Search

Background: Due to its non-invasive and widely applicable features, photodynamic therapy (PDT) has been a prominent treatment approach against cancer in recent years. However, its widespread application in clinical practice is limited by the dark toxicity of photosensitizers and insufficient penetration of light sources. This study assessed the anticancer effects of a novel photosensitizer 5-(4-amino-phenyl)-10,15,20-triphenylporphyrin with diethylene-triaminopentaacetic acid (ATPP-DTPA)-mediated PDT (hereinafter referred to as ATPP-PDT) under the irradiation of a 450-nm blue laser on colorectal cancer (CRC) in vivo and in vitro ., Methods: After 450-nm blue laser-mediated ATPP-PDT and the traditional photosensitizer 5-aminolevulinic acid (5-ALA)-PDT treatment, cell viability was detected through Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays. Reactive oxygen species (ROS) generation was quantified by flow cytometry and fluorescence microscopy. Western blotting and transcriptome RNA sequencing and functional experiments were used to evaluate cell apoptosis and its potential mechanism. Anti-tumor experiment in vivo was performed in nude mice with subcutaneous tumors., Results: ATPP-DTPA had a marvelous absorption in the blue spectrum. Compared with 5-ALA, ATPP-DTPA could achieve significant killing effects at a lower dose. Owing to generating an excessive amount of ROS, 450-nm blue laser-mediated PDT based on ATPP-DTPA resulted in evident growth inhibition and apoptosis in CRC cells in vitro . After transcriptome RNA sequencing and functional experiments, p38 MAPK signaling pathway was confirmed to be involved in the regulation of apoptosis induced by 450-nm blue laser-mediated ATPP-PDT. Additionally, animal studies using xenograft model confirmed that ATPP-PDT had excellent anti-tumor effect and reasonable biosafety in vivo ., Conclusions: PDT mediated by 450-nm blue laser combined with ATPP-DTPA may be a novel and effective method for the treatment of CRC., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Objective: The mechanisms of lung injury in acute respiratory distress syndrome (ARDS) are not well understood.Piezo1 was recently identified as a mechanotransduction protein. The present study found the expression of Piezo1 in type II pneumocytes and investigated its role in mediating ARDS-related lung injury., Methods: Sprague-Dawley rats were used to establish an ARDS model, the expression of Piezo1,lung injuries, apoptosis as well as calcium influx were assessed., Results: Piezo1 was expressed in type II pneumocytes as shown by immunofluorescence staining and expression was increased in the ARDS model. Knockdown of Piezo1 reduced apoptosis which was related to the elevation of Bcl-2.Calcium influx played a vital role in Piezo1-induced apoptosis., Conclusion: Piezo1 was expressed in type II pneumocytes. Mechanical stretch of alveoli during ARDS induced activation of the Piezo1 channel,which resulted in calcium influx. The increased intracellular Ca2+ induced the apoptosis of type II pneumocytes, which may be related to the Bcl-2 pathway.

Phytoestrogens are estrogen-like compounds of plant origin. The pharmacological activities of phytoestrogens are predominantly due to their antioxidant, anti-inflammatory and lipid-lowering properties, which are mediated via the estrogen receptors (ERs): estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) and possibly G protein-coupled estrogen receptor 1 (GPER). Gypenoside XVII (GP-17) is a phytoestrogen that is widely used to prevent cardiovascular disease, including atherosclerosis, but the mechanism underlying these therapeutic effects is largely unclear. This study aimed to assess the anti-atherogenic effects of GP-17 and its mechanisms in vivo and in vitro. In vivo experiments showed that GP-17 significantly decreased blood lipid levels, increased the expression of antioxidant enzymes and decreased atherosclerotic lesion size in ApoE-/- mice. In vitro experiments showed that GP-17 significantly prevented oxidized low-density lipoprotein (Ox-LDL)-induced endothelial injury. The underlying protective mechanisms of GP-17 were mediated by restoring the normal redox state, up-regulating of the ratio of Bcl-2 to Bax and inhibiting the expression of cleaved caspase-3 in Ox-LDL-induced human umbilical vein endothelial cell (HUVEC) injury. Notably, we found that GP-17 treatment predominantly up-regulated the expression of ERα but not ERβ. However, similar to estrogen, the protective effect of GP-17 could be blocked by the ER antagonist ICI182780 and the phosphatidylinositol 3-kinase (PI3K) antagonist LY294002. Taken together, these results suggest that, due to its antioxidant properties, GP-17 could alleviate atherosclerosis via the ERα-mediated PI3K/Akt pathway.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Panels from Figure 4A appear similar to panels from Figure 1 of the article previously published by Z. Ding, F. Xu, J. Tang, G. Li, P. Jiang, Z. Tang and H. Wu in Neoplasma 63(3) (2016) 351–361 http://www.elis.sk/index.php?page=shop.product_details&flypage=flypage.tpl&product_id=4703&category_id=128&option=com_virtuemart&vmcchk=1&Itemid=1. One of the conditions of submission of a paper for publication is that authors declare explicitly that the paper has not been previously published and is not under consideration for publication elsewhere. Re-use of any data should be appropriately cited. As such this article represents a misuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

