugs approved or in clinical trials for the therapy of BCL identified that the clinical BET (Bromodomain and Extra Terminal domain) inhibitor OTX015 significantly potentiated the activity of CYH33 against BCL in vitro and in vivo, which was associated with enhanced inhibition on c-MYC expression and induction of cell cycle arrest and apoptosis. Our findings provide the rationale of combined CYH33 with BET inhibitors for the therapy of B cell lymphoma.