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Ginger-derived compounds are abundant sources of anticancer natural products. However, the anticancer effects of (E)-3-hydroxy-1-(4′-hydroxy-3′,5′-dimethoxyphenyl)-tetradecan-6-en-5-one (3HDT) have not been examined. This study aims to assess the antiproliferation ability of 3HDT on triple-negative breast cancer (TNBC) cells. 3HDT showed dose-responsive antiproliferation for TNBC cells (HCC1937 and Hs578T). Moreover, 3HDT exerted higher antiproliferation and apoptosis on TNBC cells than on normal cells (H184B5F5/M10). By examining reactive oxygen species, mitochondrial membrane potential, and glutathione, we found that 3HDT provided higher inductions for oxidative stress in TNBC cells compared with normal cells. Antiproliferation, oxidative stress, antioxidant signaling, and apoptosis were recovered by N-acetylcysteine, indicating that 3HDT preferentially induced oxidative-stress-mediated antiproliferation in TNBC cells but not in normal cells. Moreover, by examining γH2A histone family member X (γH2AX) and 8-hydroxy-2-deoxyguanosine, we found that 3HDT provided higher inductions for DNA damage, which was also reverted by N-acetylcysteine. In conclusion, 3HDT is an effective anticancer drug with preferential antiproliferation, oxidative stress, apoptosis, and DNA damage effects on TNBC cells. [ABSTRACT FROM AUTHOR]

The high frequency of chemotherapy resistance is ultimately responsible for clinical relapse in acute lymphoblastic leukemia (ALL). Nevertheless, the molecular mechanism relevant to glucocorticoid (GC) resistance remains ambiguous. Quantitative real-time polymerase chain reaction and Western blot were performed to detect the expressions of paraoxonase 2 (PON2), Bcl-2 and Bax. shRNA was used to knockdown PON2 expression in SUP-B15 and REH cell. CCK-8 and flow cytometry assay were conducted to monitor the changes of proliferation and apoptosis in ALL cells. The growth of ALL REH cells in vivo was determined using transplanted tumor model. This study was designed to identify GC resistance-associated genes by means of the transcriptome chip from the public Gene Expression Omnibus database, and preliminarily investigation of dexamethasone (DEX)-resistance mechanism in ALL. We disclosed that PON2 expression was elevated in ALL patients and especially higher in DEX-resistance ALL patients. Then, cell apoptosis assay suggested that silencing of PON2 dramatically promoted in DEX-resistant ALL cells apoptosis and the activity of Caspase 3 induced by DEX administration. In xenograft tumor model, PON2 knockdown significantly reduced DEX-resistant ALL cells growth in immunodeficient mice. Collectively, inhibition of PON2 may represent a novel method to restore the sensitivity of treatment-resistant ALL to GC-induced cell death. [ABSTRACT FROM AUTHOR]

Objective. To analyze the mechanism of LINC00461 regulating the recurrence of diffuse large B cell lymphoma (DLBCL) through microRNA (miR)-411-5p/BCL2 interacting protein 3 (BNIP3) pathway. Methods. DLBCL samples in TCGA and GSE12453 were used for differential analysis to find long noncoding RNA (lncRNA) related to DLBCL recurrence. The 4 DLBCL data with the highest and lowest expression levels of LINC00461 in the TCGA database were selected for GSEA enrichment analysis. The targeting relationships of miR-411-5p with LINC00461 and BNIP3 were verified by the dual luciferase report. Blood samples from DLBCL patients were used to analyze the correlation between miR-411-5p and LINC00461 or BNIP3. LINC00461, miR-411-5p, or BNIP3 was overexpressed or silenced by transfection, and a tumor-bearing nude mice model was constructed to detect their effects on proliferation and apoptosis. Results. The level of LINC00461 in DLBCL was significantly higher than that in normal cases, and the level in recurrence DLBCL was significantly higher than that in nonrecurrence. The enrichment analysis results showed that the function of LINC00461 was closely related to apoptosis. The results shown that miR-411-5p bound to LINC00461 and BNIP3 and was negatively correlated with LINC00461 and BNIP3 mRNA in blood of DLBCL patients. Suppressing the level of LINC00461 inhibited cell proliferation and induced apoptosis. The inhibition of LINC00461 or overexpression of miR-411-5p reduced the expression of BNIP3 protein, thereby inducing apoptosis at the in vivo and in vitro levels. Conclusion. LINC00461 may induce miR-411-5p to "sponge," thereby increasing the expression of BNIP3 protein, and exerting the function of inhibiting apoptosis and promoting DLBCL recurrence. [ABSTRACT FROM AUTHOR]

Objectives. The purpose of this study was to identify the molecular mechanism and prognosis-related genes of Jianpi Jiedu decoction in the treatment of hepatocellular carcinoma. Methods. The gene expression data of hepatocellular carcinoma samples and normal tissue samples were downloaded from TCGA database, and the potential targets of drug composition of Jianpi Jiedu decoction were obtained from TCMSP database. The genes were screened out in order to obtain the expression of these target genes in patients with hepatocellular carcinoma. The differential expression of target genes was analyzed by R software, and the genes related to prognosis were screened by univariate Cox regression analysis. Then, the LASSO model was constructed for risk assessment and survival analysis between different risk groups. At the same time, independent prognostic analysis, GSEA analysis, and prognostic analysis of single gene in patients with hepatocellular carcinoma were performed. Results. 174 compounds of traditional Chinese medicine were screened by TCMSP database, corresponding to 122 potential targets. 39 upregulated genes and 9 downregulated genes were screened out. A total of 20 candidate prognostic related genes were screened out by univariate Cox analysis, of which 12 prognostic genes were involved in the construction of the LASSO regression model. There was a significant difference in survival time between the high-risk group and low-risk group (p < 0.05). Among the genes related to prognosis, the expression levels of CCNB1, NQO1, NUF2, and CHEK1 were high in tumor tissues (p < 0.05). Survival analysis showed that the high expression levels of these four genes were significantly correlated with poor prognosis of HCC (p < 0.05). GSEA analysis showed that the main KEGG enrichment pathways were lysine degradation, folate carbon pool, citrate cycle, and transcription factors. Conclusions. In the study, we found that therapy target genes of Jianpi Jiedu decoction were mainly involved in metabolism and apoptosis in hepatocellular carcinoma, and there was a close relationship between the prognosis of hepatocellular carcinoma and the genes of CCNB1, NQO1, NUF2, and CHEK1. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) poses a growing threat to humans due to poor prognosis. Extract of stellera chamaejasme L. (ESC) is reported to inhibit metastasis of HCC. However, the underlying mechanism of ESC in regulating the progression of HCC needs to be further investigated. Methods: 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to measure cell proliferation. Flow cytometry was employed to check cell apoptosis. Transwell assay was conducted to assess the abilities of cell migration and invasion. The protein levels of proliferating cell nuclear antigen, cleaved caspase 3 (c-caspase 3), E-cadherin, janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), and phosphorylated STAT3 were detected by Western blot. The interaction between miR-134-5p and JAK1 was predicted by starBase, which was verified by the dual-luciferase reporter assay and RNA pull-down assay. The messenger RNA levels of miR-134-5p and JAK1 were determined by quantitative real-time polymerase chain reaction. Results: The results showed that the higher concentration or the longer time treatment of ESC led to the lower survival rate of HCC cells. Besides, ESC induced apoptosis and impeded migration and invasion of HCC cells. Moreover, downregulation of miR-134-5p inverted the effects of ESC-mediated repression on HCC progression. Further studies indicated that miR-134-5p targeted the 3'-untranslated region (3'UTR) of JAK1 and reversed JAK1-mediated impacts on HCC progression. Simultaneously, ESC inactivated JAK1/STAT3 pathway by regulating the expression of miR-134-5p. Conclusion: ESC suppressed HCC progression by upregulating the expression of miR-134-5p and blocking JAK1/STAT3 pathway. [ABSTRACT FROM AUTHOR]

In parallel with the prevalence metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in most countries. It features a constellation of simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even hepatocellular carcinoma. There are no approved drugs for effective management of NAFLD and NASH. Jianpi Huoxue formula (JPHX) mainly consists of Atractylodes macrocephal (Baizhu), Salvia miltiorrhiza (Danshen), Rasux Paeonia Alba (Baishao), Rhizoma Alismatis (Zexie), and Fructus Schisandrae Chinensis (Wuweizi), which may have beneficial effects on NAFLD. The aim of the study was to identify the effect of JPHX on NAFLD. A NAFLD model was induced by methionine-choline-deficient food (MCD) in Wistar rats and orally administered with simultaneous JPHX, once a day for 8 weeks. Hepatocellular injury, lipid profile, inflammation, fibrosis, and apoptosis were evaluated. The results showed that JPHX significantly decreased the abnormal serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels compared with the MCD model (P<0.05). Furthermore, JPHX protected MCD diet-fed rats from accumulation of hepatic triglycerides (TG) and total cholesterol (TC). Histological examination demonstrated that JPHX noticeably normalized the NAFLD activity score (NAS). Moreover, JPHX ameliorated liver inflammation by decreasing TNF-α levels and reduced collagen and matrix metalloproteinases in MCD diet-fed rats. In addition, JPHX prevented rats from MCD-induced cellular apoptosis, as suggested by TUNEL staining, and suppressed the activation of caspase 3 and 7 proteins. JPHX also inhibited the phosphorylation of JNK. In conclusion, JPHX exhibited a hepatoprotective effect against NAFLD in an MCD experimental model. [ABSTRACT FROM AUTHOR]

