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Long non-coding RNA (lncRNA) TSPEAR-AS2 (TSPEAR Antisense RNA 2) participates in many human diseases, while its roles in rheumatoid arthritis (RA) are unknown. Plasma expression levels of TSPEAR-AS2 and microRNA (miR)-212-3p in both RA patients and healthy controls were measured by RT-qPCR. Diagnostic potentials of plasma TSPEAR-AS2 and miR-212-3p were assessed by ROC curve analysis. Normalized expression levels of TSPEAR-AS2 and miR-212-3p were subjected to Pearson's correlation coefficient to evaluate their corrections. TSPEAR-AS2 was significantly downregulated in RA patients, while plasma expression levels of miR-212-3p were significantly increased in RA patients. The expression of TSPEAR-AS2 and miR-212-3p showed promising diagnostic value for RA. Plasma expression levels of TSPEAR-AS2 and miR-212-3p were significantly and inversely correlated in RA patients but not in healthy controls. Besides, overexpression of TSPEAR-AS2 decreased the apoptosis of RA HFLSs, while miR-212-3p increased cell apoptosis. In addition, miR-212-3p attenuated the effects of overexpression of TSPEAR-AS2. Overexpression of TSPEAR-AS2 decreased the expression levels of miR-212-3p in HFLS, while overexpression of miR-212-3p did not affect the expression of TSPEAR-AS2. In conclusion, TSPEAR-AS2 is downregulated in RA and its overexpression can decrease the apoptosis of RA HFLSs by downregulating miR-212-3p.

This study aims to explore the crosstalk between GRP78/PERK/ATF-4 signaling pathway and renal apoptosis induced by nephropathogenic infectious bronchitis virus (NIBV). Hy-Line brown chickens were divided into two groups (Con, n  = 100 and Dis, n  = 200). At 28 days of age, each chicken in the Dis group was intranasally injected with SX9 strain (10 -5 /0.2 ml). Venous blood and kidney tissues were collected at 1, 5, 11, 18 and 28 days postinfection. Our results showed that NIBV infection upregulated the levels of creatinine, uric acid, and calcium (Ca 2+ ) levels. Histopathological examination revealed severe hemorrhage and inflammatory cell infiltration near the renal tubules. Meanwhile, NIBV virus particles and apoptotic bodies were observed by ultramicro electron microscope. In addition, RT-qPCR and Western blot showed that NIBV upregulated the expression of GRP78, PERK, eIF2α, ATF-4, CHOP, Caspase-3, Caspase-9, P53, Bax, and on the contrary, downregulated the expression of Bcl-2. Furthermore, immunofluorescence localization analysis showed that the positive expression of Bcl-2 protein was significantly decreased. Correlation analysis indicated that endoplasmic reticulum (ER) stress gene expression, apoptosis gene expression, and renal injury were potentially related. Taken together, NIBV infection can induce renal ER stress and apoptosis by activating of GRP78/PERK/ATF-4 signaling pathway, leading to kidney damage. IMPORTANCE Nephropathogenic infectious bronchitis virus (NIBV) induced renal endoplasmic reticulum stress in chickens. NIBV infection induced kidney apoptosis in chickens. GRP78/PERK/ATF-4 signaling pathway is potentially related to renal apoptosis induced by NIBV.

Increasing evidence indicates autophagy and apoptosis are involved in the toxicity mechanism of heavy metals. Our previous studies showed that cadmium (Cd) could induce autophagy and apoptosis in duck kidneys in vivo, nevertheless, the interaction between them has yet to be elucidated. Herein, the cells were either treated with 3CdSO 4 ·8H 2 O (0, 1.25, 2.5, 5.0 μM Cd) or/and 3-methyladenine (3-MA) (2.5 μM) for 12 h and the indictors related autophagy and apoptosis were detected to assess the correlation between autophagy and apoptosis induced by Cd in duck renal tubular epithelial cells. The results demonstrated that Cd exposure notably elevated intracellular and extracellular Cd contents, the number of autophagosomes and LC3 puncta, up-regulated LC3A, LC3B, Beclin-1, Atg5 mRNA levels, and Beclin-1 and LC3II/LC3I protein levels, down-regulated mTOR, p62 and Dynein mRNA levels and p62 protein level. Additionally, autophagy inhibitor 3-MA decreased Beclin-1, LC3II/LC3I protein levels and increased p62 protein level. Moreover, co-treatment with Cd and 3-MA could notably elevate Caspase-3, Cyt C, Bax, and Bak-1 mRNA levels, Caspase-3 and cleaved Caspase-3 protein levels, and cell apoptotic rate as well as cell damage, decreased mitochondrial membrane potential (MMP), Bcl-2 mRNA level and the ratio of Bcl-2 to Bax compared to treatment with Cd alone. Overall, these results indicate Cd exposure can induce autophagy in duck renal tubular epithelial cells, and inhibition of autophagy might aggravate Cd-induced apoptosis through mitochondria-mediated pathway., (Copyright © 2020 Elsevier Inc. All rights reserved.)

