Histology and histopathology Vol.29, nº 4 (2014)
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- PublicationOpen AccessM1- and M2-macrophage polarization in thioacetamide (TAA)-induced rat liver lesions; a possible analysis for hepato-pathology(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Wijesundera, Kavindra Kumara; Izawa, Takeshi; Murakami, Hiroshi; Tennakoon, Anusha Hemamali; Golbar, Hossain M.; Katou-Ichikawa, Chisa; Tanaka, Miyuu; Kuwamura, Mitsuru; Yamate, Jyoji“Classically activated macrophages (M1)” and “alternatively activated macrophages (M2)”, which appear in injured tissues, control either inflammation or remodeling. The mechanism remains unclear. To clarify the M1-/M2-macrophage polarization in acute liver injury, M1- and M2-related factors were analysed in F344 rats by a single injection of TAA (300 mg/kg BW), and liver samples were collected on post injection (PI) hour 10 and days 1 to 10. Macrophage immunopheno-types were analyzed by single and double immuno-labeling. M1-/M2-related factors were analyzed by real-time RT-PCR. On PI hour 10 (when centrilobular lesions were not still developed), expressions of IFN-γ, TNF-α, IL-1ß, and IL-6 for M1, and IL-4 for M2 were already increased, followed by increased expressions of IL-10 and TGF-ß1 for M2 on PI days 1-3 with development of centrilobular lesions and subsequent reparative fibrosis. On PI hour 10, CD204+ and MHC class II+ macrophages already increased in the intact periportal/Glisson’s sheath regions, accompanied by an increased number of granzyme B+ NK cells. Reactive cells at PI hour 10 might produce M1-related factors. In addition to these macrophages, CD68+ and CD163+ macrophages, and CD3+ T cells appeared in the injured centrilobular region on PI days 1-3; there were macrophages reacting simultaneously to CD68/MHC class II, CD163/MHC class II, CD68/CD204, CD163/CD204, and MHC class II/CD204 in varying degrees. Although CD68+ and CD163+ macrophages are regarded as M1- and M2-types, respectively, the double labeling indicated that macrophage immunophenotypes are interchangeable in injured regions and subsequent fibrosis. An M1-/M2-macrophage paradigm would be useful to analyze hepatotoxicity and to understand the pathogenesis. Histol Histopathol 29, 497-511 (2014)
- PublicationOpen AccessGender-related differences in kidney of rats with chronic renal failure(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Lemos, Carla C.S.; Mandarim-de-Lacerda, Carlos A.; Carvalho, Jorge J.; Bregman, RachelChronic renal failure is characterized by adaptive mechanisms secondary to the loss of functioning nephrons. Clinical and experimental studies suggest participation of gender-related hormones on renal function and progression of chronic renal failure. We evaluated the effect of castration on renal alterations in male and female Wistar control rats and after 30 days of chronic renal failure (CRF) induced by 5/6 nephrectomy. The CRF male group showed higher proteinuria. Glomerular hypertrophy was similar amogroups. Podocyte morphology showed disorders of foot processes and thickening of the basement membrane in the CRF male group. The CRF female group showed fewer alterations compared to males. Castration changed the profile in CRF male animals and the filtration barrier was preserved. CRF males showed the presence of alfa-smooth muscle actin suggesting an early prefibrotic event in this group. After castration this phenomenon was not observed. Noteworthy, in females, castration exacerbated the presence of alfa-smooth muscle actin. In summary, proteinuria was higher in males and appeared early in the course of CRF, probably contributing to fibrotic events. Data were influenced by gender suggesting that male sex hormones aggravate renal alterations. Histol Histopathol 29, 479-487 (2014)