Although hepatitis B virus (HBV)-related cirrhosis and hepatocellular carcinoma (HCC) cause a sever health problem worldwide, the underlying mechanisms are still elusive. This study aimed to investigate the responses of different cell types isolated from HBV transgenic mice. A cross-sectional set of hepatocytes and oval cells were obtained from HBV transgenic and control mice. Flow cytometry, immunohistochemistry and microarray were applied to investigate the cell biology of the hepatocytes and oval cells. Our results showed that HBV induced the proliferation of both cell oval cells and hepatocytes, and induced cell death of HBV hepatocytes while had minimal effects on oval cells. Further molecular and pathways analysis identified some genes and signaling pathways may be responsible for the different responses between oval cells and hepatocytes. In addition, analyses of selectively ten genes by IHC staining in human samples were consistent with microarray data. In summary, HBV transgenic mice is a useful model for studying the biological behaviors of oval cells affected by HBV and HBV-cirrhosis. Also, our results help better understand the mechanisms of HBV induced cirrhosis, and provide novel progenitor markers or prognostic/therapeutic markers. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Ketoconazole induces apoptosis in HCC cells by triggering excessive mitophagy. • Downregulation of cyclooxygenase 2 (COX-2) is key in the induction of excessive mitophagy via the PINK1/Parkin axis. • HCC characterized by high COX-2 expression may benefit more from ketoconazole treatment than other subtypes. • Ketoconazole acts synergistically with sorafenib in the suppression of HCC growth in vitro and in vivo. Background & Aims Hepatocellular carcinoma (HCC) is a common cancer worldwide and remains a major clinical challenge. Ketoconazole, a traditional antifungal agent, has attracted considerable attention as a therapeutic option for cancer treatment. However, its mechanism of action is still not clearly defined. We aimed to evaluate the effect of ketoconazole on HCC and investigate the underlying mechanisms. Methods We examined the antitumor effect of ketoconazole on HCC cells, cell line-derived xenografts, and a patient-derived xenograft (PDX) model. Ketoconazole-induced mitophagy was quantified by immunofluorescence, immunoblotting and transmission electron microscopy analysis. We used mitophagy inhibitors to study the role of mitophagy on HCC cell death induced by ketoconazole. The role of cyclooxygenase-2 (COX-2 [encoded by PTGS2 ]) on ketoconazole-induced mitophagy was evaluated using gain- and loss-of-function methods. The synergistic effect of ketoconazole with sorafenib on HCC was measured in vivo and in vitro. Results Ketoconazole stimulated apoptosis in HCC cells by triggering mitophagy in vitro and in vivo. Mechanistically, ketoconazole downregulated COX-2, which led to PINK1 accumulation and subsequent mitochondrial translocation of Parkin (PRKN), and thereby promoted mitophagy-mediated mitochondrial dysfunction. Inhibiting mitophagy alleviated ketoconazole-induced mitochondrial dysfunction and apoptosis, supporting a causal role for mitophagy in the antitumor effect of ketoconazole. In the HCC PDX model, ketoconazole demonstrated a marked antitumor effect characterized by COX-2 downregulation, mitophagy activation, and apoptosis induction. Moreover, ketoconazole acted synergistically with sorafenib to suppress HCC xenograft growth in vivo. Conclusion Our results demonstrate a novel link between ketoconazole and mitophagy machinery, providing preclinical proof of concept for the use of ketoconazole in HCC treatment. Lay summary Hepatocellular carcinoma (HCC) is a common malignancy worldwide and remains a major clinical challenge. Our study reveals that ketoconazole, a broad-spectrum antifungal agent, activates PINK1/Parkin-mediated mitophagy by downregulating COX-2, consequently resulting in the acceleration of apoptosis and thereby inhibiting the growth of HCC. Furthermore, ketoconazole acts synergistically with sorafenib in the suppression of HCC growth in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Background/Aims: Cellular senescence, or permanent growth arrest, is known as an effective tumor suppressor mechanism that can be induced by different stressors, such as oncogenes, chemotherapeutics or cytokine cocktails. Previous studies demonstrated that the growth-repressing state of oncogene-induced senescent cells depends on argonaute protein 2 (Ago2)-mediated transcriptional gene silencing and Ago2/Rb corepression of E2F-dependent cell cycle genes. Cytokine-induced senescence (CIS) likewise depends on activation of the p16Ink4a/Rb pathway, and consecutive inactivation of the E2F family of transcription factors. In the present study, we therefore analyzed the role of Ago2 in CIS. Methods: Human cancer cell lines were treated with interferon-gamma (IFN-γ) and tumor necrosis factor (TNF) to induce senescence. Senescence was determined by growth assays and measurement of senescence-associated β-galactosidase (SA-β-gal) activity, Ago2 translocation by Ago2/ Ki67 immunofluorescence staining and western blot analysis, and gene transcription by quantitative polymerase chain reaction (qPCR). Results: IFN-γ and TNF permanently stopped cell proliferation and time-dependently increased SA-β-gal activity. After 24 – 48 h of cytokine treatment, Ago2 translocated from the cytoplasm into the nucleus of Ki67-negative cells, an effect which was shown to be reversible. Importantly, the proinflammatory cytokine cocktail suppressed Ago2-regulated cell cycle control genes, and siRNA-mediated depletion of Ago2 interfered with cytokine-induced growth inhibition. Conclusion: IFN-γ and TNF induce a stable cell cycle arrest of cancer cells that is accompanied by a fast nuclear Ago2 translocation and repression of Ago2-regulated cell cycle control genes. As Ago2 downregulation impairs cytokine-induced growth regulation, Ago2 may contribute to tissue homeostasis in human cancers. [ABSTRACT FROM AUTHOR]

Gemcitabine (GEM)‐based chemotherapy is a commonly used treatment for pancreatic cancer. However, acquired drug resistance, a major problem in pancreatic cancer treatment, causes a reduction in the survival rate of patients with cancer. In this study, we attempted to reveal the molecular mechanism of GEM resistance. Our data showed that GEM treatment inhibits cell growth, induces apoptosis, and activates autophagy via the AMP‐activated protein kinase (AMPK) pathway. The combination of GEM treatment and AMPK knockdown resulted in a dramatic increase of apoptosis and inhibition of autophagy. Additionally, inhibition of mammalian target of Rapamycin induced autophagy. Our findings show the potential therapeutic implications of the combined treatment with GEM and AMPK inhibitors for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that 5ɑ-androst-3β,5,6β-triol (Triol), a synthesized steroid compound, showed notable neuroprotective effect in cultured cortical neurons. In the present study, we explored whether and how Triol have neuroprotective effect on retinal ganglion cells (RGCs) in a chronic ocular hypertension (COH) rat model. COH model was produced by injecting superparamagnetic iron oxide micro-beads into the anterior chamber, and Triol was administrated (4.8 μg/100 g, i.p., once daily for 4 weeks). Immunohistochemistry experiments showed that in whole flat-mounted COH retinas, the number of CTB-labeled survival RGCs was progressively reduced, while TUNEL-positive signals were significantly increased from 1 to 4 weeks after the micro-bead injection. Triol administration significantly attenuated the reduction in the number of CTB-labeled RGCs, and partially reduced the increased number of TUNEL-positive signals in COH retinas. Furthermore, Triol administration partially reduced the levels of malondialdehyde (MDA) and reactive oxygen species (ROS), and significantly rescued the activities of mitochondrial respiratory chain complex (MRCC) I/II/III in COH retinas. Our results suggest that Triol prevents RGCs from apoptotic death in COH retinas by reducing the lipid peroxidation and enhancing the activities of MRCCs. [ABSTRACT FROM AUTHOR]