High doses of molybdenum (Mo) and cadmium (Cd) cause adverse reactions on animals, but the joint toxic effects of Mo and Cd on duck renal tubular epithelial cells are not fully illustrated. To investigate the combined effects of Mo and Cd on oxidative stress and mitochondrial apoptosis in primary duck renal tubular epithelial cells, the cells were either treated with (NH 4 ) 6 Mo 7 O 24 ·4H 2 O (480, 960 μM Mo), 3CdSO 4 ·8H 2 O (2.5, 5.0 μM Cd) or combination of Mo and Cd for 12 h, and then the joint cytotoxicity was evaluated. The results demonstrated that Mo or/and Cd exposure could induce release of intracellular lactate dehydrogenase, reactive oxygen species generation, acidification, increase levels of malondialdehyde and [Ca 2+ ]i, decrease levels of glutathione, glutathione peroxidase, catalase, superoxide dismutase, total antioxidant capacity, Na + /K + -ATPase, Ca 2+ -ATPase, and mitochondrial membrane potential; upregulate mRNA levels of Caspase-3, Bak-1, Bax, and cytochrome C, inhibit Bcl-2 mRNA level, and induce cell apoptosis in a dose-dependent manner. Furthermore, the changes of these indicators in co-treated groups were more remarkable. The results indicated that exposure to Mo or/and Cd could induce oxidative stress and apoptosis via the mitochondrial pathway in duck renal tubular epithelial cells and the two metals may have a synergistic effect., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Oxaliplatin has been widely applied in clinical tumor chemotherapy, the treatment failure of which mainly blames on low susceptibility resulted from intrinsic or acquired drug resistance in tumor cells. Microenvironmental hypoxia is one of the important pathological features of solid tumors, which is closely related to the radiochemotherapy tolerance and poor prognosis. Cinnamaldehyde is extracted from Cinnamomum cassia with inhibiting effect against kinds of tumors. In this study, we demonstrated that hypoxia reduced the sensitivity to oxaliplatin in colorectal cancer (CRC) cells via inducing EMT and stemness. Nonetheless, cinnamaldehyde increased the curative effect of oxaliplatin by promoting apoptosis both in vitro and in vivo. Mechanistically, cinnamaldehyde and oxaliplatin synergistically reversed hypoxia-induced EMT and stemness of CRC cells and suppressed hypoxia-activated Wnt/β-catenin pathway synergistically. These consequences uncovered the potential therapeutic value of cinnamaldehyde and provided novel ideas on improving the sensitivity of oxaliplatin in CRC therapy., (Copyright © 2019. Published by Elsevier Inc.)

To investigate the effects of co-exposure to molybdenum (Mo) and cadmium (Cd) on oxidative stress and cell apoptosis in caprine livers, 36 Boer goats were randomly divided into four groups with nine goats in each group. Three groups were randomly assigned with one of three oral treatments of CdCl2 (0.5 mg Cd kg(-1)·BW) and [(NH4)6Mo7O24·4H2O] (15 mg Mo kg(-1)·BW, 30 mg Mo kg(-1)·BW, 45 mg Mo kg(-1)·BW), while the control group received deionized water. Liver tissues on days 0, 25, and 50 were subjected to determine antioxidant activity indexes and the messenger RNA (mRNA) expression levels of ceruloplasmin (CP), cysteinyl aspartate-specific proteinase-3 (caspase-3), second mitochondria-derived activator of caspases (Smac), and cytochrome-C (Cyt-C) genes. The results showed that significant reductions were observed in total antioxidant capacity (T-AOC) and total superoxide dismutase (T-SOD) activities (P < 0.05), while activities or contents of malondialdehyde (MDA), nitric oxide (NO), and nitric oxide synthase (NOS) were increased (P < 0.05). The mRNA expression levels of CP, caspase-3, Smac, and Cyt-C genes were upregulated (P < 0.05). In addition, histopathological lesions showed different degrees of vacuolar degeneration and edematous and mitochondrial swelling. The results suggest that co-exposure to Mo and Cd could induce oxidative stress and cell apoptosis possibly associated with mitochondrial intrinsic pathway in goat liver and show possible synergistic effects between the two elements.