The downstream transcriptional factor of the hedgehog (Hh) pathway, GLI family zinc finger 1 (GLI1), plays a crucial role in regulating tumor progression. In the present study, we demonstrated that silibinin, a natural flavonoid antioxidant isolated from extracts of the milk thistle herb, exerts its anticancer capabilities by restraining GLI1 function in renal cell carcinoma (RCC) cells in vitro and in vivo. In the present study, we confirmed that silibinin induced growth inhibition of RCC through caspase-dependent apoptosis and downregulation of GLI1 and BCL2, which could be partially reversed by GLI1 overexpression. Moreover, we determined that the decreased GLI1 expression by silibinin was mediated by the mammalian target of rapamycin (mTOR) pathway. The in vivo mouse xenograft study also showed that silibinin significantly reduced RCC tumor growth and specifically targeted the mTOR-GLI1-BCL2 signaling pathway. In conclusion, our findings demonstrated for the first time that silibinin induces apoptosis of RCC cells through inhibition of the mTOR-GLI1‑BCL2 pathway. These findings also indicate that GLI1 is a novel regulator for the potential therapeutic application of silibinin against RCC.

Metformin, an oral antidiabetic agent, has been reported to potentiate chemotherapeutic-induced cytotoxicity. In this study, we investigated the effects and molecular mechanisms of metformin in sensitizing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human bladder cancer cells. Metformin alone did not induce apoptosis, but markedly potentiated TRAIL-induced apoptosis in 253J and RT4 bladder cancer cells. To elucidate the underlying mechanism, we examined the modulatory effects of metformin on the key components of the TRAIL signaling pathway and found that metformin did not alter the expression levels of death receptor 4 (DR4) and death receptor 5 (DR5), but significantly reduced the cellular Fas-associated death domain (FADD)-like interleukin-1β-converting enzyme (FLICE) inhibitory protein (c-FLIP) levels, contributing toward the sensitization to TRAIL. Further experiments showed that metformin did not affect the mRNA level, proteasomal degradation, and protein stability of c-FLIPL. However, metformin inhibited the mTOR/S6K1 pathway in 253J and RT4 cells, which usually regulates protein translation; moreover, knockdown of S6K1 effectively reduced the levels of c-FLIPL, indicating that metformin downregulates c-FLIP through inhibition of the mTOR/S6K1 pathway. In addition, AMP-activated protein kinase (AMPK) inhibitor compound C did not prevent the inhibitory effects of metformin on the mTOR/S6K1 pathway and metformin-mediated sensitization to TRAIL. Taken together, our results indicate that metformin sensitizes human bladder cancer cells to TRAIL-induced apoptosis through downregulation of c-FLIP, which is mediated by the mTOR/S6K1 pathway, but independent of AMPK; furthermore, these findings provide a rationale for the combined application of metformin with TRAIL in the treatment of bladder cancer.

Objective: To investigate the effects of acyldepsipeptide 1 (ADEP1) on renal cancer cell apoptosis and on the expressions of SHH signaling pathway related protein Gli-1 and Bcl-2., Methods: The renal cancer cells (ACHN and 769-P) were treated with 50 μmol/L ADEP1 for 48 hours. The changes of cell morphology and the nucleus shape in cell apoptosis were observed under a light microscope, and cell viability was measured by MTT assay. The mRNA levels of SHH and Gli-1 were detected by real-time quantitative PCR (qRT-PCR), and the protein levels of Gli-1 and Bcl-2 were determined by Western blotting., Results: ADEP1 induced renal cancer cell apoptosis through reducing the transcription of SHH and Gli-1, and decreasing Gli-1 and Bcl-2 protein expressions., Conclusion: ADEP1 could induce renal cancer cell apoptosis by the inhibition on SHH signaling pathway related proteins.

The excessive apoptosis of cells of the nucleus pulposus may plays an important role in intervertebral disc (IVD) degeneration. It has been shown that the pro-inflammatory cytokine tumour necrosis factor (TNF)-α can induce disc cell apoptosis. Insulin-like growth factor (IGF)-1 can promote nucleus pulposus cell proliferation; however, whether or not IGF-1 inhibits TNF-α-induced apoptosis in the nucleus pulposus has not yet been elucidated. In this study, our objective was to create a potentially therapeutic viral vector, which could be used to achieve the enforced expression of IGF-1 in rabbit nucleus pulposus cells. Furthermore, we investigated the ability of IGF-1 to reverse TNF-α-induced apoptosis in cells of the nucleus pulposus. Isolated nucleus pulposus cells were cultured to a confluent monolayer, digested with collagenase Ⅱ and purified using trypsin and differential adhesion methods. Nucleus pulposus cells were positively identified using type Ⅱ collagen immunohistochemistry. Following transfection with adenoviral vectors engineered to overexpress recombinant human IGF-1 (Ad-hIGF-1) or TNF-α, the cells were observed under a light microscope. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end-labeling (TUNEL) and flow cytometry (FCM) were used to assess the rate of apoptosis. The Ad-hIGF-1 viral vector was effectively transduced into the nucleus pulposus cells and increased IGF-1 expression as confirmed by RT-PCR and western blot analysis. In the TNF-α-treated group, a large number of apoptotic cells was observed that exhibited morphological changes associated with this form of cell death. Minimal apoptosis was observed in the Ad-hIGF-1-treated group and the control group showed no obvious signs of apoptosis. TUNEL assay revealed that the rate of apoptosis in the Ad-hIGF-1 group was significantly reduced compared with the TNF-α-treated group (P<0.01). This result was confirmed using FCM. The rate of apoptosis was also significantly increased in the TNF-α-exposed cells compared with the control group (P<0.01). Our findings strongly suggest that the adenoviral vector expressing hIGF-1 can successfully infect nucleus pulposus cells in vitro and effectively enhance the expression of IGF-1. In addition, IGF-1 reversed the TNF-α -induced apoptosis of nucleus pulposus cells. Thus, Ad-hIGF-1 may be useful in the development of clinical interventions for disc degeneration.

