Molecular Medicine Reports

Our medical research library holds 11 studies published in Molecular Medicine Reports (2009–2023). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 11 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: D. A. Spandidos
• Published: 2008 to the present, Greece
• Language: English
• ISSN: 1791-2997 (print), 1791-3004 (electronic)
• Its record in the NLM Catalog

2020s

• Immunohistochemical expression of cAMP in fluoroedenite‑induced malignant pleural mesothelioma: Preliminary results. G. Broggi, V. Filetti, G. Magro, et al. 2023;28(1). PubMed · Publisher

  Abstract

  Despite advances in understanding of the biology of malignant pleural mesothelioma (MPM), the prognosis of this malignancy remains poor. Although asbestos still remains the main pathogenic agent of MPM, other asbestos‑like fibers such as fluoro‑edenite (FE) fibers, induce MPM. Notable incidence and mortality rates of MPM have been found in Biancavilla, Italy, where FE fibers have been extracted from building materials for >50 years. Cyclic adenosine monophosphate (cAMP) is a secondary messenger that plays a key role in several physiological and pathological mechanisms regulating protein kinase A (PKA) and the CREB pathway. Hyperactivation of the cAMP/PKA/CREB pathway is involved in many neoplastic processes, including tumor cell proliferation, invasion and metastatic spread. The present study investigated immunohistochemical expression of cAMP in patients with FE‑induced MPM, which included six males and four females with an age range of 50‑93 years. There was high immunoexpression of cAMP in 5 out of 10 tumors while the remaining 5 cases showed low immunoexpression. In addition, there was a correlation between cAMP overexpression and decreased survival times (mean overall survival times, 7.5 months in high expression group vs. 18 months in low expression group).

• Transcriptomic alterations in malignant pleural mesothelioma cells in response to long‑term treatment with bullfrog sialic acid‑binding lectin. T. Tatsuta, A. Nakasato, S. Sugawara, et al. 2021;23(6). PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a universally lethal type of cancer that is increasing in incidence worldwide; therefore, the development of new drugs for MPM is an urgent task. Bullfrog sialic acid‑binding lectin (cSBL) is a multifunctional protein that has carbohydrate‑binding and ribonuclease activities. cSBL exerts marked antitumor activity against numerous types of cancer cells, with low toxicity to normal cells. Although in vitro and in vivo studies revealed that cSBL was effective against MPM, the mechanism by which cSBL exerts antitumor effects is not fully understood. To further understand the mechanism of action of cSBL, the present study aimed to identify the key molecules whose expression was affected by cSBL. The present study established cSBL‑resistant MPM cells. Microarray analyses revealed that there were significant pleiotropic changes in the expression profiles of several genes, including multiple genes involved in metabolic pathways in cSBL‑resistant cells. Furthermore, the expression of some members of the aldo‑keto reductase family was revealed to be markedly downregulated in these cells. Among these, it was particularly interesting that cSBL action reduced the level of AKR1B10, which has been reported as a biomarker candidate for MPM prognosis. These findings revealed novel aspects of the effect of cSBL, which may contribute to the development of new therapeutic strategies for MPM.

2010s

• Oxidative and cytotoxic stress induced by inorganic granular and fibrous particles. S. Helmig, D. Walter, J. Putzier, et al. 2018;17(6):8518-8529. PubMed · Publisher

  Abstract

  The hazards of granular and fibrous particles have been associated with the generation of reactive oxygen species (ROS), which in turn is often associated with physicochemical properties exhibited by these particles. In the present study, the ability of various types of fibrous and granular dusts to generate oxidative stress, and their cytotoxicity, was investigated. Biopersistent granular dusts employed in the present study included micro‑ and nanosized titanium dioxide with rutile or anatase crystal structure modifications. Additionally, glass fibres, chrysotile and crocidolite asbestos representative of fibrous dust were selected. Detailed characterisation of particles was performed using scanning electron microscopy, and the effect of exposure to these particles on cell viability and intracellular ROS generation was assessed by PrestoBlue and 2',7'‑dichlorofluorescein assays, respectively. A549 human lung epithelial adenocarcinoma cells were exposed to increasing concentrations (0.1‑10 µg/cm2) of particles and fibres for 24 h. Subsequently, the gene expression of X‑linked inhibitor of apoptosis (XIAP), superoxide dismutase (SOD)1 and SOD2 were analysed by reverse transcription‑quantitative polymerase chain reaction. All investigated granular particles induce ROS production in A549 lung carcinoma cells within 24 h. Hematite increased ROS production in a dose‑dependent manner. A concentration of >1 µg/cm2 TiO2 na with its disordered surface, demonstrated the greatest ability to generate ROS. Therefore, the crystalline surface structure of the particle may be considered as a determinant of the extent of ROS induction by the particle. Fibrous particle compared with granular particles were associated with a lower ability to generate ROS. Glass fibres did not significantly increase ROS production in A549 cells, but elevated gene expression of SOD2 was observed. The results demonstrated that in general, the ability of particles to generate ROS depends on their number and crystal phase. Therefore, the present study helps to understand the cause of particle toxicity.