Molybdenum (Mo) is an essential element for human beings and animals; however, high dietary intake of Mo can lead to adverse reactions. Cadmium (Cd) is one of the major transitional metals which have toxic effects in animals. The toxicity of simple Cd or Mo has been researched frequently. However, the toxicity of Mo combined with Cd was rarely studied. To investigate the toxicity of Mo combined with Cd in liver of goats, 36 Boer goats were randomly divided into four groups and assigned with one of the three oral treatments of CdCl2 (0.5 mg kg(-1) Cd) and [(NH4)6Mo7O24·4H2O] (15 mg kg(-1) Mo, group I; 30 mg kg(-1) Mo, group II; 45 mg kg(-1) Mo, group III), while the control group received deionized water. Blood samples were collected on days 0, 10, 20, 30, 40, and 50 to determine antioxidant indices in serum. In addition, liver tissues were collected on days 0, 25, and 50 for detecting the messenger RNA (mRNA) expression levels of Bcl-2 and Bax. Moreover, liver tissues at 50 days were subjected to histopathological analysis with the optical microscope. The results revealed a significant increase (P < 0.05 or P < 0.01) in the levels of nitric oxide (NO), malonaldehyde (MDA), and the activity of nitrix oxide synthase (NOS) and a significant decline (P < 0.05) in the activities of total superoxide dismutase (T-SOD) and total antioxidative capacity (T-AOC). The mRNA expression level of Bcl-2 was suppressed (P < 0.05), while the expression of Bax was increased (P < 0.05) in liver. The histopathological changes were observed in the liver of goats including a small amount of erythrocyte, the unclear structure of hepatic cord and hepatic sinusoid, granular degeneration, vacuolar degeneration, and steatosis. In conclusion, combined chronic toxicity of Cd with different levels of Mo might induce goat liver cell apoptosis and cause oxidative stress in serum, and it showed a possible synergistic relationship between the two elements.

The present experiment aims at evaluating chronic toxic effects of the combination of cadmium (Cd) and molybdenum (Mo) according to residual element contents, apoptosis gene expression, and ultrastructure and histopathology changes of caprine spleen. In total, 36 Boer goats were randomly divided into four groups with the equal number in each group. The control group was orally administered with deionized water while the experimental groups I, II, and III were administered with the equal quantity of CdCl2 (1 mg kg(-1) BW) and (NH4)6·Mo7O24·4H2O including 15, 30, and 45 mg·Mo kg(-1) BW, respectively. Three individuals from each group were treated with euthanasia on days 0, 25, and 50. The data showed that the content of splenic residual Mo and Cd increased (P < 0.05) in the experimental groups on days 25 and 50, while no significant difference was observed in the content of Cu. The apoptosis-related gene expression levels including Bcl-2, Bax, Caspase-3, Smac, and ceruloplasmin (CP) were also determined. Results showed that significant reductions were observed in Bcl-2 and CP expressions (P < 0.01), while Caspase-3 gene was up-regulated (P < 0.05). However, no significant difference was observed in Smac and Bax expressions. Furthermore, on day 50, spleen tissues were presented to observe ultrastructural changes in lesions by means of transmission electron microscopy, with fragmentized nucleus, vesiculation of cytoplasm, mitochondria hyperplasia, and increasing lysosomes included. In addition, histopathology results corroborated the toxicity by showing cell hemorrhage, thickening central arteries, and enhanced capsule thickness. To sum up, our study revealed that the combination of Cd and Mo could induce remarkable damage to the spleen of goats by promoting cell apoptosis in the mitochondrial pathway and affecting the deposition of Mo and Cd.

Molybdenum (Mo) is an essential trace element for animals and humans. However, the high dietary intake of Mo leads to disease conditions in heavy metal pollution areas. To the best of our knowledge, the effect of high levels of Mo on the apoptosis of hepatocyte in goats has not been investigated. Therefore, the aim of the present in vivo study was to investigate the impact of Mo on mitochondrial oxidative stress and apoptosis genes in the liver using real-time quantitative polymerase chain reaction (RT-qPCR) and transmission electron microscopy, respectively. Thirty-six healthy goats were randomly divided into three groups: two groups treated with ammonium molybdate [(NH4)6·Mo7O24·H2O] at 15 and 45 mg Mo kg(-1) BW, respectively, and a control group without treatment. Liver samples were collected from individual goats at different time intervals. The levels of oxidative stress in the mitochondrial membrane and expression of liver-related apoptosis genes, including Bcl-2, Cyt c, caspase-3, and Smac, were examined. The results demonstrated that the levels of superoxide dismutase (SOD) and catalase (CAT) expression were significantly down-regulated in liver cells, whereas malondialdehyde (MDA), nitric oxide (NO), and total nitric oxide synthase (T-NOS) expression was up-regulated (P < 0.01). The expression of Smac, Cyt c, and caspase-3 was significantly up-regulated, whereas Bcl-2 expression was down-regulated in liver cells (P < 0.01). In addition, histopathological examination revealed varying degrees of vacuolization, irregularity, nuclear fission, and mitochondrial swelling and high-density electrons in the cytoplasm of hepatocytes in groups treated with 15 and 45 mg Mo kg(-1) BW. Thus, these results suggested that high molybdenum induced hepatocyte apoptosis and might involve a mitochondrial pathway.