Objective: To explore the effect of Ronggan Mixture (RM) on immunoregulation and hepatocyte apoptosis-related factors in concanavalin A (Con A) induced acute immunological liver injury mice., Methods: Totally 60 hepatitis B virus (HBV) transgenic mice were randomly divided into 6 groups, i.e., the blank control group, the model group, the RM group, the Herba Artemisiae Scopariae (HAS) group, the Yinchenhao Decoction (YD) group, and the Bifendate group, 10 mice in each group. The acute immunological liver injury model was established by tail vein injection of ConA. Fourteen days before modeling, normal saline was administered to mice in the blank control group and the model group. RM, YD, HAS decoction, and Bifendate solution was respectively given to mice in the RM group, the YD group, the HAS group, and the Bifendate group. The medication was performed once daily. One h after the last gastrogavage, phosphate buffer solution (PBS) was injected to mice in the blank control group from the tail vein. Modeling was conducted by injecting Con A at 3 microg/g body weight from the tail vein. Mice were sacrificed 8 h after modeling. Blood or tissue samples were collected to detect lab indicators such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), tumor necrosis factor alpha (TNF-alpha), interferon gamma (INF-gamma), IL-4, IL-10, Fas, FasL, Bax, and bcl-2., Results: There was significant difference in all lab indicators between the normal group and the blank control group (P < 0.05, P < 0.01). Compared with the model group, ALT and AST levels were significantly lower in the RM group and the Bifendate group (P < 0.01); TBil significantly decreased in the RM group (P < 0.01). The expression level of TNF-alpha decreased in the RM group (P <0.05). The expression level of IFN-gamma decreased in the RM group and the YD group (P < 0.05). The expression level of IL-4 could be elevated in all medicated groups (P < 0.05). RM could elevate the expression level of IL-10 (P < 0.05). The expression level of Fas in the liver tissue decreased in the RM group and the YD group (P < 0.05). The expression level of FasL decreased and the expression of bcl-2 gene increased in the RM group (both P < 0.05). The expression level of Bax was down-regulated in the RM group and the YD group (P < 0.05). The ratio of bcl-2/Bax was up-regulated in the RM group (P < 0.05). Meanwhile, RM showed better effect in decreasing expressions of ALT and AST than HAS (P < 0.05). The effect of increasing IL-10 expression levels was better in the RM group than in the YD group (P < 0.01). The effect of decreasing expressions of Fas and FasL was better in the RM group than in the HAS group, the YD group, and the Bifendate group (P < 0.05). The effect of enhancing the expression of IL-10 in the liver tissue was better in the RM group than in the HAS group (P < 0. 05)., Conclusion: RM had protective effect on Con A induced acute immunological liver injury mice, which might be achieved by changing the immunological balance of Thl/Th2 factors (decreasing expressions of TNF-alpha and IFN-gamma, elevating expressions of IL-10 and IL-4) and regulating hepatocyte apoptosis-related factors (down-regulating gene expressions of Fas, FasL, and Bax; up-regulating bcl-2 gene expression, and up-regulating the bcl-2/Bax ratio).

After N-acetylglucosaminyltransferase V (GnT-V) activity was down-regulated by the transfection of its antisense cDNA(GnTV-AS), apoptosis of H7721 cells was appeared and the apoptosis induced by 80 microM all-transretinoic acid (ATRA) was facilitated, while ATRA itself could not induce apparent apoptosis in mock cells transfected with the vector. In the study of the molecular mechanism of this phenomenon, it was found that GnTV-AS reduced the expressions of anti-apoptotic proteins, such as phosphorylated protein kinase B and phosphorylated Bad as well as Bcl-2 and Bcl-X (L), and elevated those of pro-apoptotic proteins, including Bax, full length caspase-3 and its activated fragments as well as anti-oncoprotein p53. In the contrast, ATRA up regulated the expressions of Bax and activated caspase-3 fragments only. After the GnTV-AS transfected cells were treated with ATRA, phosphorylated PKB and Bad were further decreased, while Bax and activated caspase-3 fragment were further increased, leading to the enhanced apoptosis in flow-cytometry analysis when compared with GnTV-AS cells not treated with ATRA. It was speculated that the decreased phospho-Bad resulted from the reduced phospho-PKB and the up regulation of p53 caused the elevated activity of Bax. The increased active caspase-3 was the consequence of the elevated Bax/ Bcl-2(Bcl-X(L)) activity ratio in the cells.