• Immunomodulatory effects in workers exposed to naturally occurring asbestos fibers. C. Ledda, C. Costa, S. Matera, et al. 2017;15(5):3372-3378. PubMed · Publisher

  Abstract

  Natural asbestiform fibers are defined 'naturally occurring asbestos' (NOA) and refer to the mineral as a natural component of soils or rocks. The release of NOA fibers into the air from rocks or soils by routine human activities or natural weathering processes represents a risk for human beings. Fluoro-edenite (FE) is a NOA fiber detected in the benmoreitic lava in the area of Biancavilla, South-west slope of Mt. Etna. The aim of the present study was to investigate FE immunotoxicity pathways in a group of 38 occupationally exposed construction workers, in order to find any biological markers of its effect. Subjects underwent respiratory function tests and HRCT total chest scanning. Serum IL-1β, IL-6, IL-8 and TNF-α were measured. The presence of PPs was significantly greater in subjects exposed than in the control (25 vs. 2). In subjects exposed to FE, IL-1β and TNF-α values were significantly higher than the controls. The previously observed increase of IL-1β and IL-18 showed a probable involvement of the proteic complex defined inflammosome by FE fibers.

• Impact of biopersistent fibrous dusts on glycolysis, glutaminolysis and serine metabolism in A549 cells. S. Wache, S. Helmig, D. Walter, et al. 2017;16(6):9233-9241. PubMed · Publisher

  Abstract

  The conversion rates of different metabolic pathways summarized as a metabolic signature mirror the physiological functions and the general physiological status of a cell. The present study compared the impact of crocidolite and chrysotile asbestos, glass fibers and multi‑walled carbon nanotubes (MWCN) of two different lengths (1‑2 µm and 5‑15 µm) on the conversion rates in glycolysis, glutaminolysis and serine metabolism of A549 cells. The concentration tested was 1 µg/cm2 for all fibers. A concentration of 5 µg/cm2 was additionally used for chrysotile and crocidolite, and 25 µg/cm2 for glass fibers and MWCN. With respect to the inhibitory effect on cell proliferation and the extent of metabolic alterations, the present study revealed the following ranking among the fibers tested: Chrysotile>crocidolite>glass fibers>MWCN 5‑15 µm>MWCN 1‑2 µm. For the asbestos and glass fibers this ranking correlated best with the number of fibers. It appeared that the results observed for MWCN did not match this correlation. However, electron microscopy revealed an agglomeration of MWCN. The agglomeration decreased the toxicologically relevant number of fibers by forming larger particle‑like shapes and explained the smaller effects of MWCN 5‑15 µm and 1‑2 µm on cell proliferation and metabolism.

• New insights on 'old' toxicants in occupational toxicology (Review). C. Costa, E. Miozzi, M. Teodoro, et al. 2017;15(5):3317-3322. Review PubMed · Publisher

  Abstract

  In order to deliver the best possible working environment, it is essential to identify professional conditions that could be harmful for worker's health and prevent (or limit) the occurrence of such conditions. The appropriate use of personal protective equipment and the development of appropriate regulations allowed to reduce the prevalence of 'classic' occupational diseases, such as occupational hearing loss or asbestosis, just to name a few. Nowadays, environmental pollution seems to be one of the most relevant concerns for human and animal health, and toxicology is becoming one of the most prominent fields of interest in occupational settings. An increasing number of studies demonstrate that the presence of toxicants in the workplace could be responsible for the development of chronic diseases, even at doses that were considered 'safe'. The present review summarizes some of the most recent advancements in occupational toxicology, focusing on topics that have long been debated in the past and that have recently returned to the fore.