In order to clarify the effects of the combination of Mo and Cd on goat and relationship between the two elements, combined chronic toxicity of cadmium with different levels of molybdenum in vivo on apoptosis gene and ultrastructure of spleen was evaluated with the methods of RT-qPCR and transmission electron microscopy. A total of thirty-six goats were randomly distributed in equal number into four groups. These groups were randomly assigned with one of three oral treatments of CdCl2 (0.5 mgCd kg(-1)) and [(NH4)6Mo7O24·4H2O] (15 mg Mo kg(-1), group I; 30 mg Mo kg(-1), group II; 45 mg Mo kg(-1), group III), while the control group received deionized water. Spleen tissues were taken from individual goat at different time intervals to measure the levels of apoptosis genes including Bcl-2, Bax, Cyt c, Caspase-3, Smac and ceruloplasmin (Cp). The results revealed that a significant suppression in Bcl-2 expression and increase in Cyt c, Caspase-3 and Cp expression in splenic cells. The Bax expression in group I and II was up-regulated, however, it displayed reduction in group III, whereas no statistical significance was observed on Smac expression. In addition, histopathologic injury revealed remarkable morphplogical changes on the splenocytes in the means of apoptosis including fragmentized nucleus, apoptotic body and vesiculation of cytoplasma and mitochondria. Taken together, combined chronic toxicity of cadmium with different levels of molybdenum induce goat spleen cell apoptosis associated with mitochondrial intrinsic pathway, and the two elements showed possible antergic relationship., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Molybdenum (Mo) is an essential microelement for the health of animals and human beings, and high dietary intake of Mo can lead to pathological conditions. However, the cytotoxic effects of high levels of Mo on the renal cells in ruminants have not been reported. Therefore, this in vivo study in goats was designed to investigate the impact of Mo on kidney-related apoptosis genes, and histopathological and ultrastructural changes in renal cells using real-time quantitative polymerase chain reaction (RT-qPCR), light microscopy, and transmission electron microscopy. A total of 48 goats were randomly distributed in equal number into four groups and assigned with one of three oral treatments of ammonium molybdate (15, 30, and 45 mg Mo kg(-1) BW), while control group received no Mo. Kidney tissues were taken from individual goat at days 0, 25, and 50 for determining expression of apoptosis genes including Bax, Bcl-2, Cyt c, caspase-3, and Smac. The results revealed that the expression of Bax, Smac, Cyt c, and caspase-3 was significantly (P < 0.05 or P < 0.01) upregulated in renal cells, whereas Bcl-2 was downregulated (P < 0.01). Histopathological lesions showed degeneration of renal tubule, glomerular atrophy, and dilation of Bowman's capsule. In addition, ultrastructural injury that predicted varying degrees of vacuolization, irregularity, fission of the nucleus, and swelling of mitochondria was observed in the cytoplasma of cells in groups treated with 30 and 45 mg Mo kg(-1). This concluded that high levels of molybdenum, which induces apoptosis of caprine renal cells, might be involved in the mitochondrial intrinsic pathway.

Cell therapy has emerged as an attractive therapeutic modality to treat myocardial infarction (MI) via repairing damaged myocardium, and mesenchymal stem cells (MSCs) are an appealing therapeutic approach for cardiac regeneration. However, the clinical application of MSC-based therapy is restricted because of the poor survival of implanted cells, and this poor survival remains poorly understood. Using a tumor necrosis factor (TNF)-α-induced bone marrow (BM)-MSC injury model in vitro and a rat MI model in vivo, we showed in the current study that miR-23a was involved in TNF-α-induced BM-MSC apoptosis through regulating caspase-7 and that the injection of BM-MSCs overexpressing miR-23a could improve left ventricular (LV) function and reduce infarct size in the rat MI model. Our findings elucidate the etiology of MI and provide an alternative treatment strategy for patients with heart failure caused by MI who are not optimal candidates for surgical treatment., (Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.)