Objective To observe the effects of photodynamic therapy (PDT) with hematoporphyrin monomethyl ether (HMME) on venous neointimal hyperplasia (VNH) in arteriovenous fistulas (AVFs) in rabbits. Methods We established models of AVF by end-to-side anastomosis of the common carotid artery to the jugular vein in 32 adult rabbits, which were randomized into 4 groups (n=8), including a control group without any intervention, an HMME group with HMME treatment only, a light illumination (without HMME) group, and a HMME-PDT group receiving both the photosensitizer and light illumination. Color Doppler ultrasound was used to detect the blood flow after the operation. At 30 d after the operation, the jugular vein tissue was collected for assessing VNH and measurement of the lumen area using HE and Masson staining and for detecting the expression of proliferating cell nuclear antigen (PCNA) and ɑ-smooth muscle actin (ɑ-SMA) using immunohistochemistry; Western blotting was performed to analyze the expression of proliferating cell nuclear antigen (PCNA), Bcl-2, ɑ-SMA, Caspase3, Caspase9 and Bax. Results The jugular vein tissues showed significantly lessened VNH and increased lumen area in HMME-PDT group compared with the other groups (P < 0.05). The results of immunohistochemistry showed that the expression of PCNA and ɑ-SMA was decreased and Caspase3 expression was increased significantly in HMME-PDT group compared with the other groups (P < 0.05). Western blotting results showed that among the 4 groups, the expression of Caspase3, Caspase9 and Bax were the highest (P < 0.05) while those of PCNA, Bcl-2, ɑ-SMA and Bcl-2/Bax ratio the lowest in HMME-PDT group (P < 0.05). Conclusion HMME-PDT can effectively reduce VNH in AVFs in rabbits by suppressing proliferation and promoting apoptosis of the vascular smooth muscle cells via the Bcl-2/Bax pathway.

Metabolic alteration drives renal cell carcinoma (RCC) development, while the impact of melatonin (MLT), a neurohormone secreted during darkness, on RCC cell growth and underlying mechanisms remains unclear. We detected concentration of metabolites through metabolomic analyses using UPLC-MS/MS, and the oxygen consumption rate was determined using the Seahorse Extracellular Flux analyzer. We observed that MLT effectively inhibited RCC cell growth both in vitro and in vivo. Additionally, MLT increased ROS levels, suppressed antioxidant enzyme activity, and induced apoptosis. Furthermore, MLT treatment upregulated key TCA cycle metabolites while reducing aerobic glycolysis products, leading to higher oxygen consumption rate, ATP production, and membrane potential. Moreover, MLT treatment suppressed phosphorylation of Akt, mTOR, and p70 S6 Kinase as well as the expression of HIF-1α/VEGFA in RCC cells; these effects were reversed by NAC (ROS inhibitors). Conversely, MLT synergistically inhibited cell growth with sunitinib and counteracted the Warburg effect induced by sunitinib in RCC cells. In conclusion, our results indicate that MLT treatment reverses the Warburg effect and promotes intracellular ROS production, which leads to the suppression of Akt/mTOR/S6K signaling pathway, induction of cell apoptosis, and synergistically inhibition of cell growth with sunitinib in RCC cells. Overall, this study provides new insights into the mechanisms underlying anti-tumor effect of MLT in RCC cells, and suggests that MLT might be a promising therapeutic for RCC. [ABSTRACT FROM AUTHOR]

Simple Summary: To explore new drugs for malignant neuroblastoma, we used bioinformatics to analyze the prognostic genes, and successfully found the small molecular drug BI-D1870 based on the professional gene–drug analysis website 'Connectivity Map'. In vivo and in vitro experiments confirmed that BI-D1870 effectively inhibited the malignant proliferation of neuroblastoma. Moreover, we found that BI-D1870 mainly inhibited the mitosis of tumor cells by regulating the PI3K-Akt-mTORC1 signal axis, thereby promoting cell apoptosis and ultimately inhibiting tumor growth. This is a drug prediction method based on a combination of massive gene map analysis and clinical survival practices, which has significant accuracy advantages over single gene changes. Furthermore, this is also the first study to explore the therapeutic benefits of BI-D1870 on NB, providing a novel clinically applicable solution for the treatment of neuroblastoma. Introduction: Neuroblastoma (NB) is one of the most common extracranial solid malignant tumors in children. The 5-year survival rate of high-risk or refractory NB is less than 50%. Therefore, developing new effective therapeutics for NB remains an urgent challenge. Materials and Methods: Based on the NB dataset TARGET-NBL in the TCGA database, the prognosis-related genes were analyzed using univariate cox regression (p < 0.01). The protein network interaction of prognostic genes was analyzed using STRING to obtain 150 hub genes with HR > 1 and 150 hub genes with HR < 1. The Connectivity Map database was used to predict a therapeutic drug: BI-D1870, a ribosomal S6 kinase inhibitor. The inhibitory effect of BI-D1870 on NB was investigated through in vivo and in vitro experiments, and its inhibitory mechanism was explored. Results: Both the in vivo and in vitro experiments showed that BI-D1870 could inhibit tumor proliferation and induce tumor apoptosis. Furthermore, we proved that BI-D1870 caused G2/M phase arrest and mitosis damage in cells. RNA-seq of cells showed that BI-D1870 may inhibit the growth of NB by inhibiting the PI3K-Akt-mTOR axis. Western blot and immunofluorescence testing showed that BI-D1870 inhibited the PI3K-Akt-mTORC1 signal pathway to regulate the phosphorylation of RPS6 and 4E BP1 proteins, inhibit protein translation, and inhibit microtubule formation, thus preventing mitotic proliferation and inducing apoptosis. Conclusions: This study provides strong support that BI-D1870 may be a potential adjuvant therapy for NB. [ABSTRACT FROM AUTHOR]