The combination of Endostatin ( ES) and Herpes Simplex Virus thymidine kinase ( HSV- TK) gene therapy is known to have antitumor activity in bladder cancer. The potential effect of ES and TK therapy in glioma has not yet been investigated. In this study, pTK-internal ribosome entry site ( IRES), pIRES- ES, and pTK- IRES- ES plasmids were constructed; pIRES empty vector served as the negative control. The recombinant constructs were transfected into human umbilical vein endothelial cells ( HUVECs) ECV304 and C6 rat glioma cell line. Ganciclovir ( GCV) was used to induce cell death in transfected C6 cells. We found that ECV304 cells expressing either ES or TK- ES showed reduced proliferation, decreased migration capacity, and increased apoptosis, as compared to untransfected cells or controls. pTK- IRES- ES/ GCV or pTK- IRES/ GCV significantly suppressed cell proliferation and induced cell apoptosis in C6 cells, as compared to the control. In addition, the administration of pIRES- ES, pTK- IRES/ GCV, or pTK- IRES- ES/ GCV therapy improved animal activity and behavior; was associated with prolonged animal survival, and a lower microvessel density ( MVD) value in tumor tissues of C6 glioma rats. In comparison to others, dual gene therapy in form of pTK- IRES- ES/ GCV had a significant antitumor activity against C6 glioma. These findings indicate combined TK and ES gene therapy was associated with a superior antitumor efficacy as compared to single gene therapy in C6 glioma. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is one of the most common tumors of the hematological system and remains incurable. Recent studies have shown that long noncoding RNA NORAD is a potential oncogene in a variety of tumors. However, the general biological role and clinical value of NORAD in MM remains unknown. In this study, we measured NORAD expression in bone marrow of 60 newly diagnosed MM, 30 post treatment MM and 17 healthy donors by real-time quantitative polymerase chain reaction (qPCR). The NORAD gene was knockdown by lentiviral transfection in MM cell lines, and the effects of NORAD on apoptosis, cell cycle and cell proliferation in MM cells were examined by flow cytometry, CCK8 assay, EDU assay and Western blot, and the differential genes after knockdown of NORAD were screened by mRNA sequencing, followed by in vivo experiments and immunohistochemical assays. We found that knockdown of NORAD promoted MM cell apoptosis, induced cell cycle G1 phase arrest, and inhibited MM cell apoptosis in in vivo and in vitro experiments. Mechanistically, NORAD plays these roles through the BMP6/P-ERK1/2 axis. We discuss a novel mechanism by which NORAD acts pro-tumorigenically in MM via the BMP6/P-ERK1/2 axis. [ABSTRACT FROM AUTHOR]

Neuropathic pain, caused by a lesion or dysfunction of the somatosensory nervous system, is a severe debilitating condition with which clinical treatment remains challenging. Jun activation domain-binding protein (JAB1) is a multifunctional protein that participates in several signaling pathways, controlling cell proliferation and apoptosis. However, the expression and possible function of JAB1 in the pathogenesis of neuropathic pain has not been elucidated. This study aimed to investigate the possible involvement of JAB1. Here, employing a neuropathic pain model induced by chronic constriction injury (CCI) on rats, we reported the role of JAB1 in the maintenance of neuropathic pain. By western blot, we found that CCI markedly up-regulated JAB1 expression in the dorsal root ganglion (DRG) and spinal cord. Immunofluorescent assay demonstrated that JAB1 was extensively localized in IB4-, CGRP- and NF200-positive neurons in the injured L5 DRG, and mainly co-localized with NeuN in spinal cord. In addition, we showed that CCI induced phosphorylation of p65 and JNK in vivo. Intrathecal injection of JAB1 siRNA significantly attenuated the CCI-induced JNK and p65 phosphorylation and alleviated both mechanical allodynia and heat hyperalgesia in rats. Taken together, these results suggested that JAB1 promotes neuropathic pain via positively regulating JNK and NF-κB activation. [ABSTRACT FROM AUTHOR]

To clarify the mechanisms of Nosema ceranae parasitism, we deep-sequenced both honey bee host and parasite mRNAs throughout a complete 6-day infection cycle. By time-series analysis, 1122 parasite genes were significantly differently expressed during the reproduction cycle, clustering into 4 expression patterns. We found reactive mitochondrial oxygen species modulator 1 of the host to be significantly down regulated during the entire infection period. Our data support the hypothesis that apoptosis of honey bee cells was suppressed during infection. We further analyzed genome-wide genetic diversity of this parasite by comparing samples collected from the same site in 2007 and 2013. The number of SNP positions per gene and the proportion of non-synonymous substitutions per gene were significantly reduced over this time period, suggesting purifying selection on the parasite genome and supporting the hypothesis that a subset of N. ceranae strains might be dominating infection. [ABSTRACT FROM AUTHOR]

Activated protein kinase C δ (PKC δ) associated with cardiac hypertrophy moves from the cytoplasm to the mitochondria and subsequently triggers the apoptotic signalling pathway. The underlying mechanisms remain unknown. The aim of the present study was to investigate whether mitochondrial translocation of PKC δ phosphorylates multiple sites of Bcl-2, resulting in an imbalance between Bcl-2 and Bak or Bax, thus enhancing the susceptibility of hypertrophic cardiomyocytes to angiotensin II (AngII)-induced apoptosis. Chronic pressure overload was induced by transverse aortic constriction (TAC) in rats. The apoptotic rate increased in hypertrophied cardiomyocytes. In AngII-treated hearts (10 nmol/L, 60 min), there was an increase in the number of TERMINAL deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL)-positive cells; PKC δ inhibition with 500 nmol/L δV1-1 for 60 min prevented the AngII-induced increase in apoptosis. In the hypertrophied myocardium, PKC δ expression increased, whereas that of Bcl-2 decreased compared with the synchronous control. Treatment of hearts with 10 nmol/L AngII for 60 min activated PKC δ and induced translocation of PKC δ to the mitochondria, where activated PKC δ facilitated the phosphorylation of Bcl-2 at serine-87 and serine-70 sites. The multisite phosphorylated Bcl-2 was released from the mitochondria, and exhibited reduced affinity for Bak and Bax. The imbalance between Bcl-2 and Bak/Bax induced the release of mitochondrial cytochrome c and then activated the caspase 3 apoptotic pathway during AngII stimulation (10 nmol/L, 60 min) of hypertrophied cardiomyocytes. Inhibition of PKC δ reduced these effects of AngII. The results suggest that PKC δ can counteract the anti-apoptotic effect of Bcl-2 and may promote cardiomyocyte apoptosis through multisite phosphorylation of Bcl-2 in hypertrophied cardiomyocytes. [ABSTRACT FROM AUTHOR]

Cylindromatosis (CYLD), a deubiquitinase and regulator of microtubule dynamics, has important roles in the regulation of inflammation, immune response, apoptosis, mitosis, cell migration and tumorigenesis. Although great progress has been made in the biochemical and cellular functions of CYLD, its role in animal development remains elusive. In this study, we identified Drosophila CYLD (dCYLD) as a negative regulator of the Hippo pathway in vivo. dCYLD associates and colocalizes with Hpo, a core component of the Hippo pathway, in the cytoplasm, and decreases Hpo activity through limiting its phosphorylation at T195. We also showed that dCYLD limits Hippo signal transduction as evidenced by decreasing phosphorylation and thereby increasing activity of Yki, the key downstream effector of the Hippo pathway. These findings uncover dCYLD as a negative regulator of the Hippo pathway and provide new insights into the physiological function of dCYLD in animal development. [ABSTRACT FROM AUTHOR]

Context: Protoporphyrin IX (PpIX), a well-known sensitizer that can enhance laser light or ultrasound induced cytotoxicity in photodynamic and sonodynamic therapy. However, PpIX alone could effectively cause anti-tumor effect and the underlying mechanisms are rarely been reported. Therefore, this study was to investigate the possible mechanism by which PpIX revealed anti-proliferative effect on murine leukemia L1210 cells. Materials and methods: The accumulation of PpIX in L1210 cells and normal peripheral blood mononuclear cells (PBMCs) was evaluated with flow cytometry. The subcellular localization of PpIX and apoptosis-inducing factor (AIF) translocation were determined by confocal microscope. The cell viability was examined by MTT assay. Annexin V-PE/7-AAD and DAPI staining were used to detect apoptotic cells. The mitochondrial membrane potential (MMP) changes were tested by rhodamine123 staining. DNA damage was measured by comet assay. Results: PpIX preferentially accumulated in L1210 cells compared to PBMCs and PpIX mainly located in the mitochondria of L1210 cells. PpIX at a concentration of 1 µg/ml or above exerted significant anti-tumor effect and the cell viability loss presented PpIX dose-dependent manner. Typical apoptotic features such as chromatin condensation were observed by DAPI staining. Annexin V-PE/7-AAD analysis showed 5 µg/ml PpIX could induce about 24% cell apoptosis, which was inhibited by cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore. In addition, the PpIX caused MMP loss, AIF translocation to nucleus and serious DNA damage were also suppressed by CsA. Conclusion: The results indicate mitochondria-dependent apoptosis were involved in PpIX caused cell damage on L1210 cells. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effects and underlying mechanisms of early and late subconjunctival injection of bevacizumab on the inhibition of corneal neovascularization (NV). Methods: Corneal NV was induced by closed eye contact lens wear followed by a silk suture tarsorrhaphy in rabbits. Weekly subconjunctival injections of bevacizumab (5.0 mg) for 1 month were started immediately (early treatment group) or 1 month after induction of corneal NV with continuous induction (late treatment group). The severity of corneal NV was evaluated. Immunostaining was used to evaluate the intracorneal diffusion of bevacizumab, and the existence of pericytes and smooth muscle cells around the NV. The expression of AM-3K, an anti-macrophage antibody, vascular endothelial growth factor (VEGF) with its receptors (VEGFR1 and VEGFR2), and vascular endothelial apoptosis were also evaluated. Western blot analysis was performed to quantify the expression level of VEGF, VEGFR1 and VEGFR2 on corneal epithelium and stroma in different groups. Results: Early treatment with bevacizumab inhibited corneal NV more significantly than late treatment. Intracorneal diffusion of bevacizumab was not different among different groups. Immunostaining showed pericytes and smooth muscle cells around newly formed vessels as early as 2 weeks after induction. Immunostaining and Western blot analysis showed that VEGF, VEGFR1, and VEGFR2 on corneal stroma increased significantly in no treatment groups and late treatment groups, but not in early treatment group. Bevacizumab significantly inhibited macrophage infiltration in the early but not late treatment group. Sporadic vascular endothelial apoptosis was found at 4 weeks in the late but not early treatment group. Conclusions: Early but not late injection of bevacizumab inhibited corneal NV. Late injection of bevacizumab did not alter macrophage infiltration, and can't inhibit the expression of VEGF, VEGFR1, and VEGFR2 on corneal vessels. The inhibition of corneal NV in early treatment group does not occur via vascular endothelial apoptosis. [ABSTRACT FROM AUTHOR]