We examined the effects of CD40 activation with dexamethasone (Dex) or 60Co-gamma-irradiation on the growth of malignant B cells in vitro, using the human multiple myeloma (MM) cell line, XG2, and the B lymphoma Daudi cell line as models. Both lines are resistant to Dex and irradiation; 10(-7)M Dex or 10 Gy of gamma-irradiation induced only minimal growth arrest and apoptosis of the cells. Treatment of the cells with the agonistic anti-CD40 monoclonal antibody 5C11 partially inhibited the proliferation of the Daudi cells; XG2 underwent apoptosis. XG2 is an Interleukin-6 (IL-6)-dependent myeloma cell line and CD40 activation blocked XG2 in the G1 phase of the cell cycle, in a manner similar to the effect of IL-6 deprivation. Daudi was blocked in the G2/M phase after treatment with the agonistic CD40 mAb 5C11. Furthermore, the activation of CD40 on Daudi and XG2 enhanced their sensitivity to dexamethasone-and gamma-irradiation -induced growth arrest and apoptosis. CD40 activation stimulated both anti-apoptotic Bcl-XL and pro-apoptotic Bax mRNA synthesis in the Daudi cell line; CD40 activation increased the Bax mRNA level but had no effect on the Bcl-XL mRNA level in the XG2 cell line. Apoptosis in both cell lines was associated with an increasing ratio of Bax-to-Bcl-XL both in mRNA and in protein levels. It is concluded that use of the anti-CD40 mAb 5C11 either by itself or in combination with chemotherapy and/or radiotherapy may have significant therapeutic potential.

Hexavalent chromium (Cr(VI)) is a hazardous substance that poses significant risks to environmental ecosystems and animal organisms. However, the specific consequences of Cr(VI) exposure in terms of liver damage remain incompletely understood. This study aims to elucidate the mechanism by which Cr(VI) disrupts mitochondrial dynamics, leading to hepatic injury in ducks. Forty-eight healthy 8-day-old ducks were divided into four groups and subjected to diets containing varying doses of Cr(VI) (0, 9.28, 46.4, and 232 mg/kg) for 49 days. Our results demonstrated that Cr(VI) exposure resulted in disarranged liver lobular vacuolation, along with increasing the serum levels of ALT, AST, and AKP in a dose-dependent manner, which indicated liver damage. Furthermore, Cr(VI) exposure induced oxidative stress by reducing the activities of T-SOD, SOD, GSH-Px, GSH, and CAT, while increasing the contents of MDA and H2O2. Moreover, Cr(VI) exposure downregulated the activities of CS and MDH, resulting in energy disturbance, as evidenced by the reduced AMPK/p-AMPK ratio and PGC-1α protein expression. Additionally, Cr(VI) exposure disrupted mitochondrial dynamics through decreased expression of OPA1, Mfn1, and Mfn2 and increased expression of Drp-1, Fis1, and MFF proteins. This disruption ultimately triggered mitochondria-mediated apoptosis, as evidenced by elevated levels of caspase-3, Cyt C, and Bax, along with decreased expression of Bcl-2 and the Bcl-2/Bax ratio, at both the protein and mRNA levels. In summary, this study highlights that Cr(VI) exposure induces oxidative stress, inhibits the AMPK-PGC-1α pathway, disrupts mitochondrial dynamics, and triggers liver cell apoptosis in ducks. [ABSTRACT FROM AUTHOR]

Lung cancer is the most commonly diagnosed type of cancer and the leading cause of cancer-associated death worldwide. MicroRNAs (miRNAs) are non-coding single-stranded RNA molecules of ∼20–25 nucleotides in length. Single nucleotide polymorphisms are a class of genetic variation in the human genome, which when present in miRNA genes are associated with the risk of developing cancer. This study aimed to identify whether the miRNA (miR)-608 polymorphism rs4919510 influenced the incidence of lung cancer, and to explore the underlying mechanisms of miR-608 in the pathogenesis of the disease. A total of 37 patients with non-small cell lung cancer (NSCLC) were selected to determine the expression levels of miR-608; 96 NSCLC patients and 136 cancer-free healthy controls were recruited to determine the incidence of miR-608 rs4919510 in lung cancer patients. Additionally, the impact of miR-608 on the expression of predicted target genes, cell migration, viability, proliferation, and apoptosis was also assessed. We found that the presence of miR-608 rs4919510 did not affect the susceptibility of patients to NSCLC or the maturation of miR-608. miR-608 expression levels were found to be downregulated in NSCLC tissues. Furthermore, overexpression of miR-608 promoted doxorubicin-induced apoptosis in NSCLC cell lines A549 and HCC4006 by inhibiting the expression of transcription factor activating enhancer-binding protein 4 (TFAP4), and high expression levels of TFAP4 were observed in NSCLC tissues. Therefore, our results may provide valuable insights for the chemotherapeutical treatment of NSCLC.