• Pro-oxidant activity of sulforaphane and cisplatin potentiates apoptosis and simultaneously promotes autophagy in malignant mesothelioma cells. Y.J. Lee, S.H. Lee. 2017;16(2):2133-2141. PubMed · Publisher

  Abstract

  Sulforaphane (SFN) is an isothiocyanate compound derived from glucoraphanin, which is found in cruciferous vegetables, and has been heralded as a chemopreventive and/or chemotherapeutic agent. The present study investigated the effects of SFN on enhancing the anticancer role of cisplatin (cis-dichlorodiammineplatinum; CDDP) in H‑28 malignant mesothelioma cells. At concentrations demonstrating limited toxicity in MeT‑5A normal human mesothelial cells, combination treatment with the two compounds exhibited synergistic growth‑inhibiting and apoptosis‑promoting activities, as demonstrated by a series of proapoptotic events, including reactive oxygen species accumulation, loss of mitochondrial membrane potential, upregulation of p53 expression, increased B‑cell lymphoma 2 (Bcl‑2) associated X protein/Bcl‑2 ratio, activation of caspase‑3, the occurrence of a sub‑G0/G1 peak and an increase in cells with pyknotic and fragmented nuclei, Annexin V‑phycoerythrin‑positive staining and G2/M phase‑transition delay in the cell cycle. The phosphorylation levels of Akt and mammalian target of rapamycin were reduced by the combination treatment, which was accompanied by a significant increase in the level of autophagosomal marker protein microtubule‑associated protein 1 light chain 3B‑II and the accumulation of acidic vesicular organelles. Pretreatment with the antioxidant N‑acetylcysteine attenuated both apoptosis and autophagy, whereas inhibition of autophagy by bafilomycin A1 potentiated apoptotic cell death following the combination treatment with SFN and CDDP. Considering the pro‑oxidant‑based combinational approach, the results of the present study provide a rationale for targeting cytoprotective autophagy as a potential therapeutic strategy for malignant mesothelioma.

• The c-Jun N-terminal kinase signaling pathway mediates chrysotile asbestos-induced alveolar epithelial cell apoptosis. P. Li, T. Liu, D.W. Kamp, et al. 2015;11(5):3626-34. PubMed · Publisher · Free full text

  Abstract

  Exposure to chrysotile asbestos exposure is associated with an increased risk of mortality in combination with pulmonary diseases including lung cancer, mesothelioma and asbestosis. Multiple mechanisms by which chrysotile asbestos fibers induce pulmonary disease have been identified, however the role of apoptosis in human lung alveolar epithelial cells (AEC) has not yet been fully explored. Accumulating evidence implicates AEC apoptosis as a crucial event in the development of both idiopathic pulmonary fibrosis and asbestosis. The aim of the present study was to determine whether chrysotile asbestos induces mitochondria‑regulated (intrinsic) AEC apoptosis and, if so, whether this induction occurs via the activation of mitogen‑activated protein kinases (MAPK). Human A549 bronchoalveolar carcinoma‑derived cells with alveolar epithelial type II‑like features were used. The present study showed that chrysotile asbestos induced a dose‑ and time‑dependent decrease in A549 cell viability, which was accompanied by the activation of the MAPK c‑Jun N‑terminal kinases (JNK), but not the MAPKs extracellular signal‑regulated kinase 1/2 and p38. Chrysotile asbestos was also shown to induce intrinsic AEC apoptosis, as evidenced by the upregulation of the pro‑apoptotic genes Bax and Bak, alongside the activation of caspase‑9, poly (ADP‑ribose) polymerase (PARP), and the release of cytochrome c. Furthermore, the specific JNK inhibitor SP600125 blocked chrysotile asbestos‑induced JNK activation and subsequent apoptosis, as assessed by both caspase‑9 cleavage and PARP activation. The results of the present study demonstrated that chrysotile asbestos induces intrinsic AEC apoptosis by a JNK‑dependent mechanism, and suggests a potential novel target for the modulation of chrysotile asbestos‑associated lung diseases.

• Induction of altered mRNA expression profiles caused by fibrous and granular dust. S. Helmig, E. Dopp, S. Wenzel, et al. 2014;9(1):217-28. PubMed · Publisher