Sodium/iodide symporter (NIS) acts as a vital role in regulation of iodide uptake in thyroid cancer. However, the efficient approach to increase NIS expression and the mechanism of NIS-mediated iodide uptake in thyroid cancer remain unclear. Small activating RNA (saRNA) was used to promote NIS expression. And the cell viability, apoptosis, and autophagy were detected using Cell count-kit 8 (CCK-8), Annexin V-FITC/PI double staining, and GFP-LC3 immunofluorescence assays, respectively. The protein levels of caspase 3, Bax, Bcl-2, ATG5, ATG12, LC3B Ⅱ to LC3B Ⅰ, Beclin 1, P62, AMPK, mTOR, P70S6K, actin, and phosphorylation of AMPK, mTOR, P70S6K were determined by western blotting. Moreover, a nude murine node with transplanted NC-dsRNA or NIS-482-transfected SW579 cells was used to examine the effect of NIS-mediated autophagy in vivo. And the levels of caspase 3 and ki67 were examined by immunohistochemical staining assay. saRNA mediated NIS mRNA and protein upregulated in SW579 cells. saRNA-mediated NIS expression inhibited cell proliferation, induced apoptosis and autophagy, and promoted iodide uptake in SW579 cells. Moreover, the effects of NIS on cells were enhanced by autophagy activator Rapamycin whereas reversed by autophagy inhibitor 3-Methyladenine (3-MA). For mechanism analysis, we found that NIS upregulation exerted the effects on cell proliferation, apoptosis, autophagy, and iodide uptake via regulating AMPK/mTOR pathway. We also demonstrated that saRNA-mediated NIS expression promoted iodide uptake in vivo. saRNA-mediated NIS expression acted as a critical role in increasing iodide uptake via AMPK/mTOR pathway in thyroid cancer. [ABSTRACT FROM AUTHOR]

There is increasing evidence that starvation induces autophagy, which may be protective during starvation, in an AMPK-dependent manner. Polysaccharides from Fuzi (FPS) reportedly have protective effects on nutrition-limited livers. The present study was designed to determine whether FPS protected H9c2 cells against starvation-induced cytotoxicity using an AMPK/mTOR-dependent mechanism. H9c2 cells were incubated in serum and glucose starvation media for 12 hours to establish a cell injury model. 3-Methyladenine (3MA, an autophagy inhibitor) was used to identify the exact role of autophagy in starvation. Cells were incubated with different FPS concentrations, and the cell injury levels, autophagy activity and AMPK/mTOR phosphorylation were measured. Adenine 9-β-D-arabinofuranoside (Ara-A, an AMPK inhibitor) and 5-amino-4-imidazole-carboxamide riboside (AICAR, an AMPK activator) were used to identify whether the AMPK/mTOR pathway was involved in FPS-mediated cardioprotection. We demonstrated that starvation decreased cell viability in a time-dependent manner, and 3MA-induced autophagy inhibition aggravated the reduced cell viability. FPS treatment attenuated the cell viability decrement and the starvation-induced decline in the mitochondrial membrane potential (MMP), and autophagy; also, the AMPK/mTOR pathways were activated during treatment. Ara-A treatment abolished the protective effect of FPS, while AICAR treatment had a similar effect to FPS. We conclude that autophagy attenuates starvation-induced cardiomyocyte death, and FPS increases autophagy activity to protect against starvation-induced cytotoxicity in H9c2 cells, likely through AMPK/mTOR pathway activation. [ABSTRACT FROM AUTHOR]

Arabinogalactan (ICPA) was isolated from the medicinal plant Ixeris chinensis (Thunb.) Nakai, and was used as the reducing agent to stabilize selenium nanoparticles (SeNPs). ICPA-decorated SeNPs (ICPA-SeNPs) were synthesized with Na2SeO3 and ICPA, and their average diameter was 82.6 ± 2.5 nm. ICPA-SeNPs had good dispersity in phosphate-buffered saline (PBS) with a hydrodynamic size of 156.2 ± 2.8 nm. They were stable in PBS solution with a zeta potential of −24.8 ± 0.6 mV. The anti-hepatoma activity of ICPA-SeNPs was investigated in vitro. ICPA-SeNPs significantly suppressed the growth of SMMC-7721 and HepG2 hepatoma cells. They entered SMMC-7721 cells via energy- and caveolae-dependent endocytosis. ICPA-SeNPs were able to increase reactive oxygen species levels, reduce mitochondrial membrane potential, and increase caspase-3 expression in SMMC-7721 cells, which led to the apoptosis of SMMC-7721 cells. They also arrested the cell cycle of SMMC-7721 cells in the S phase. These findings indicate that ICPA could enhance the stability of SeNPs and inhibit SMMC-7721 cell proliferation via the mitochondrial pathway. ICPA-SeNPs could be developed as an antitumor agent for hepatocellular carcinoma treatment. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate the effect of neuregulin 1β (NRG1β) on the neuronal apoptosis and the expressions of Bcl-2 and Bax proteins in experimental dementia model rats. Methods: Thirty adult healthy male Wistar rats were randomly divided into control group, model group and treated group consisting of 10 rats, respectively. The experimental dementia models were established by injecting beta-amyloid protein 1–40 (Aβ1–40) stereotactically into the left lateral ventricle, and treated by injecting NRG1β into right lateral ventricle. The cognitive capacity of rats was evaluated with Y-electric maze. The neuronal apoptosis was counted by TUNEL assay. The expressions of Bcl-2 and Bax were determined with immunohistochemistry assay and double immunofluorescence labeling. Results: The cognitive ability in model group rats decreased, along with the number of neuronal apoptosis and the expressions of Bcl-2 and Bax increased significantly than those in control group (P <0.05). After treatment with NRG1β, the cognitive ability of rats improved, the number of neuronal apoptosis reduced and the expression of Bcl-2 increased while Bax decreased significantly than those in model group (P <0.05). Conclusion: NRG1β could inhibit neuronal apoptosis by regulating the expressions of Bcl-2/Bax to improve the capacity of learning and memory in experimental dementia rats. [Copyright &y& Elsevier]

An increasing body of evidence suggests that apoptosis of structural cells in the lung might be an important upstream event in the pathogenesis of chronic obstructive pulmonary disease (COPD). AP-2α is one of the important transcription factors involved in the modulation of apoptosis in carcinogenesis and idiopathic-dilated cardiomyopathy. The relationship between AP-2α and apoptosis in COPD remains to be elucidated. The aim of the present study was to investigate the expression of AP-2α in the lung tissues of rats with COPD induced by smoking and its possible protective effect on cigarette smoke extract (CSE) induced endothelial cell apoptosis. Sprague-Dawley rats ( n = 24) were randomly assigned to normal and COPD groups. The COPD group was exposed to smoke from 20 commercial unfiltered cigarettes for 80 d before morphological assessment of the lung tissue was performed. The expression of AP-2α in lung tissues was measured by Western blotting. To demonstrate the relationship between apoptosis and AP-2α, in vitro cell experiments were carried out. Cells were treated with different concentrations of CSE before proliferation was measured by MTT. Apoptosis was then determined by Hoechst staining and the expression of cleaved caspase-3 and AP-2α by Western blotting over time following treatment with 5% CSE. Cells were then infected with an AP-2α adenovirus vector and the expression of cleaved caspase-3 and AP-2α was compared to the control groups by Western blotting. The COPD group showed larger air spaces and significant decrease of FEV/FVC compared with the rats in the control group ( P<0.05). The expression of AP-2α was significantly higher in the lung tissue of rats with COPD compared with those of controls ( P<0.05). In the ECV304 cells, CSE induced apoptosis ( P<0.01) and caspase-3 activation in a time-dependent manner and reduced the cell proliferation rate in a dose-dependent manner ( P<0.005). Moreover, 5% CSE treatment increased endogenous AP-2α protein expression. AP-2α overexpression inhibited 5% CSE-induced cell apoptosis and activated caspase-3 expression ( P<0.05) AP-2α protects ECV304 cells against CSE-induced apoptosis and may play an important role in smoking induced-apoptosis in COPD. [ABSTRACT FROM AUTHOR]

Abstract: Multiple myeloma is an incurable hematological malignancy. Different studies demonstrated the occurrence of genetic and epigenetic alterations in multiple myeloma. Histone lysine methylation has emerged as a central epigenetic change in the organization of eukaryotic chromatin with far-reaching implications for the regulation of cell proliferation, cell-type differentiation, gene expression, genome stability, overall development, and genesis of cancer. Triptolide is the principal active ingredient in extracts from the Chinese herb Tripterygium wilfordii Hook.F (TwHF), and numerous studies have elucidated its antitumor property. Our experiments discovered that triptolide inhibited the proliferation of multiple myeloma cell line U266 in a time- and dose-dependent manner, induced G2/M cell cycle arrest and caspase-dependent apoptosis. Triptolide could decrease the expression of histone H3K4, H3K27 and H3K36 trimethylation in parallel with histone methyltransferases SMYD3, EZH2 and NSD1 respectively, which possibly was the anti-myeloma mechanism of triptolide. [ABSTRACT FROM AUTHOR]