Oxidative stress can adversely affect the health status of the body, more specifically by causing intestinal damage by disrupting the permeability of the intestinal barrier. This is closely related to intestinal epithelial cell apoptosis caused by the mass production of reactive oxygen species (ROS). Baicalin (Bai) is a major active ingredient in Chinese traditional herbal medicine that has antioxidant, anti-inflammatory, and anti-cancer properties. The purpose of this study was to explore the underlying mechanisms by which Bai protects against hydrogen peroxide (H2O2)-induced intestinal injury in vitro. Our results indicated that H2O2 treatment caused injury to IPEC-J2 cells, resulting in their apoptosis. However, Bai treatment attenuated H2O2-induced IPEC-J2 cell damage by up-regulating the mRNA and protein expression of ZO-1, Occludin, and Claudin1. Besides, Bai treatment prevented H2O2-induced ROS and MDA production and increased the activities of antioxidant enzymes (SOD, CAT, and GSH-PX). Moreover, Bai treatment also attenuated H2O2-induced apoptosis in IPEC-J2 cells by down-regulating the mRNA expression of Caspase-3 and Caspase-9 and up-regulating the mRNA expression of FAS and Bax, which are involved in the inhibition of mitochondrial pathways. The expression of Nrf2 increased after treatment with H2O2, and Bai can alleviate this phenomenon. Meanwhile, Bai down-regulated the ratio of phosphorylated AMPK to unphosphorylated AMPK, which is indicative of the mRNA abundance of antioxidant-related genes. In addition, knockdown of AMPK by short-hairpin RNA (shRNA) significantly reduced the protein levels of AMPK and Nrf2, increased the percentage of apoptotic cells, and abrogated Bai-mediated protection against oxidative stress. Collectively, our results indicated that Bai attenuated H2O2-induced cell injury and apoptosis in IPEC-J2 cells through improving the antioxidant capacity through the inhibition of the oxidative stress-mediated AMPK/Nrf2 signaling pathway. [ABSTRACT FROM AUTHOR]

Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosisinducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced nonsmall- cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25mg/m2 on days 1 and 8 and cisplatin 30mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 μg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p < 0.0001). ORR was 46.78% in the dulanermin arm versus 30.00% in the placebo arm (p = 0.0019). Median OS was 14.6 months in the dulanermin arm versus 13.9 months in the placebo arm (HR, 0.94; 95% CI, 0.74 to 1.21, p = 0.64). The most common grade ≥ 3 adverse events (AEs) were oligochromemia, leukopenia, neutropenia, and oligocythemia. Overall incidence of AEs, grade ≥ 3 AEs, and serious AEs were similar across the two arms. Conclusion Addition of dulanermin to the NP regimen significantly improved PFS and ORR. However, our results showed that the combination of dulanermin with chemotherapy had a synergic activity and favorable toxic profile in the treatment of patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Solasodine is a main active component isolated from Solanum incanum L. that performs a wide range of functions containing anti-oxidant, anti-infection, and neurogenesis promotion. In this study, we explored the influence of solasodine on three types of human colorectal cancer ( CRC) cell lines. The results show that solasodine prohibited CRC cell proliferation dose- and time-dependently and impeded CRC cell motility by downregulating MMPs. Solasodine was also found to fuel caspase-cascade reaction and increase the ratio between Bax and Bcl-2 so as to induce CRC cell apoptosis. When cells were pretreated with AKT activator (insulin-like growth factor-1) followed by solasodine, the solasodine-induced apoptosis was partially abrogated by insulin-like growth factor-1. Moreover, solasodine hindered tumor development and stimulated similar mechanisms in vivo. In general, our study provides the first evidence that solasodine has a suppressive effect on CRC cells and that this agent may be a novel therapeutic drug for CRC treatment. [ABSTRACT FROM AUTHOR]