Background: Emerging studies manifested that exosomal RNAs had pivotal roles in human cancer therapies. This article aimed to research the regulatory mechanism of exosomal circRNA-plasmacytoma variant translocation 1 (circ-PVT1) in cisplatin (DDP) resistance of gastric cancer (GC). Methods: Exosomes were isolated by ExoQuick® method and ultracentrifugation and then identified through transmission electron microscope and the examination of exosome markers. Related proteins were detected using Western blot. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied for measuring circ-PVT1, microRNA-30a-5p (miR-30a-5p), and Yes-associated protein 1 (YAP1) expression. The half inhibitory concentration (IC50) of DDP was assessed by 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT). Cell apoptosis and invasion were, respectively, determined using flow cytometry and transwell assay. Target relationship was confirmed by dual-luciferase reporter assay. The impact of circ-PVT1 on DDP resistance was explored via xenograft tumor assay. Results: Exosomal circ-PVT1 was upregulated while miR-30a-5p was downregulated in DDP-resistant GC serums and cells. Circ-PVT1 knockdown repressed DDP resistance in DDP-resistant GC cells via promoting apoptosis and decreasing invasion or autophagy by negatively targeting miR-30a-5p. YAP1 was a direct target of miR-30a-5p. MiR-30a-5p overexpression inhibited DDP resistance via reducing YAP1. Circ-PVT1 modulated YAP1 expression by targeting miR-30a-5p. Circ-PVT1 depression expedited DDP sensitivity of GC via miR-30a-5p/YAP1 axis in vivo. Conclusion: Exosomal circ-PVT1 facilitated DDP resistance via modulating autophagy, invasion and apoptosis by miR-30a-5p/YAP1 axis in GC cells. Exosomal circ-PVT1 might be a prospective indicator in DDP therapy of GC. [ABSTRACT FROM AUTHOR]

Agarwood is a traditional medicine used for treating some diseases, including painful and ischemic diseases. This study was carried out to investigate the potential cardioprotective effect of the whole-tree agarwood-inducing technique-produced agarwood alcohol extract (WTAAE) on isoproterenol- (ISO-) induced myocardial ischemia (MI) in rats and explore the underlying molecular mechanisms. Compared to the MI group, WTAAE pretreatment significantly improved ST wave abnormal-elevation, mitigated myocardial histological damage; decreased creatinine kinase (CK), lactate dehydrogenase (LDH), alanine transaminase (ALT), and aspartate transaminase (AST) levels; reduced hydrogen peroxide (H2O2) and lipid peroxide (LPO) production; and increased total antioxidant capacity (T-AOC) and catalase (CAT) activities. Moreover, agarwood alcohol extracts (AAEs) markedly enhanced the mRNA levels of Nrf2-ARE pathway, and Bcl-2 reduced the apoptotic Bax family mRNA expressions. In addition, the effect of WTAAE was greater than that of wild agarwood alcohol extract (WAAE) and burning-chisel-drilling agarwood alcohol extract (FBAAE). All of these data indicate that WTAAE exerted the protective effects of MI, and its mechanism was associated with upregulating Nrf2-ARE and suppressing Bcl-2 pathways. [ABSTRACT FROM AUTHOR]

To compare the pathogenicity of isolates of sequence type 7 (ST-7) Neisseria meningitidis (N. meningitidis) belonging to four different serogroups (A, B, C, and X). Four ST-7 N. meningitidis isolates serogrouped as A, B, C, and X and characterized by different capsule structures, were examined for their adhesion and invasion properties, and their ability to induce cytokine release and apoptosis in the host cell (the A549 cell line). Among the four ST-7 N. meningitidis isolates, the serogroup A isolate possessed the strongest adhesion and invasion ability. This isolate also induced the release of the highest levels of the proinflammatory mediators interleukin-6, interleukin-1β, and interferon, and the highest apoptosis rate in the host cells. However, there was no significant difference in interleukin-8 and tumor necrosis factor-α secretion between the four isolates. Based on the findings, the serogroup X N. meningitidis isolate had the weakest pathogenicity, whereas there was almost no difference in the pathogenicity of the isolates from serogroups B and C. The differences in the capsular structure of the four isolates of ST-7 N. meningitidis affected their pathogenic capacities. The findings also imply that the hyperinvasive ST-7 N. meningitidis lineage may include hypoinvasive isolates. [ABSTRACT FROM AUTHOR]

Background: Myeloid-derived suppressor cells (MDSCs) play immunosuppressive roles in cancers and some infectious diseases; however, their role in dengue fever (DF) remains unknown. This study evaluated the clinical significance of MDSCs in DF patients.Methods: This study comprised 178 non-severe DF patients, 20 non-dengue fever (NDF) controls, and 30 healthy donors. The DF patients were divided into the following five groups based on the fever duration from its onset to the day of sample collection: fever duration of 1-2, 3-4, 5-6, 7-8, and > 9 days. Among these DF patients, 14 were monitored for eight days, and their peripheral blood samples were collected every two days. The mononuclear cells were isolated and analyzed using flow cytometry. The correlation between the MDSCs and clinical and immunological indicators of the DF patients was evaluated using Spearman analysis.Results: The count of the peripheral blood MDSCs, especially monocytic MDSCs, of the 178 DF patients were dramatically higher than those of the NDF and healthy controls, and remarkably decreased with the fever duration. Moreover, the MDSC count correlated with some indicators, including the dengue viral load (rho = 0.367, p < .001), body temperature (rho = 0.263, p = .005), prothrombin time (rho = 0.475, p < .001), CD4+ T cell number (rho = - 0.317, p < .001), CD8+ T cell number (rho = - 0.361, p < .001), "programmed cell death protein 1" (PD-1) (rho = - 0.347, p < .001), "T cell immunoglobulin domain and mucin domain-3" (Tim3) (rho = - 0.258, p = .001), interferon-α (IFN-α) (rho = 0.43, p < .001), and "regulated upon activation normal T-cell expressed and secreted" (RANTES) (rho = 0.278, p = .019). Furthermore, the level of arginase-1, but not nitric oxide, was higher in the DF patients than in the healthy controls and was closely related to the number of MDSCs (rho = 0.265, p = .024).Conclusions: Our study reveals a significant correlation between MDSCs and DF clinical indicators, posing MDSCs as potential target cells for DF treatment. [ABSTRACT FROM AUTHOR]