Abstract: Gambogic acid (GA), a major active component of gamboge, exhibits potent anticancer activity in many kinds of cancer cells. However, the anticancer mechanism of GA is not clearly understood. Here we showed that GA could cause growth inhibition, induce the G0/G1 phase cell cycle arrest and apoptosis in human chronic myelogenous leukemia cell line K562 cells. Since steroid receptor coactivator-3 (SRC-3), overexpressed in many human malignancies including leukemia, is a central target for cancer therapy, we also explored the effects of GA on SRC-3 and SRC-3-regulated gene products in K562. GA treatment downregulated the expression of SRC-3 and then inhibited the activity of Akt kinase and its downstream targets p70 S6 kinase 1 (S6K1) and glycogen synthase kinase 3β (GSK3β) without changes in total protein levels of these three proteins, which thus influenced the expression of the apoptosis related gene Bcl-2 in K562 cells. These results suggest that GA might exhibit its strong antitumor effects via the interruption of SRC-3. [Copyright &y& Elsevier]

Gambogic acid, the main active compound of gamboge resin of Garcinia hanburryi, has recently exhibited marked antitumour potency on solid tumours of various derivations. We demonstrate here that gambogic acid also present powerful antileukaemic potency through both growth arrest and apoptosis induction in Jurkat cells, which was accompanied by typical apoptotic morphological changes and sharp decreased expression of Bcl-xL and Bcl-2. Furthermore, nucleophosmin, recently demonstrated to be mutated and aberrantly localized in the cytoplasm of leukaemia blasts in a high proportion of patients with acute myeloid leukaemia, was over-expressed in Jurkat cells. As the sole site of nucleocytoplasmic communication, the protein components of nuclear pore complex, such as NUP98, NUP88, NUP214 complex, were also deregulated in Jurkat cells. Especially, NUP98 was found to distribute mainly at the cell membrane, while NUP88 and NUP214 situated not just at the nuclear envelope, but also in the cytoplasm. However, in vitro treatment with gambogic acid resulted in significantly reduced expression of nucleophosmin and all three nucleoporins in a dose-dependent manner. Moreover, most of NUP88 and NUP214 nucleoporins were relocated to the nuclear rim in the gambogic acid-treated cells. These results suggest that the fact that nucleophosmin and some nucleoporins might act as new targets of gambogic acid, correlates well with the sensitivity to gambogic acid, as well as the rate of apoptosis induced by gambogic acid. Mechanisms that regulate nucleocytoplasmic transport of proteins may provide novel opportunities for drug development. [ABSTRACT FROM AUTHOR]

Abstract: Purpose/Objective. : To investigate whether exogenous PUMA expression suppresses the growth of drug-resistant choriocarcinoma cells and sensitizes them to chemotherapeutic agents. Methods. : An adenovirus expressing PUMA (Ad-PUMA), alone or in combination with chemotherapeutic agents( 5-FU, vp16, MTX), was used to treat drug-resistant choriocarcinoma cells jeg-3/vp16 and parental jeg-3. The growth inhibitory and proapoptotic effects of Ad-PUMA both in vitro and in vivo were examined. The mechanisms of PUMA-mediated growth suppression and apoptosis were investigated by an analysis of caspase 3 activation and the change of mitochondrial membrane potential. The levels of PUMA, p53 and caspase 3 were detected by Western blotting. Result. : PUMA was expressed lower in jeg-3/vp16 than in jeg-3. jeg-3/vp16 responded much less sensitively to 5-FU and vp16 treatment than jeg-3, though PUMA was up-regulated in both cells. Exogenous PUMA expression resulted in potent growth suppression of jeg-3/vp16 and jeg-3 through induction of apoptosis. Ad-PUMA sensitized jeg-3 and jeg-3/vp16 to chemotherapeutic agents. When Ad-PUMA 10MOI and 5-FU, vp16 or MTX were combined respectively, IC50 of drugs decreased by 8.66-, 18.66- and 13.06-fold compared with those treated by anticancer drugs alone in jeg-3/vp16, while in jeg-3, IC50 decreased only by 1.80-, 1.78- and 2.76-fold. Ad-PUMA restored the sensitivity of choriocarcinoma cells to chemotherapeutic agents by enhancing apoptosis induced by anticancer drugs. Similar results could be observed in vivo. Xenograft tumors were inhibited by Ad-PUMA or vp16. In the drug-resistant group, the inhibitory rate increased from 14.57% to 78.93% in vp16 and vp16 combined with Ad-PUMA subgroups. While in the parental group, the inhibitory rate increased but slightly, from 66.39% to 71.56%. Conclusion. : PUMA is an important player in the therapeutic responses to chemotherapeutic agents of choriocarcinoma cells. In addition to its role in inhibiting tumor growth, low dose of Ad-PUMA significantly restored the sensitivity of choriocarcinoma cells to chemotherapeutic agents in vitro and in vivo. Exogenous PUMA is potentially useful as a sensitizer in treating drug-resistant choriocarcinoma. [Copyright &y& Elsevier]

Abstract: In this research, we investigated striatal neurogenesis in 3-, 6-, 12-, and 18-month-old rats after cerebral ischemic injury. All rats were subjected to a 20-min middle cerebral artery occlusion (MCAO), given 5′-bromodeoxyuridine (BrdU, 30 mg/kg, i.p.) once daily during days 4–7 and sacrificed 2 weeks after MCAO. Neurogenesis was assessed with double immunohistochemical/immunofluorescence labeling of BrdU and doublecortin (DCX), microtubule-associated protein 2 (MAP-2), or 67-kDa glutamic acid decarboxylase (GAD67). In 6-, 12-, and 18-month-old rats, the numbers of nestin+, BrdU+–DCX+ (a marker of newborn neuronal progenitors/immature neuron), BrdU+–MAP-2+ (a marker of newborn mature neuron), and BrdU+–GAD67 + (a marker of newborn GABAergic neuron) cells decreased dramatically in the ipsilateral striatum to MCAO compared with that in 3-month-old rats. The results indicated that stroke-induced striatal neurogenesis still existed in aging rats. However, the capacity of neurogenesis in older rats was considerably lower than that in young adults. Meanwhile, the apoptosis of neural precursors and immature neurons, indicated by double labeling of active caspase-3 and nestin/DCX/Tuj-1(β-tubulin III)/CRMP-4 (collapsin response-mediated protein-4), increased noticeably in the ipsilateral striatum of older rats. Taken together, the results suggested that aging-related attenuation of ischemia-induced striatal neurogenesis might be related to decrease of neural precursors and increase of apoptosis of newborn neurons. [Copyright &y& Elsevier]

Abstract: Mitochondrial thioredoxin (mtTrx) can be oxidized in response to inducers of oxidative stress; yet the functional consequences of the oxidation have not been determined. This study evaluated the redox status of mtTrx and its association to oxidant-induced apoptosis. Results showed that mtTrx was oxidized after exposure to peroxides and diamide. Overexpression of mtTrx protected against diamide-induced oxidation and cytotoxicity. Oxidation of mtTrx was also achieved by knocking down its reductase; and lead to increased susceptibility to cell death. The data indicate that the redox status of mtTrx is a regulatory mechanism underlying the vulnerability of mitochondria to oxidative injury. [Copyright &y& Elsevier]

Abstract: Mitochondrial oxidative stress plays important roles in aging and age-related degenerative disorders. The newly identified mitochondrial thioredoxin (mtTrx; Trx2) is a key component of the mitochondrial antioxidant system which is responsible for the clearance of reactive intermediates and repairs proteins with oxidative damage. Here, we show that in cultured SH-SY5Y human neuroblastoma 1cells, overexpression of mtTrx inhibited apoptosis and loss of mitochondrial membrane potential induced by a chemical oxidant, tert-butylhydroperoxide (tBH). The effects of calcium ionophore (Br-A23187) were not affected by mtTrx, suggesting the protection was specific against oxidative injury. The mitochondrial glutathione pool was oxidized by tBH, and this oxidation was not inhibited by increased mtTrx. Consequently, the antioxidant function of mtTrx is not redundant, but rather in addition, to that of GSH. Mutations of Cys90 and Cys93 to serines rendered mtTrx ineffective in protection against tBH-induced cytoxicity. These data indicate that mtTrx controls the mitochondrial redox status independently of GSH and is a key component of the defensive mechanism against oxidative stress in cultured neuronal cells. [Copyright &y& Elsevier]

Defines the changes in the redox state of glutathione and thioredoxin that occur as cells progress from a proliferating state to a more differentiated state and to apoptosis. Expression of the redox state; Redox reactions involving thioredoxin; Potential for cellular regulation via thioredoxin and glutathione redox.