Aflatoxin B1 (AFB1) is a stable mycotoxin that contaminates animal feed on a large scale and causes severe damage to intestinal cells, induces inflammation and stimulates autophagy. Transient receptor potential mucolipin subfamily 1 (TRPML1) is a regulatory factor of autophagy, but the underlying mechanisms of TRPML1-mediated autophagy in AFB1 intestine toxicity remain elucidated. In the present study, AFB1 (0, 5, 10 μg/mL) was shown to reduce cell viability, increase reactive oxygen species (ROS) accumulation and apoptosis rate. Additionally, AFB1 caused structural damage to mitochondria and lysosomes and increased autophagosomes numbers. Furthermore, AFB1 promoted Ca2+ release by activating the TRPML1 channel, stimulated the expression of autophagy-related proteins, and induced autophagic flux blockade. Moreover, pharmacological inhibition of autophagosome formation by 3-methyladenine attenuated AFB1-induced apoptosis by downregulating the levels of TRPML1 and ROS, whereas blockade of autophagosome-lysosomal fusion by chloroquine alleviated AFB1-induced apoptosis by upregulating TRPML1 expression and exacerbating ROS accumulation. Intriguingly, blocking AFB1-induced autophagic flux generated ROS- and TRPML1-dependent cell death, as shown by the decreased apoptosis in the presence the free radical scavenger N-Acetyl- L -cysteine and the TRPML1 inhibitor ML-SI1. Overall, these results showed that AFB1 promoted apoptosis of IPEC-J2 cells by disrupting autophagic flux through activation of the ROS/TRPML1 pathway. [Display omitted] • AFB1 induces ROS accumulation and apoptosis in porcine intestinal epithelial cells. • AFB1 causes the blockage in autophagic flux in porcine intestinal epithelial cells. • Inhibition of autophagosome formation by 3-MA attenuate AFB1-induced apoptosis. • Blocking autophagosome-lysosome fusion by CQ exacerbates AFB1-induced apoptosis. • Inhibition of TRPML1 activates autophagic flux to relieve AFB1-induced apoptosis. [ABSTRACT FROM AUTHOR]

In this study, folic acid-conjugated lipid nanoparticles were successfully prepared to enhance the active targeting of capsaicin (CAP) in ovarian cancers. The particles were nanosized and exhibited a controlled release of drug in the physiological conditions. The folic acid (FA)-conjugated system exhibited a remarkably higher uptake of nanoparticles in the cancer cells compared to that of non-targeted system. The folate-conjugated CAP-loaded lipid nanoparticles (CFLN) upon interacting with cancer cells were internalized via receptor-mediated endocytosis mechanism and resulted in higher concentration in the cancer cells. Consistently, CFLN showed a remarkably higher toxic effect compared to that of non-targeted nanoparticle system. CFLN showed significantly higher cancer cell apoptosis with nearly 39% of cells in apoptosis chamber (early and late) compared to only ∼21% and ∼11% for CAP-loaded lipid nanoparticles (CLN) and CAP. The loading of drug in the lipid nanoparticle system extended the drug retention in the blood circulation and allowed the active targeting to specific cancer cells. The prolonged circulation of drug attributed to the antifouling property of polyethylene glycol molecule in the structure. Overall, study highlights that using targeting moiety could enhance the therapeutic response of nanomedicines in the treatment of solid tumors. [ABSTRACT FROM AUTHOR]

We examined the effects of CD40 activation with dexamethasone (Dex) or60Co-?-irradiation on the growth of malignant B cellsin vitro, using the human multiple myeloma (MM) cell line, XG2, and the B lymphoma Daudi cell line as models. Both lines are resistant to Dex and irradiation; 10-7M Dex or 10 Gy of ?-irradiation induced only minimal growth arrest and apoptosis of the cells. Treatment of the cells with the agonistic anti-CD40 monoclonal antibody 5C11 partially inhibited the proliferation of the Daudi cells; XG2 underwent apoptosis. XG2 is an Interleukin-6 (IL-6)-dependent myeloma cell line and CD40 activation blocked XG2 in the G1 phase of the cell cycle, in a manner similar to the effect of IL-6 deprivation. Daudi was blocked in the G2/M phase after treatment with the agonistic CD40 mAb 5C11. Furthermore, the activation of CD40 on Daudi and XG2 enhanced their sensitivity to dexamethasone-and ? -irradiation -induced growth arrest and apoptosis. CD40 activation stimulated both anti-apoptotic Bcl-XL and pro-apoptotic Bax mRNA synthesis in the Daudi cell line; CD40 activation increased the Bax mRNA level but had no effect on the Bcl-XL mRNA level in the XG2 cell line. Apoptosis in both cell lines was associated with an increasing ratio of Bax-to-Bcl-XL both in mRNA and in protein levels. It is concluded that use of the anti-CD40 mAb 5C11 either by itself or in combination with chemotherapy and/or radiotherapy may have significant therapeutic potential. [ABSTRACT FROM AUTHOR]