- PublicationOpen AccessPrognostic impact of NDRG2 and NDRG3 in prostate cancer patients undergoing radical prostatectomy(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Ren, Guo-feng; Tang, Ling; Yang, Ai-qing; Jiang, Wei-wei; Huang, Yi-mingAim: To investigate the clinicopathologic significance of NDRG2 and NDRG3, and their involvement in recurrence-free survival (RFS) and overall survival (OS) of prostate cancer (PCa). Methods: NDRG2 and NDRG3 expression in 206 pairs of primary PCa and corresponding noncancerous prostate tissue samples from the same specimens were detected by immunohistochemistry. The association of NDRG2 and NDRG3 expression with the clinicopathologic features and with the prognosis of PCa was subsequently assessed. Results: In PCa tissues, NDRG2 expression was significantly downregulated, while NDRG3 expression was significantly upregulated (both P<0.001), compared with those in corresponding noncancerous prostate tissues. In addition, the downregulation of NDRG2 in PCa tissues was significantly correlated with advanced pathological stage (P=0.001), positive metastatic status (P=0.001) and high Gleason score (P=0.003), while the upregulation of NDRG3 in PCa tissues was significantly correlated with advanced pathological stage (P=0.006), positive metastatic status (P=0.001) and lymph node status (P=0.002). Furthermore, multivariate survival analysis showed low NDRG2 and high NDRG3 immunoreactivities were both significantly associated with short RFS and short OS in PCa independently of routine clinicopathological predictors. Conclusion: Our data offer convincing evidence for the first time that the aberrant expression of NDRG2 and NDRG3 may contribute to the malignant progression of PCa. More importantly, both the downregulation of NDRG2 and the upregulation of NDRG3 may be efficient prognostic indicators for PCa. Histol Histopathol 29, 535-542 (2014)
- PublicationOpen AccessTreatments of the injured tendons in Veterinary Medicine: from scaffolds to adult stem cells(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Patruno, Marco; Martinello, TizianaIn order to treat frequently occurring conditions such as traumatic rupture or over-strain tendinopathies, the techniques of tissue engineering and cell-based therapies have become an accepted modus operandi since other available remedies appear to be ineffective in restoring the original structure and function of the injured tissue. However, the mechanisms accounting for the effectiveness of novel regenerative approaches in treating equine tendon and ligament injuries remain poorly characterised. In this review we summarize and discuss the most significant results of our research regarding bioscaffold technology for treating complete tendon tears and the use of adult stem cells for treating tendon lesions induced by over-strain. Histol Histopathol 29, 417-422 (2014)
- PublicationOpen AccessEpithelial expression of vanilloid and cannabinoid receptors: a potential role in burning mouth syndrome pathogenesis(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Borsani, Elisa; Majorana, Alessandra; Cocchi, Marco Angelo; Conti, Giulio; Bonadeo, Sara; Padovani, Alessandro; Lauria, Giuseppe; Bardellini, Elena; Rezzani, Rita; Rodella, Luigi FabrizioBurning mouth syndrome (BMS) is an intra-oral burning sensation for which presently no medical or dental causes have been found, and in which the oral mucosa appears normal. It remains an unknown disease for which there is still no long-term treatment. The aim of this study was to assess the epithelial alteration of transient receptor potential vanilloid channel type 1 (TRPV1) and cannabinoid receptors type 1 (CB1) and type 2 (CB2) in the human tongue. The study was performed on eight healthy controls and eight BMS patients. All patients underwent a 3-mm punch biopsy at the anterolateral aspect of the tongue close to the tip. TRPV1, CB1 and CB2 immunohistochemistry was carried out showing an altered expression of all receptors. In BMS patients there was increased TRPV1, decreased CB1 and increased CB2 expression in tongue epithelial cells also associated with a change in their distribution. It would appear that these receptors are related to BMS. These data could be useful for future characterization of BMS epithelial markers and therapy. Histol Histopathol 29, 523-533 (2014)