  Abstract

  Natural and synthetic fibres and particles are being introduced into the workplace and environment daily. Comparative analyses of the induced signalling pathways are essential in order to understand the potential hazards of these particles. To identify the molecular characteristics of particles and fibres, we selected crocidolite and chrysotile asbestos as representatives for fibered dust and titanium dioxide (TiO2) (100-200 nm), zirconium dioxide (ZrO2) (50-100 nm) and hematite (Fe2O3) (20 nm) as representatives for bio-persistent granular dust. SV-40 virus-transformed human bronchial epithelial cells (BEAS-2B) were exposed to well-defined fibres and particles. RT2 Profiler™ PCR Array Human Stress & Toxicity PathwayFinder was used to compare the relative mRNA expression of 84 genes. A detailed characterization of the dust samples used in this study was accomplished to ensure comparability to other studies. Investigation of mRNA expression of 84 signalling molecules attributed to pathways such as DNA damage and repair; oxidative/metabolic stress; growth arrest and senescence; inflammation, proliferation and carcinogenesis; and heat shock and apoptosis revealed that crocidolite and chrysotile asbestos induced mRNA expression of pathway molecules involved in proliferation and carcinogenesis, as well as inflammation. Titanium dioxide, zirconium dioxide and hematite mainly induced pathway molecules responsible for oxidative/metabolic stress and inflammation. Our findings suggest that the hazards of fibered dust mainly include the induction of direct toxicity by altering signalling pathways such as carcinogenesis and proliferation, while granular dust shows indirect toxicity by altering signalling pathways involved in inflammatory processes. PCR arrays, therefore, may be a helpful tool to estimate the hazard risk of new materials.

2000s

• Activation of the PI3K-AKT pathway in human malignant mesothelioma cells. Y. Suzuki, H. Murakami, K. Kawaguchi, et al. 2009;2(2):181-8. PubMed · Publisher

  Abstract

  Malignant mesothelioma (MM) is a highly aggressive neoplasm, which is associated with asbestos exposure. The dysregulated phosphatidylinositol 3-kinase (PI3K)-AKT pathway plays an important role in cell proliferation, survival and motility in various cancers. In this study, we analyzed the activation status and underlying mechanisms of this pathway in MM cells using 21 cell lines. AKT activation was observed in 13 (62%) of the 21 MM cell lines under serum-starved conditions. Two cell lines, ACC-MESO-1 and Y-MESO-25, showed no expression of PTEN protein, while 7 other cell lines showed low expression of PTEN mRNA and protein compared to expression levels in an immortalized normal mesothelial cell line, MeT-5A. We found that PTEN inactivation in the ACC-MESO-1 and Y-MESO-25 lines was due to a 39.4-kb deletion including PTEN exon 2, and to a 7.7-kb deletion including exon 1, respectively. Re-expression of PTEN in these cells reduced the activity of colony formation in vitro. In contrast, no mutation of PIK3CA or LKB1 was found in any of the MM cell lines. These findings suggest that AKT is frequently activated in MM cells, in part due to the downregulation of PTEN. Thus, the PI3K-AKT signaling pathway is a potential therapeutic target for MM.

• CYP1A1 and CYP1B1 polymorphisms as modifying factors in patients with pneumoconiosis and occupationally related tumours: A pilot study. J. Schneider, U. Bernges. 2009;2(6):1023-8. PubMed · Publisher

  Abstract

  CYP1A1 and CYP1B1 are involved in the metabolism of carcinogens. The effect of CYP1A1 and CYP1B1 polymorphisms as genetic modifiers of risk was investigated in individuals with asbestos, silica dust or ionizing radiation-induced occupational tumours compared to exposed non-cancer subjects suffering from pneumoconiosis, particularly in relation to tobacco smoking. CYP1A1 T6235C, CYP1A1 A4889G and CYP1B1 codon 432 polymorphisms were determined by real-time PCR analysis in patients with asbestos-related lung cancer (n=39), patients with diffuse malignant mesotheliomas (n=19), lung cancer in silicosis patients (n=7), uranium miners with lung cancer (UMLC) (n=40), patients with asbestosis (n=181), and silicosis patients (n=204). The results were compared to those from a healthy unexposed control group (n=50) not exposed to carcinogenic (or fibrogenic) agents in the workplace. An additional healthy control group (n=134) comprised smokers and ex-smokers. Allele frequencies were within the range described for Caucasians. Multivariate analysis revealed that patients with occupational diseases with the susceptible CYP1A1 T6235C genotype had a calculated risk ranging from OR=0.5 (95% CI 0.18-1.36) for UMLC to OR=1.23 (95% CI 0.39-4.05) for uranium miners with silicosis. The risk for patients with the susceptible CYP1A1 A4889G allele was calculated as being between OR=0.39 (95% CI 0.10-1.54) for mesothelioma patients and OR=1.54 (95% CI 0.49-4.89) for UMLC. CYP1B1 Val432Leu polymorphisms were associated with a risk of OR=0.56 (95% CI 0.2-1.55) for UMLC and OR=1.52 (95% CI 0.68-3.39) for asbestos-exposed lung cancer patients. By analyzing the interaction between tobacco smoking, type of exposure to carcinogens and the genotypes, it was determined that smoking and the presence of the susceptible genotypes did not have a combined effect. In this pilot study, the analyzed polymorphism had no consistent modifying effect on pneumoconiosis or occupationally related tumours.

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