Circular RNA ABCB10 (circ-ABCB10) modulates cellular functions and microRNA (miR)-1271 in epithelial ovarian cancer (EOC). The present study aimed to investigate the interaction between circ-ABCB10 and miR-1271 in regulating EOC cellular function and the calpain small subunit 1 (Capn4)/Wnt/β-catenin signaling pathway. circ-ABCB10 and miR-1271 expression levels were detected in EOC cells (OVCAR3, UWB1.289, SKOV3 and CAOV3) and normal ovarian epithelial cells (IOSE80) via reverse-transcription quantitative PCR. SKOV3 cells were transfected with control short hairpin (sh)RNA plasmids, control inhibitor, circ-ABCB10 shRNA plasmids and miR-1271 inhibitor. UWB1.289 cells were transfected with control overexpression plasmids, control mimic, circ-ABCB10 overexpression plasmids and miR-1271 mimic. Subsequently, cell proliferation, apoptosis, invasion and the Capn4/Wnt/β-catenin signaling pathway were assessed. In addition, a luciferase activity assay was performed. circ-ABCB10 expression was significantly increased in OVCAR3, SKOV3 and CAOV3 cells compared with IOSE80 cells, but was not significantly altered in UWB1.289 cells. miR-1271 expression was significantly decreased in OVCAR3, UWB1.289, SKOV3 and CAOV3 cells compared with IOSE80 cells. In both SKOV3 and UWB1.289 cells, circ-ABCB10 negatively regulated miR-1271, whereas miR-1271 did not affect circ-ABCB10. Furthermore, circ-ABCB10 enhanced cell proliferation, invasion and the Capn4/Wnt/β-catenin signaling pathway, but inhibited cell apoptosis, whereas miR-1271 suppressed cell proliferation, invasion and the Capn4/Wnt/β-catenin signaling pathway, but facilitated cell apoptosis. Moreover, miR-1271 attenuated the proproliferative, proinvasive and antiapoptotic effects of circ-ABCB10, and reversed the positive regulation of circ-ABCB10 on the Capn4/Wnt/β-catenin signaling pathway. Besides, the luciferase activity assay indicated that circ-ABCB10 directly bound to miR-1271. In conclusion, the present study indicated that circ-ABCB10 promoted cell proliferation and invasion, and suppressed apoptosis by regulating the miR-1271-mediated Capn4/Wnt/β-catenin signaling pathway in EOC. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) is a myeloid neoplasm accounts for 7.6% of hematopoietic malignancies. AML is a complex disease, and understanding its pathophysiology is contributing to the improvement in the treatment and prognosis of AML. In this study, we assessed the expression profile and molecular functions of CCAAT enhancer binding protein gamma (CEBPG), a gene implicated in myeloid differentiation and AML progression. Methods: shRNA mediated gene interference was used to down-regulate the expression of CEBPG in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. Genes and pathways affected by knockdown of CEBPG were identified by gene expression analysis using RNA-seq. One of the genes affected by knockdown of CEBPG was Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), a known repressor of translation. Knockdown of EIF4EBP1 was used to assess its potential role in AML progression downstream of CEBPG. Results: We explored the ChIP-Seq data of AML cell lines and non-AML hematopoietic cells, and found CEBPG was activated through its distal enhancer in AML cell lines. Using the public transcriptomic dataset, the Cancer Cell Line Encyclopedia (CCLE) and western blotting, we also found CEBPG was overexpressed in AML. Moreover, we observed that CEBPG promotes AML cell proliferation by activating EIF4EBP1, thus contributing to the progression of AML. These findings indicate that CEBPG could act as a potential therapeutic target for AML patients. Conclusion: In summary, we systematically explored the molecular characteristics of CEBPG in AML and identified CEBPG as a potential therapeutic target for AML patients. Our findings provide novel insights into the pathophysiology of AML and indicate a key role for CEBPG in promoting AML progression. [ABSTRACT FROM AUTHOR]

Objective To analyze the role of peroxisome proliferator-activated receptors ( PPAR- y ) expression in P. acnes-induced pyroptosis, cell proliferation and apoptosis in human keratinocytes (HaCaT) so as to provide a new theoretical basis for clinical treatment. Methods Expression patterns of PPAR- y in acne and normal skin tissues were evaluated using IHC. By lentiviral transfection, PPAR-y was upregulated in HaCaT cells, and the expression of PPAR-y was verified by Western blot. ELISA was performed to analyze the levels of P. acnes-induced pyroptotic-associated inflammatory factors IL-1p and IL-18. EdU assay and flow cytometry were used to detect the cell proliferation and apoptosis ability. Western blot was used to determine the levels of NLR family pyrin domain containing 3 (NLRP3), cysteinyl aspartate specific proteinase-1 (caspase-1), Gasdermin D (GSDMD) and PPAR-y expression. Results PPAR-y expression was significantly decreased in acne (P < 0.05). Compared with the control, the P. acnes-induced pyroptotic-associated inflammatory factors IL-ip and IL-18 were increased ( P < 0.01 ), the pyroptotic-associated proteins were increased significantly ( P < 0.05 ) . After treatment with P. acnes, the up-regulated PPAR-y reduced the expression of IL-ip and IL-18 and HaCaT cell apoptosis, promoted the cell proliferation, up-regulated the expression of NLRP3, Caspase-1 and GSDMD in human keratinocytes all in a statistically significant way (all P < 0.05). Conclusion PPAR-y can effectively regulate P. acnes-induced pyroptosis, cell proliferation and apoptosis in human keratinocytes. [ABSTRACT FROM AUTHOR]

Cooking of foods and the burning of biomass and fossil fuels in stoves are the main sources of cooking fumes, with carbon black and polycyclic aromatic hydrocarbons as main components. The toxicity of carbon black and polycyclic aromatic hydrocarbons has been well studied individually, but the combined toxicity is much less understood. Carbon black can adsorb benzo(a)pyrene to form a complex which displays an altered physical form which in this study has been constructed to simulate particles in the cooking fumes and explore the combined toxic effect on rat alveolar macrophages. The complex-induced cell apoptosis and blocked cell autophagy flux compared with both individually. The mechanism of toxicity may be by intracellular reactive oxygen species generation, impairing the mitochondrial membrane potential and activating apoptosis signaling pathways. [ABSTRACT FROM AUTHOR]

Diabetes is associated with neurological complications, and accumulated evidence shows that biological pathways in diabetes are targeted by noncoding RNA transcripts. In this study, the role of long intergenic noncoding RNA (lincRNA) p21/microRNA‐221 (miR‐221)/fructooligosaccharide (FOS) axis was investigated in the mice with diabetes treatment. The streptozotocin‐induced diabetic mouse model was established. The learning ability and the pathological changes in mice were analyzed. After that, the interaction among miR‐221, lincRNA p21, and FOS was explored and verified. The subcellular location of lincRNA p21 was identified. Finally, the cell cycle and apoptosis of the hippocampus neurons were measured. In the diabetic mice, the levels of blood glucose were higher and the leaning abilities were inhibited. miR‐221 was highly expressed in the diabetic mice whereas lincRNA p21 and FOS were poorly expressed. miR‐221 could bind with both lincRNA p21 and FOS. miR‐221 silencing or lincRNA p21 overexpression in the diabetes mice reduced the cell apoptosis rate, and the expression of Bax and cleaved Caspase‐3, whereas increase the Bcl‐2 expression. Overexpression of lincRNA p21 promotes FOS expression by binding to miR‐221, thereby, inhibiting hippocampal neuron apoptosis in diabetic mice. This may offer potential targets for diabetes. [ABSTRACT FROM AUTHOR]

Abstract Background Androgen has been implicated in aging-related cardiac remodeling, but its precise role in aging heart remains controversial. We aimed to investigate the role of testosterone in the development of aging-related cardiac remodeling and the mechanisms involved. Methods Wild type and Axl knockout mice (Axl−/−) were randomized into three groups: the young group (n = 30, 3 months old), the aging group (n = 30, 18 months old), the testosterone undecanoate treatment group (TU, n = 30, 18 months old). Mice in the TU group were given testosterone undecanoate (39 mg/kg) by subcutaneous injection on the back at fifteen-months-old, once a month, a total of three times. The old group received solvent reagent (corn oil) by the same method. Results The aging mice exhibited a decrease in serum testosterone, and Gas6 levels and an increase in apoptosis, and manifested cardiac fibrosis. Testosterone injection to wild type mice increased the levels of testosterone and Gas6 in serum and decreased cardiac apoptosis and fibrosis. Axl−/−mice receiving testosterone injection exhibited no obvious improvement in cardiac remodeling although the levels of testosterone and Gas6 in serum elevated. Conclusions These data indicated that testosterone replacement therapy (TRT) alleviates cardiac fibrosis and apoptosis, at least in part by enhancing Gas6 expression. Moreover, deletion of Axl disables testosterone, which indicated that Axl is an important downstream regulator of testosterone. TRT would improve aging-related cardiac remolding via Gas6/Axl signaling pathway, implicating its therapeutic potential to treat aging-related heart disease. Highlights • Testosterone decreases cardiomyocyte apoptosis in aging mice. • Testosterone ameliorates cardiac fibrosis in aging mice. • Testosterone increases the level of Gas6. • Testosterone protects from cardiac aging in a Gas6/Axl dependent manner. [ABSTRACT FROM AUTHOR]