- PublicationOpen AccessMelatonin influences pancreatic cancerogenesis(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Jaworek, Jolanta; Leja-Szpak, AnnaPancreatic cancer has fatal prognosis because of the absence of early symptoms, late diagnosis and the resistance to radio- and chemotherapy. Melatonin, an indoleamine discovered in the pineal gland, has also been detected in the gastrointestinal system and its specific receptors have been identified in the pancreas. Some evidence indicates that melatonin could modulate the process of pancreatic oncogenesis: 1) Melatonin, as direct scavenger of radical oxygen and nitrogen species (ROS and RNS) and activator of antioxidant enzymes effectively protects the pancreatic tissue against oxidative stress and inflammatory damage. 2) In pancreatic carcinoma cell line (PANC-1) melatonin used at high doses affects the Bax/Bcl protein balance, and stimulates the expressions of caspase-9 and caspase-3, thus activating the mitochondrial pathway of apoptosis. On the contrary, low concentrations of melatonin turn on the production of anti-apoptotic heat shock proteins: HSP27, HSP70, and HSP90, which prevents the activation of caspase-3. 3) Melatonin reduces angiogenesis and decreases proliferation of endothelial cells through inhibition of vascular endothelial factor (VEGF). 4) Melatonin strengthens the immune defense of the organism via activation of peripheral effector T cells and suppression of T regulatory cells. 5) In animal studies melatonin has been found to increase the efficacy of oncostatic drugs, to reduce the side effects of chemotherapy and to decrease morbidity. These observations suggest that melatonin at high doses could be potentially taken into consideration as the supportive treatment in the therapy of pancreatic cancer, although the effect of melatonin on apoptosis requires further study. Histol Histopathol 29, 423-431 (2014)
- PublicationOpen AccessToxicological aspects of injectable gold-hyaluronan combination as a treatment for neuroinflammation(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Pedersen, Dan Sonne; Locht, Linda J.; Tran, Thao P.; Markholt, Sara; Rungby, Jørgen; Larsen, AgneteSecondary inflammatory reactions to stroke or trauma contribute to irreplaceable loss of brain tissue of the affected patients. Likewise, neuroinflammatory processes are the main pathophysiological feature in Multiple Sclerosis (MS), a common neurodegenerative disease among young adults. In the search for safe and efficient ways to reduce inflammation within nervous tissue older immunosuppressive remedies have been re-investigated. The anti-inflammatory properties of gold salts are well known but result in uncontrollable systemic spread of gold ions, generating side effects such as nephrotoxicity, limiting their use. Recent studies have circumvented this obstacle by introducing metallic gold implants as a localized source of immune-modulating gold ions and suspension in hyaluronic acid (HA) enables injection of small amounts of gold in the natural spaces of the brain. By injecting >25 µm gold beads in HA intracerebrally we recently showed a slowing of disease progression in a rodent model of MS. The toxicological aspects were, however, not assessed. The present study investigates the viability of neuronal and macrophage cell cultures exposed to the gold/HA combination and the possible risk associated with unilateral gold/HA injection in young Balb/CA mice in the first 7 to 21 days of gold-exposure. Tracing by autometallography of gold accumulations throughout the brain exhibited sparse gold uptake in glia and neurons of hippocampus and cortex, and striatum and cerebellum were void of staining. No systemic spread of gold was seen in liver or kidney, nor were there signs of obstruction of the ventricular system. Both cell cultures of J774 macrophages and CCL neurons accumulated gold from gold/HA-exposure with no signs of reduced viability. In conclusion, our findings indicate that gold/HA is not overtly neuro- or cytotoxic, nor does intraventricular exposure result in widespread gold accumulation or tissue damage, warranting further studies into the pharmacological properties of this novel form of gold treatment. Histol Histopathol 29, 447-456 (2014)