Cervical cancer greatly contributes to cancer‑associated mortalities worldwide. The growing incidence of cervical cancer is of primary concern, and has signaled the need for multiple treatment options. Despite preliminary responses to chemotherapy and/or surgical interventions, the tumors consistently relapse. Previously, natural products gained attention for their diverse bioactivities, which include however are not limited to, neuroprotective, antimicrobial and anticancer effects. The present study evaluated the anticancer activity of fucosterol against a panel of human cancer cell lines. Results indicated that fucosterol exhibited selective inhibitory activity against human HeLa cervical cancer cell line with an IC50 of 40 μM. Fucosterol also induced apoptosis in HeLa cells and prompted reactive oxygen species mediated alterations in mitochondrial membrane potential. It triggered cell cycle arrest of HeLa cells at G2/M check point and exerted inhibitory effects on cell migration. The activation of the phosphoinositide‑3‑kinase (PI3K)/AKT Serine/Threonine Kinase 1 (AKT)/mechanistic target of Rapamycin (mTOR) pathway is important in cancer tumorigenesis, progression and chemotherapy resistance. The results demonstrated that fucosterol significantly inhibited the expression levels of key proteins of the PI3K/Akt/mTOR signaling pathway. Overall, the results of the present study suggest that fucosterol may prove beneficial in the management of cervical cancer. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most common cancer worldwide and its treatment remains a challenge. Effective control of cell survival and proliferation is critical in the prevention of oncogenesis and successful treatment of cancer. Long non-coding RNAs (lncRNAs) have emerged as primary regulators of carcinogenesis. Growth arrest specific 5 (GAS5), a lncRNA, is known to be aberrantly expressed in several types of cancer, however, the role of GAS5 in CRC remains unclear. In the present study, GAS5 mRNA expression was measured in CRC and adjacent normal mucosa tissue samples from 53 patients using reverse transcription-quantitative polymerase chain reaction analysis, in addition to seven CRC cell lines. GAS5 mRNA expression was observed to be markedly downregulated in human CRC tissues and cell lines. Decreased GAS5 expression was associated with an increase in tumor diameter [odds ratio (OR), 0.176 (95% CI, 0.053-0.586); P=0.003] and later tumor-node-metastasis stage [OR, 0.261 (95% CI, 0.083-0.819); P=0.019]. Patients with decreased GAS5 expression exhibited decreased overall survival rates compared with patients with increased GAS5 expression (P=0.015). The Cox proportional hazards model demonstrated that downregulated GAS5 expression was an independent prognostic factor for CRC (hazard ratio, 0.236; 95% confidence interval, 0.067-0.827; P=0.024). Functional assays demonstrated that overexpression of GAS5 inhibited cell proliferation and survival, and induced G0/G1 cell cycle arrest and apoptosis; however, knockdown of GAS5 expression enhanced cell proliferation, and reduced G0/G1 arrest and apoptosis. In conclusion, the results of the present study suggest that GAS5 is essential in the control of apoptosis and cell growth in CRC. Therefore, GAS5 may represent a novel prognostic and diagnostic marker of CRC, in addition to being a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Sirtuin-1 (SIRT1) is a downstream target of Leptin, and its inhibition promotes p53-mediated apoptosis. This study aimed to evaluate the expression and prognostic significance of Leptin and SIRT1 in osteosarcoma. Leptin and SIRT1 levels in osteosarcoma samples from 89 patients were evaluated by immunohistochemical staining. The correlations between Leptin and SIRT1 expression with clinical parameters were analyzed by Spearman's test and Pearson's chi-squared test. Prognostic factors were identified by Univariate and multivariate Cox regression analysis. We found that Leptin and SIRT1 expression was low in 23.6% and 20.2%; moderate in 25.8% and 24.7%; and high in 50.5% and 55.1% of patients with osteosarcoma, respectively. Both Leptin and SIRT1 expression were significantly associated with the Enneking stage, distant metastasis and neo-adjuvant chemotherapy. Leptin expression and SIRT1 expression were significantly correlated and they were significantly associated with shorter overall survival. Among osteosarcoma patients who received neo-adjuvant chemotherapy, both Leptin and SIRT1 expression were significantly associated with overall survival of osteosarcoma patients in univariate analysis, but only SIRT1 expression was significantly associated with overall survival of osteosarcoma patients in multivariate analysis. In conclusion, Leptin and SIRT1 expressions are significantly associated with shorter overall survival of osteosarcoma patients, and SIRT1 expression is a significant independent prognostic indicator in patients with osteosarcoma. [ABSTRACT FROM AUTHOR]