Epilepsy is associated with increased morbidity and mortality together and places a large financial burden on individuals and society. To evaluate the anticonvulsant action of protodioscin (PDSN) in experiments with animals with pilocarpine-induced convulsions. We assessed the activity of PDSN in pilocarpine induced seizures in combination with different agents which are acting via diverse receptors, such as atropine, memantine, nimodipine, diazepam, and flumazenil, to determine the exact receptors responsible for the action of PDSN. Furthermore, the level of antioxidant markers was investigated in the cerebellum and cerebral cortex in mice to define the antioxidant action of PDSN. The effects of PDSN on proapoptotic markers (i.e., Bcl-2, Bax, and caspase-3) was investigated via western blot analysis. PDSN significantly enhanced latency to the first convulsion and survival compared to the group treated with pilocarpine alone. Moreover, PDSN improved animal survival, and subjects experiencing no convulsions. Striatal glutamate and aspartate levels were not modified, and gamma amino butyric acid (GABA) levels increased, as a result of treatment with PDSN. The results suggest that the anticonvulsive action of PDSN is dependent on inhibitory amino acids. PDSN treatment also significantly decreased nitrite levels in the blood and brain cortex compared to the normal control. In the western blot analysis, PDSN exerted its neuroprotective effect via the upregulation of Bcl-2 and downregulation of Bax and caspase-3. The results of this study suggest that PDSN exerts neuroprotective effects via multiple mechanisms. [ABSTRACT FROM AUTHOR]

The lungs are highly susceptible to injury, including ischemia/reperfusion (I/R) injury. Pulmonary I/R injury can occur when correcting conditions such as primary pulmonary hypertension, and is also relatively common after lung transplantation or other cardiothoracic surgery. Methods to reduce pulmonary I/R injury are urgently needed to improve outcomes following procedures such as lung transplantation. Remote liver ischemic preconditioning (RLIPC) is an effective cardioprotective measure, reducing damage caused by subsequent cardiac I/R injury, but little is known about its potential role in pulmonary protection. Here, we analyzed the efficacy and mechanistic basis of RLIPC in a rat model of pulmonary I/R injury. RLIPC reduced lung I/R injury, lessening structural damage, inflammatory cytokine production and apoptosis. In addition, RLIPC preserved pulmonary function compared to controls following lung I/R injury. RLIPC stimulated phosphorylation of pulmonary STAT3, a component of the SAFE signaling pathway, but not phosphorylation of RISK pathway signaling proteins. Accordingly, STAT3 inhibition using AG490 eliminated the pulmonary protection afforded by RLIPC. Our data demonstrate for the first time that RLIPC protects against pulmonary I/R injury, via a signaling pathway requiring STAT3 phosphorylation. [ABSTRACT FROM AUTHOR]

An increasing number of studies have focus upon β-adrenergic receptor blockers and their anti-tumor effects. However, the use of Carvedilol (CVD), the third generation β-AR blocker, has not been explored for use against T-ALL. In this study, the level of β-ARs was explored in pediatric T-ALL patients. Moreover, the antitumor effects of CVD against T-ALL were assessed in vitro and in vivo , and the underlying mechanisms were investigated. The viability of T-ALL cells following CVD treatment was detected using a CCK-8 assay, and the apoptotic and cell cycle effects were measured using flow cytometry. The protein levels of β-ARs, cAMP, Epac, JAK2, STAT3, p-STAT3, PI3K, p-PI3K, AKT, p -AKT, mTOR, cyclin D1, PCNA, and cleaved caspase-3 were assessed by Western blotting. In vivo experiments were used to investigate the effect of CVD on T-ALL growth in mice. The results indicated that β-ARs were highly expressed in the newly diagnosed T-ALL cells when compared to those in the control group (P < 0.05). In vitro , CVD significantly inhibited T-ALL cell viability, promoted apoptosis and blocked the G0/G1 phase of cell cycle. After CVD treatment, the protein levels of β-ARs, cAMP, Epac, PI3K, p-PI3K, AKT, p -AKT, mTOR, JAK2, STAT3, p-STAT3, cyclin D1 and PCNA were significantly downregulated (P < 0.05); whereas cleaved caspase-3 was significantly upregulated (P < 0.05). In vivo , the volume and weight of the xenograft tumors were significantly decreased in the CVD group (P < 0.05). CVD promoted xenograft tumor apoptosis and reduced the proportion of CEM-C1 cells in murine peripheral blood and bone marrow (P < 0.05). Our results demonstrate that β-ARs are expressed in T-ALL. CVD has a strong antitumor effect against T-ALL and inhibits β-AR associated signaling pathways. Therefore, CVD may provide a potential therapy for T-ALL. • The expression of β-ARs in patients with T-ALL and T-ALL cells was first discovered. • β-adrenergic receptors are positive regulators of T-ALL viability. • We find for the first time that carvedilol has a strong anti T-ALL effect. • Carvedilol can inhibit T-ALL cells proliferation and promotes apoptosis. • Carvedilol can inhibit cAMP/Epac, PI3K/AKT/mTOR and JAK2/STAT3 signaling pathways. [ABSTRACT FROM AUTHOR]

Synergistic apoptosis and ferroptosis strategy is quite promising for tumor treatment. Herein, a kind of polyacrylic acid-stabilized, carboxymethyl chitosan-coated, doxorubicin (DOX)-loaded copper phosphate nanoparticles (NPs) were prepared by a simple method for synergistic apoptosis and ferroptosis against tumor cells. The finally formed PAA-Cu3(PO4)2-DOX-CMCS (PCPDC) NPs displayed suitable hydrodynamic size (208.7 nm) and surface charge. When uptaken by tumor cells, they were degraded under acidic circumstances, releasing DOX and Cu2+ ions. The released Cu2+ ions reacted with glutathione (GSH) to produce Cu+ ions and deplete GSH. Through Cu+ ions-mediated Fenton-like reaction, H2O2 can be converted to hydroxyl radical to produce lipid hydroperoxides. Furthermore, the depleted GSH down-regulated the expression of glutathione peroxidase 4 (GPX4) protein, promoting the accumulation of lipid hydroperoxides to enhance ferroptosis. The released DOX can effectively induce apoptosis in tumor cells. These developed Cu3(PO4)2-based nanomaterials can kill tumor cells effectively through the synergistic apoptosis and ferroptosis strategy. [ABSTRACT FROM AUTHOR]

This study was to investigate the effects of oxidative stress in cigarette smoke (CS)-induced cell apoptosis in mice with emphysema. Thirty-two mice were divided into four groups: the control group, the CS group, the CS + Pifithrin-α group, and the CS + NAC group. Pathological changes and apoptosis in lung tissue of mice were detected. The activity of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (T-AOC) were measured using spectrophotometer. The proteins expression of p53, Bcl-2, Bax, and caspase-3 were determined by western blot. The results showed that cell apoptosis, lung structural damage, and the activity of MDA, as well as the expression of apoptosis-related proteins Bax, total caspase-3, and cleaved caspase-3 were increased in CS-treated mice. The activity of SOD, CAT, and T-AOC, as well as the expression of anti-apoptosis protein Bcl-2 were decreased in CS-treated mice when compared with the control group. However, Pifithrin-α (p53 inhibitor) and N-Acetylcysteine (NAC) could reduce cell apoptosis, lung structural damage and oxidative stress, accelerate the expression of Bcl-2, while suppressing the expression of Bax, total caspase-3 and cleaved caspase-3. More importantly, the treatment with NAC even inhibited the expression of p53. In conclusions, oxidative stress linking the p53 is involved in cell apoptosis in CS-treated emphysema mice. [ABSTRACT FROM AUTHOR]

Tamoxifen (TAM) resistance presents a major clinical obstacle in the management of estrogen-sensitive breast cancer, highlighting the need to understand the underlying mechanisms and potential therapeutic approaches. We showed that dysregulated mitochondrial dynamics were involved in TAM resistance by protecting against mitochondrial apoptosis. The dysregulated mitochondrial dynamics were associated with increased mitochondrial fusion and decreased fission, thus preventing the release of mitochondrial cytochrome c to the cytoplasm following TAM treatment. Dynamin-related GTPase protein mitofusin 1 (MFN1), which promotes fusion, was upregulated in TAM-resistant cells, and high MFN1 expression indicated a poor prognosis in TAM-treated patients. Mitochondrial translocation of MFN1 and interaction between MFN1 and mitofusin 2 (MFN2) were enhanced to promote mitochondrial outer membrane fusion. The interaction of MFN1 and cristae-shaping protein optic atrophy 1 (OPA1) and OPA1 oligomerization were reduced due to augmented OPA1 proteolytic cleavage, and their apoptosis-promoting function was reduced due to cristae remodeling. Furthermore, the interaction of MFN1 and BAK were increased, which restrained BAK activation following TAM treatment. Knockdown or pharmacological inhibition of MFN1 blocked mitochondrial fusion, restored BAK oligomerization and cytochrome c release, and amplified activation of caspase-3/9, thus sensitizing resistant cells to apoptosis and facilitating the therapeutic effects of TAM both in vivo and in vitro. Conversely, overexpression of MFN1 alleviated TAM-induced mitochondrial apoptosis and promoted TAM resistance in sensitive cells. These results revealed that dysregulated mitochondrial dynamics contributes to the development of TAM resistance, suggesting that targeting MFN1-mediated mitochondrial fusion is a promising strategy to circumvent TAM resistance. • Mitochondrial dynamic shifts toward fusion in TAM-resistant cells. • Enhanced MFN1-MFN2 interaction promotes OMM fusion. • Reduced MFN1-OPA1 interaction and OPA1 oligomerization causes incomplete IMM fusion. • The increased MFN1 impedes BAK activation which restrains the release of Cyt c. • Knockdown or inhibition of MFN1 sensitizes resistant cells to TAM-induced apoptosis. [ABSTRACT FROM AUTHOR]