- PublicationOpen AccessExpression of 11ß-hydroxysteroid dehydrogenase type 2 is deregulated in colon carcinoma(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Moravec, Martin; Švec, Jiří; Ergang, Peter; Mandys, Václav; Řeháková, Lenka; Zádorová, Zdena; Hajer, Jan; Kment, Milan; Pácha, JiříAlthough the effects of glucocorticoids on proliferation, differentiation and apoptosis are well known, and steroid hormones have been identified to play a role in pathogenesis and the development of various cancers, limited data are available regarding the relationship between the local metabolism of glucocorticoids and colorectal adenocarcinoma (CRC) formation. Glucocorticoid metabolism is determined by 11ß-hydroxysteroid dehydrogenases type 1 and 2 (11HSD1, 11HSD2), which increase the local concentration of cortisol due to the reduction of cortisone, or decrease this concentration due to the oxidation of cortisol. The objective of this study was to evaluate the extent of 11HSD1 and 11HSD2 mRNA in pre-malignant colorectal polyps and in CRC. The specimens were retrieved from patients by endoscopic or surgical resection and the expression of 11HSD1 and 11HSD2 was measured by real-time PCR. The polyps were of the following histological types: hyperplastic polyps and adenomas with low- or high-grade dysplasia. The neoplastic tissue of CRC obtained during tumor surgery was also studied. It was found that 11HSD2 was not only downregulated in CRC but already in the early stages of neoplastic transformation (adenoma with low-grade dysplasia). In contrast, the level of 11HSD1 was significantly increased in CRC but not in pre-malignant polyps. The results demonstrate that the downregulation of 11HSD2 gene expression is a typical feature of the development of colorectal polypous lesions and their transformation into CRC. Histol Histopathol 29, 489-496 (2014)
- PublicationOpen AccessEGFR, KRAS, BRAF, and PIK3CA characterization in squamous cell anal cancer(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Martin, Vittoria; Zanellato, Elena; Franzetti-Pellanda, Alessandra; Molinari, Francesca; Movilia, Alessandra; Paganotti, Alessia; Deantonio, Letizia; De Dosso, Sara; Assi, Agnese; Crippa, Stefano; Boldorini, Renzo; Mazzucchelli, Luca; Saletti, Piercarlo; Frattini, MiloBackground: Combined chemoradiation therapy is the gold standard in the treatment of squamous cell anal cancer (SCAC). However, even if the response rate is very high, many patients eventually relapse or experience a recurrence, thus requiring an invasive surgical procedure that has severe side effects. Most SCAC tumors overexpress epidermal growth factor receptor (EGFR); therefore, it is reasonable to consider anti-EGFR drugs as a new treatment option, as demonstrated by anecdotal reports. Promising results obtained in other solid tumors, both squamous and non-squamous, have revealed that an increase in the EGFR gene copy number may predict the efficacy of anti-EGFR therapies, while the presence of mutations in downstream members of the EGFR pathway may confer resistance. These markers have been only sporadically considered in SCAC. Methods: We investigated the status of the EGFR gene using FISH and examined KRAS, BRAF, and PIK3CA hot-spots mutations using sequencing analysis in a cohort of 84 patients affected by SCAC. Results: Twenty-eight patients (34%) showed an increase in EGFR gene copy number due to amplification (4%) or to polysomy (30%). KRAS and PIK3CA gene mutations were found in 4 (5%) and 13 patients (16%), respectively. No mutations were found in the BRAF gene. Conclusions: The characterization of the EGFR pathway may help in identifying different subgroups of SCAC that have specific molecular features, which may have implications in what targeted therapies are used to treat each patient. Histol Histopathol 29, 513-521 (2014)
- PublicationOpen AccessSOX7: From a developmental regulator to an emerging tumor suppressor(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Stoval, Daniel B.; Cao, Paul; Sui, GuangchaoSOX7 belongs to the SOX (SRY-related HMG-box) family of transcription factors that have been shown to regulate multiple biological processes, such as hematopoiesis, vasculogenesis and cardiogenesis during embryonic development. Recent studies indicate that several SOX family members play important roles in tumorigenesis. In this review, we introduce SOX7 gene and protein structures, and discuss its expression and functional role in cancer development and progression. SOX7 is frequently downregulated in many human cancers and its reduced expression correlates with poor prognoses of several cancers. Functional studies reveal many tumor suppressive properties of SOX7 in prostate, colon, lung, and breast cancers. To