Cochlear hair cell loss results in the secondary loss of spiral ganglion cells (SGCs). The death of these SGCs is due to apoptosis. The E2F1-cyclin dependent kinase 1 (CDK1) pathway is believed to represent an important mechanism of neuronal cell death. However, the role of this pathway in spiral ganglion neuronal apoptosis has not yet been reported. In this study, we deafened guinea pigs with a subcutaneous injection of kanamycin followed by an intravenous infusion of furosemide and then assayed the expression levels of cleaved caspase-3, E2F1, CDK1 and cleaved caspase-9 during the induced SGC apoptosis. Our results revealed that co-administration of kanamycin and furosemide rapidly induced hair cell loss in the guinea pigs and then resulted in a progressive loss of SGCs. Expression levels of E2F1 and CDK1 were obviously up-regulated at 1 and 3 days after deafening. Cleaved caspase-9 also increased robustly 1 or 2 weeks after the deafening procedure. The up-regulation of E2F1, CDK1 and cleaved caspase-9 was significantly attenuated by the systemic injection of CR8 (1 mg/kg/day, intraperitoneally) starting at 5 min after deafening. These findings indicate that the activation of the E2F1-CDK1 pathway and cell cycle re-entry contributes to the apoptosis of SGCs and that the selective inhibition of this signaling cascade may represent an attractive therapeutic strategy. CR8 has the potential to protect SGCs from apoptosis. [ABSTRACT FROM AUTHOR]

Telomerase contributes to cell proliferation and survival through both telomere-dependent and telomere-independent mechanisms. In this report, we discovered that endoplasmic reticulum (ER) stress transiently activates the catalytic components of telomerase (TERT) expression in human cancer cell lines and murine primary neural cells. Importantly, we show that depletion of hTERT sensitizes cells to undergo apoptosis under ER stress, whereas increased hTERT expression reduces ER stress-induced cell death independent of catalytically active enzyme or DNA damage signaling. Our findings establish a functional link between ER stress and telomerase, both of which have important implications in the pathologies associated with aging and cancer. [ABSTRACT FROM AUTHOR]

The aim of the present study was to explore the effects of miR-218-1-3p and miR-149 on the biological function of non-small cell lung cancer (NSCLC) cells A549. Paired NSCLC and adjacent tissues were obtained from 50 NSCLC patients admitted to Shandong Provincial Chest Hospital Affiliated to Shandong University (Jinan, China) from April 2015 to May 2018. The expression levels of miR-218-1-3p and miR-149 were detected by reverse transcription-quantitative PCR (RT-qPCR). The lung adenocarcinoma A549 cells were assigned into the blank group (without transfection), negative control (NC) group (transfected with miRNA NC), and the transfected groups miR-218-1-3p mimic and miR-149 mimic groups. Proliferation and cell growth were determined by CCK-8 assay and cell invasion ability in vitro was assessed by Transwell assay. Flow cytometry was carried out for the detection of cell apoptosis. RT-qPCR results showed that the expression levels of miR-218-1-3p and miR-149 in NSCLC tissues were significantly lower than those in adjacent tissues (P<0.001). At 48 and 72 h, the cell growth of the A549 cells in the miR-218-1-3p mimic and miR-149 mimic groups was significantly lower than that in the NC and blank groups (P<0.05). The number of invasive cells in the miR-218-1-3p mimic and miR-149 mimic groups was significantly lower than that in the NC and blank groups (P<0.05). The apoptotic rate of A549 cells in the miR-218-1-3p mimic and miR-149 mimic groups was significantly higher than that in the NC and blank groups (P<0.05). In conclusion, upregulation of miR-218-1-3p and miR-149 can inhibit the proliferation, invasion and migration of A549 cells in NSCLC, thereby promoting the apoptosis of A549 cells. Thus, miR-218-1-3p and miR-149 can be used as new molecular targets for the diagnosis and treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Abstract Objective The mechanisms of lung injury in acute respiratory distress syndrome (ARDS) are not well understood.Piezo1 was recently identified as a mechanotransduction protein. The present study found the expression of Piezo1 in type II pneumocytes and investigated its role in mediating ARDS-related lung injury. Methods Sprague-Dawley rats were used to establish an ARDS model, the expression of Piezo1,lung injuries, apoptosis as well as calcium influx were assessed. Results Piezo1 was expressed in type II pneumocytes as shown by immunofluorescence staining and expression was increased in the ARDS model. Knockdown of Piezo1 reduced apoptosis which was related to the elevation of Bcl-2.Calcium influx played a vital role in Piezo1-induced apoptosis. Conclusion Piezo1 was expressed in type II pneumocytes. Mechanical stretch of alveoli during ARDS induced activation of the Piezo1 channel,which resulted in calcium influx. The increased intracellular Ca2+ induced the apoptosis of type II pneumocytes, which may be related to the Bcl-2 pathway.