Copper (Cu) is a vital micronutrient required for numerous fundamental biological processes, but excessive Cu poses potential detrimental effects on public and ecosystem health. However, the molecular details linking endoplasmic reticulum (ER) stress and apoptosis in duck renal tubular epithelial cells have not been fully elucidated. In this study, duck renal tubular epithelial cells exposed to Cu sulfate (CuSO 4) (0, 100 and 200 μM) and a PERK inhibitor (GSK2606414, GSK, 1 μM) for 12 h were used to investigate the crosstalk between ER stress and apoptosis under Cu exposure. Cell and ER morphological and functional characteristics, intracellular calcium (Ca2+) levels, apoptotic rates, ER stress and apoptosis-related mRNA and protein levels were examined. The results showed that excessive Cu could cause ER expansion and swelling, increase the expression levels of ER stress-associated genes (PERK, eIF2α, ATF4 and CHOP) and proteins (p-PERK and CHOP), induce intracellular Ca2+ overload, upregulate the expression levels of apoptosis-associated genes (Bax, Bak1, Caspase9 and Caspase3) and the cleaved-Caspase3 protein, downregulate Bcl-xl and Bcl2 mRNA levels and trigger apoptosis. PERK inhibitor treatment could ameliorate the above changed factors caused by Cu. In conclusion, these findings indicate that excessive Cu could trigger ER stress via activation of the PERK/ATF4/CHOP signaling pathway and that ER stress might aggravate Cu-induced apoptosis in duck renal tubular epithelial cells. Image 1 • Copper (Cu) has toxic effect on duck renal tubular epithelial cells. • Cu could trigger endoplasmic reticulum (ER) stress via PERK/ATF4/CHOP pathway. • Cu could induce apoptosis in duck renal tubular epithelial cells. • ER stress might aggravate Cu-induced apoptosis via PERK/ATF4/CHOP pathway. [ABSTRACT FROM AUTHOR]

Atrazine (ATR), a water-soluble herbicide commonly used to control broad-leaf and monocotyledonous weeds, presents a significant risk to environmental soil and water quality. Exposure to ATR adversely affects human and animal health, frequently resulting in cardiac impairment. Curcumin (Cur), an acidic polyphenol derivative from plants acclaimed for its pronounced anti-inflammatory and antioxidant properties, has garnered interest as a potential therapeutic agent. However, whether it has the potential to ameliorate ATR-induced cardiac toxicity via modulation of endoplasmic reticulum stress (ERS) and apoptosis pathways in mice remains unclear. Our results showed that Cur supplementation attenuates ATR-induced cardiotoxicity, evidenced by decrease in creatine kinase and lactate dehydrogenase, key biochemical markers of myocardial injury, which have a more significant protecting effect in high-dose ATR induced injury. Histopathological and electron microscopy examinations further solidified these findings, demonstrating an amelioration in organellar damage, particularly in endoplasmic reticulum swelling and subsequent mitochondrial impairment. Additionally, ATR exposure augments ERS and triggers apoptotic pathways, as indicated by the upregulation of ERS-related gene expression (ATF6, CHOP, IRE1, GRP78) and pro-apoptotic markers (BAX, BAK1, Caspase3, Caspase. Intriguingly, Cur counteracts this detrimental response, significantly reducing ERS and pro-apoptotic signals at both transcriptional and translational levels. Collectively, our findings illuminate Cur's cardioprotective effect against ATR-induced injury, primarily through its anti-ERS and anti-apoptotic activities, underscoring Cur's potential as a therapeutic for ATR-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Purpose: To study the anti-proliferative and apoptotic influences of 6,7-dimethoxy-4'-hydroxy-8- formylflavon (DHF) from the leaves of Nicotiana tabacum L. in human hepatoma HepG2 cells, and the underlying mechanisms. Methods: The anti-proliferative effect of DHF (10 - 50 μg/mL) on HepG2 cells was assessed by CCK-8 assay. The pro-apoptotic effect of DHF (10, 20 and 30 μg/mL) on HepG2 cells was investigated via flow cytometry, while the mechanisms involved were studied using western blot. Xenograft assay was employed for determination of the in vivo effect of DHF (40 mg/kg/day) on HepG2 cell-induced tumor. Results: The proliferation of HepG2 cells was inhibited by DHF (IC50 = 25.87 μg/mL) due to apoptosis. In addition, xenograft assay revealed that HepG2 cell-induced tumor growth was significantly suppressed by DHF (p < 0.05 or 0.01) without any effects on mice body weights. The expressions of Survivin and Bcl-2 proteins were significantly decreased, while those of Bax, c-caspase-9, and ccaspase- 3 proteins were significantly increased by DHF (p < 0.05 or 0.01), leading to increase in cytoplasmic levels of Smac and cytochrome c proteins. Conclusion: The underlying mechanism DHF-mediated apoptotic changes in HepG2 cells in vitro and in vivo involves induction of the mitochondrial pathway of apoptosis. Thus, DHF is a good drug candidate for the development of an effective therapy for liver cancer. [ABSTRACT FROM AUTHOR]