Perioperative or postoperative adjuvant chemotherapy based on 5-fluorouracil (5-FU) is a common first-line adjuvant therapy for gastric cancer (GC). However, drug resistance and the side effects of 5-FU have reduced its efficacy. Among these side effects, gastrointestinal (GI) toxicity is one of the most common. Xianglian Pill (XLP) is a Chinese patent medicine that is commonly used for the treatment of diarrhoea. It can reduce inflammation and has a protective effect on the intestinal mucosa. Recent studies have shown that many components of XLP can inhibite tumor cell growth. However, the therapeutic effect of XLP in combination with 5-FU on GC is unclear. To investigate whether the combination of XLP and 5-FU can enhance anti-GC activity while reducing GI toxicity. XLP was administered orally during intraperitoneal injection of 5-FU in GC mice model. Mice were continuously monitored for diarrhea and xenograft tumor growth. After 2 weeks, the mice were sacrificed and serum was collected to determine interleukin-6 levels. Pathological changes, the expression of pro-inflammatory factors and p38 mitogen-activated protein kinase (MAPK) in GI tissue were determined by Western blot analysis. Pathological changes, apoptosis levels and p38 MAPK expression levels in xenograft tissues were also determined. The results showed that XLP could alleviate GI mucosal injury caused by 5-FU, alleviated diarrhea, and inhibited the expression of nuclear factor (NF)-κB and myeloid differentiation primary response-88. Besides, XLP could promote the 5-FU-induced apoptosis of GC cells and enhance the inhibitory effect of 5-FU on tumor xenografts. Further study showed that XLP administration could regulate the expression of p38 MAPK. XLP in combination with 5-FU could alleviate its GI side effects and enhance its inhibitory effect on xenograft tumor. Moreover, these effects were found to be related to the regulation of the p38 MAPK/NF-κB pathway. [Display omitted] • XLP combined with 5-FU could alleviate the diarrhea and reduce the inflammation of gastrointestinal mucosa in GC mice model. • XLP combined with 5-FU could inhibit the growth of xenogaft and promote tumor cell apoptosis in GC mice model. • Those effects were related to the regulation of p38MAPK/NF-κB signaling pathway by XLP. [ABSTRACT FROM AUTHOR]

The immune microenvironment constructed by tumor-infiltrating immune cells and the molecular phenotype defined by hormone receptors (HRs) have been implicated as decisive factors in the regulation of breast cancer (BC) progression. Here, we found that the infiltration of mast cells (MCs) informed impaired prognoses in HR(+) BC but predicted improved prognoses in HR(−) BC. However, molecular features of MCs in different BC remain unclear. We next discovered that HR(−) BC cells were prone to apoptosis under the stimulation of MCs, whereas HR(+) BC cells exerted anti-apoptotic effects. Mechanistically, in HR(+) BC, the KIT ligand (KITLG), a major mast cell growth factor in recruiting and activating MCs, could be transcriptionally upregulated by the progesterone receptor (PGR), and elevate the production of MC-derived granulin (GRN). GRN attenuates TNFα-induced apoptosis in BC cells by competitively binding to TNFR1. Furthermore, disruption of PGR-KITLG signaling by knocking down PGR or using the specific KITLG-cKIT inhibitor iSCK03 potently enhanced the sensitivity of HR(+) BC cells to MC-induced apoptosis and exerted anti-tumor activity. Collectively, these results demonstrate that PGR-KITLG signaling in BC cells preferentially induces GRN expression in MCs to exert anti-apoptotic effects, with potential value in developing precision medicine approaches for diagnosis and treatment. • The infiltration of mast cells impaired prognoses in (HR) (+) BC but predicted improved prognoses in HR(−) BC. • HR(−) BC cells were prone to apoptosis under the stimulation of MCs, whereas HR(+) BC cells exerted anti-apoptotic effects. • PGR transcriptionally up regulates the expression of KITLG in HR(+) BC cells. • KITLG elevates the infiltration of MCs and stimulates GRN expression in MCs. • MC-derived GRN can competitively bind to TNFR1, thus inhibiting the TNF-α apoptotic pathway. [ABSTRACT FROM AUTHOR]

The butyryl galactose ester-modified coix component microemulsions (But-Gal-CMEs) was developed for enhanced liver tumor-specific targeting. The study was aimed to evaluate the hepatoma-targeting potential of But-Gal-CMEsin vitroandin vivo. But-Gal-CMEs with a uniform spherical shape exhibited a small particle size (56.68 ± 0.07 nm), a narrow polydispersity (PDI, 0.144 ± 0.005) and slightly negative surface charge (−0.102 ± 0.008 mV). In the cell uptake studies, But-Gal-CMEs showed a significant enhancement on the intracellular fluorescent intensity on HepG2 cells model, which was 1.93-fold higher relative to coix component microemulsions (CMEs). The IC50of But-Gal-CMEs against HepG2 cells was 64.250 μg/mL, which was notably stronger than that of CMEs. In the cell apoptosis studies, compared with CMEs, But-Gal-CMEs (50 μg/mL) treatment resulted in a 1.34-fold rise in total apoptosis cells of HepG2. In the biodistribution studiesin vivo, the intratumorous fluorescence of Cy5-loaded But-Gal-CMEs was 1.43-fold higher relative to that of Cy5-loaded CMEs, suggesting an obviously enhanced accumulation in the tumor sites. Taken as together, But-Gal could be incorporated into the coix component microemulsions as a novel ligand for realizing hepatoma-targeting drugs delivery. [ABSTRACT FROM AUTHOR]

Sepsis-induced cardiomyopathy (SIC) is a serious complication of sepsis with high mortality but no effective treatment. The renin angiotensin (Ang) aldosterone system (RAAS) is activated in patients with sepsis but it is unclear how the Ang II/Ang II type 1 receptor (AT1R) axis contributes to SIC. This study examined the link between the Ang II/AT1R axis and SIC as well as the protective effect of AT1R blockers (ARBs). The Ang II level in peripheral plasma and AT1R expression on monocytes were significantly higher in patients with SIC compared with those in non-SIC patients and healthy controls and were correlated with the degree of myocardial injury. The ARB losartan reduced the infiltration of neutrophils, monocytes, and macrophages into the heart and spleen of SIC mice. Additionally, losartan regulated macrophage polarization from the M1 to the M2 subtype via nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thereby maintaining the mitochondrial dynamics balance in cardiomyocytes and reducing oxidative stress and cardiomyocyte apoptosis. In conclusion, the plasma Ang II level and AT1R expression on plasma monocytes are an important biomarker in SIC. Therapeutic targeting of AT1R, for example with losartan, can potentially protect against myocardial injury in SIC. [Display omitted] • Plasma Ang II level and AT1R expression on monocytes is a useful biomarker for SIC. • Losartan blocked immune cell infiltration in spleen and myocardium of SIC mice. • Losartan can regulate macrophage polarization to alleviate SIC. • AT1R is possibly a therapeutic target to protect cardiomyocyte mitochondria. • The application of losartan may be a promising strategy for SIC treatment. [ABSTRACT FROM AUTHOR]

Postcontrast acute kidney injury (PC-AKI) is directly caused by the use of contrast, indicating a clear causal relationship between the contrast and the injury. Salvianolic acid B (Sal B), a water-soluble compound of Salvia miltiorrhiza, has a potent anti-inflammatory effect. We conducted a study to explore whether the protective effect of Sal B on iopromide-induced injury in human proximal tubular epithelial cells (HK-2 cells) is related to inhibition of the TLR4/NF-κB/NLRP3 signal pathway. The results showed that 100 μmol/L Sal B counteracted the decrease in cell viability, the increase of ROS and the number of apoptotic cells, and the decrease of mitochondrial membrane potential (ΔΨm) induced by iopromide. Molecular docking analysis showed that Sal B binds TLR4 and NLRP3 proteins. Moreover, 100 μmol/L Sal B also decreased the expression of TLR4, NLRP3, ASC, Caspase-1, IL-18, IL-1β, TNF-α, p-NF-κB, cleaved caspase-3, and the ratio of Bax/Bcl-2 induced by iopromide. TAK-242, a TLR4 antagonist, was added to further explore the mechanism of Sal B. However, the cotreatment group with TAK-242 and Sal B had no significant difference in cell viability and apoptosis rate compared to the treatment group with TAK-242 or Sal B alone. These results indicated that Sal B can inhibit the TLR4/NF-κB/NLRP3 signal pathway, resulting in the alleviation of iopromide-induced HK-2 cell injury. [ABSTRACT FROM AUTHOR]