Background Clear-cell renal cell carcinoma (ccRCC) has the highest prevalence, approximately 80%, amongst all RCC cases. Therefore, the development of novel therapeutic agents against ccRCC is imperative. Our previous studies have shown that physcion 8-O-β-glucopyranoside (PG), an anthraquinone extracted from Rumexjaponicus Houtt, exerted an anti-cancer effect in hepatocellular carcinoma cells. The present study was aimed to investigate a possible anti-neoplastic role of PG in ccRCC and the relevant underlying mechanism. Materials and methods Two human ccRCC cell lines- RCC4 and ACHN- were used as in vitro models and treated with varying concentrations of PG. Cell Counting Kit-8 (CCK-8) assay was used to determine cell viability, and Annexin-V FITC/PI staining was used to analyze the percentage of apoptotic cells after PG treatment. Commercially available kits were used to measure the rates of glucose consumption and lactate production. Changes in mitochondrial membrane potential were examined by flow cytometry, and western blotting was performed to analyze the levels of various apoptosis markers. To examine the role of HK2 in the anti-tumor effect of PG, ccRCC cells were transfected with a vector overexpressing HK2. Moreover, a xenograft model was established to evaluate the therapeutic effect of PG in vivo . Results PG decreased viability in dose-dependent manner and induced apoptosis via the intrinsic pathway, along with inhibiting glycolysis in the ccRCC cell lines. Mechanistically, PG induced apoptosis and suppressed glycolysis by downregulating HK2. In vivo data also demonstrated that PG could exert an anti-tumor activity without any adverse side-effects. Conclusion PG induced mitochondrial apoptosis and inhibited glycolysis in clear-cell renal cell carcinoma. Our findings provide preliminary experimental data that support further investigation of the therapeutic efficacy of PG in ccRCC. [ABSTRACT FROM AUTHOR]

Objectives: Krüppel-like factor 5 (KLF5) modulates multiple cell processes in different cancers. It is frequently deleted and inactivated in prostate cancer and may exert a tumor suppressor function. However, how KLF5 inhibits the progression of prostate cancer is still not clear. In the present study, we identified how KLF5 and tumor necrosis factor α (TNFα) pathway, which can induce apoptosis in cancer, regulate each other in LNCaP prostate cancer cells.Material and Methods: The expression of messenger RNA and protein was detected by real-time polymerase chain reaction assay and western blot analysis, respectively. To identify whether KLF5 regulates the activity of TNFα downstream pathway, we constructed a stable KLF5 knockdown or KLF5 overexpressing cell line with lentivirus-containing short hairpin RNA targeting KLF5 or full-length KLF5 in LNCaP cells. Cell apoptosis was determined through flow cytometry assay. In addition, the regulation of KLF5 on target gene transcription was detected by reporter luciferase activity assay, and the binding of KLF5 on target promoter was detected through oligonucleotides pull-down analysis.Results: We found that TNFα induced the expression of KLF5 at both messenger RNA and protein levels; moreover, TNFα up-regulated KLF5 through TNF receptor 1 but not through TNF receptor 2 in LNCaP cells. Knockdown of KLF5 decreased apoptosis induced by TNFα, whereas cell apoptosis was increased by KLF5 overexpression. Consistently, expression of cleaved PARP and caspase-3 induced by TNFα was decreased by KLF5 knockdown, whereas it was increased by overexpressed KLF5. JNK activity is essential for the apoptosis induced by TNFα. We found that knockdown of KLF5 not only decreased the phosphorylation of JNK induced by TNFα, but also down-regulated the transcription of mitogen-activated protein kinase kinase 7 (MKK7), an upstream kinase of JNK, by binding to the MKK7 promoter.Conclusions: Our results indicate that KLF5 is an essential transcription regulator of MKK7 kinase and promotes the apoptosis induced by TNFα in LNCaP cells. Loss of KLF5 in prostate cancer may decrease cell response to TNFα-inducing apoptosis and facilitate cancer initiation and progression; moreover, KLF5 could be a potential molecular marker for predicting the effect of high-dose TNFα on tumor growth inhibition in prostate cancer. [ABSTRACT FROM AUTHOR]

• Morpholine containing 1,3,5-triazine derivatives were synthesized. • Derivatives exert potent PI3K/mTOR inhibitory activity. • Derivatives significantly inhibit cervical cancer cells. • The most potent compound 6 h showed significant Anti-cervical cancer activity in a tumor xenograft assay. This study describes the synthesis of novel 1,3,5-triazine derivatives as potent inhibitors of cervical cancer. The compounds were initially tested for inhibition of PI3K/mTOR, where they showed significant inhibitory activity. The top-ranking molecule (compound 6 h) was further tested against class I PI3K isoforms, such as PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ, where it showed the most significant activity against PI3Kα. Compound 6 h was then tested for anti-cancer activity against triple-negative breast cancer cells (MDA-MB321), human breast cancer cells (MCF-7), human cervical cancer cells (HeLa) and human liver cancer cells (HepG2), and it showed the greatest potency against HeLa cells. The effects of compound 6 h were further evaluated against the HeLa cells, where it showed significant attenuation of cell viability by inducing cell cycle arrest in the G1 phase. Compound 6 h induced apoptosis and reduced migration and invasion of HeLa cells. Western blotting analysis showed that 6 h inhibited PI3K and mTOR with positive modulation of Bcl-2 and Bax levels in HeLa cells. The effects of compound 6 h were also investigated in a tumour xenograft mouse model, where it showed reduction of tumour volume and weight. It also inhibited the PI3K/Akt/mTOR signalling cascade in xenograft tumour tissues, as evidenced by western blotting analysis. The results of the present study suggest the possible utility of the designed 1,3,5-triazine derivative as a potent inhibitor of cervical cancer. [ABSTRACT FROM AUTHOR]

Retraction Notice to "Physcion 8-O- -glucopyranoside induces apoptosis, suppresses invasion and inhibits epithelial to mesenchymal transition of hepatocellular carcinoma HepG2 cells of hepatocellular carcinoma HepG2 cells" [Biomedicine & Pharmacotherapy 83 (2016) 372-380] This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). As such this article represents a misuse of the scientific publishing system. [Extracted from the article]