date, although a few target genes of SOX7 have been identified, SOX7-mediated gene expression has not been investigated in a cancer-relevant context. Our recent studies not only for the first time demonstrate a tumor suppressive role of SOX7 in a xenograft mouse model, but also unravel that many genes regulating cell death, growth and apoptosis are affected by SOX7, strongly supporting a pivotal role of SOX7 in tumorigenesis. Thus, currently available data clearly indicate a tumor suppressive role of SOX7, but the mechanisms underlying its gene expression and tumor suppressive activity remain undetermined. The research of SOX7 in cancers remains a fertile area to be explored. Histol Histopathol 29, 439-445 (2014)
- PublicationOpen AccessSignificance of the tumor protease cathepsin D for the biology of breast cancer(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Dian, Darius; Heublein, Sabine; Wiest, Irmi; Barthell, Lisa; Friese, Klaus; Jeschke, UdoCathepsin D is a protease involved in the metastasis and angiogenesis of mammary carcinomas. This review analyzes the significance of the tumor protease cathepsin D in mammary carcinomas as a tumor marker. We present a systematic overview based on a selective Medline search. Cathepsin D is expressed in mammary carcinomas and exhibits higher expression in invasive ductal carcinomas compared with lobular carcinomas. Nodal positive carcinomas showed reduced cathepsin D expression compared to lymph node metastases, and increased expression has been observed in hormone-receptor negative tumors. Thus, the expression of cathepsin varies between the two histological types. Increased cathepsin D expression in acinar affection has also been described. The lack of an association of cathepsin D with known prognostic factors such as CA15-3, ERalpha and ERbeta does not prevent it from being used as a tumor marker. Cathepsin has already been used along with other genes as a prognostic parameter for carcinoma patients in gene arrays. Histol Histopathol 29, 433-438 (2014)
- PublicationOpen AccessThe healing of alkali-injured cornea is stimulated by a novel matrix regenerating agent (RGTA, CACICOL20) - a biopolymer mimicking heparan sulfates reducing proteolytic, oxidative and nitrosative damage(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Cejkova, J.; Olmiere, C.; Cejka, C.; Trosan, P.; Holan, V.The efficacy of a chemically modified dextran - heparan sulfate mimicking regenerating agent (RGTA) on the healing of the rabbit cornea injured with alkali was examined. The eyes were injured with 0.15 N NaOH applied on the cornea or with 1.0 N NaOH using a 8 mm diameter filter paper disk. Then RGTA or placebo was applied on the cornea. In the last group of rabbits, corneas injured with the high alkali concentration were left without any treatment for four weeks; subsequently, the corneas were treated with RGTA or placebo. The central corneal thickness was measured using a pachymeter. The corneas were examined morphologically, immunohistochemically and for real time-PCR. Compared to control (unaffected) corneas, following the application of low alkali concentration the expression of urokinase-type plasminogen activator, metalloproteinase 9, nitric oxide synthase and xanthine oxidase was increased in the injured corneal epithelium of placebo-treated eyes, whereas the expression of antioxidant enzymes was reduced. Nitrotyrosine and malondialdehyde stainings appeared in the corneal epithelium. RGTA application suppressed the antioxidant/prooxidant imbalance and reduced the expression of the above-mentioned immunohistochemical markers. The corneal thickness increased after alkali injury, decreased during corneal healing after RGTA treatment faster than after placebo application. Following the injury with the high alkali concentration, corneal inflammation and neo-vascularization were highly pronounced in placebo-treated corneas, whereas in RGTA-treated corneas they were significantly supressed. When RGTA or placebo application was started later after alkali injury and corneas were ulcerated, subsequent RGTA treatment healed the majority of them. In conclusion, RGTA facilitates the healing of injured corneas via a reduction of proteolytic, oxidative and nitrosative damage. Histol Histopathol 29, 457-478 (2014)