Immunosuppressant Prograf® (Tacrolimus) Induces Histopathological Disorders in the Peritubular Tissue of Rat Testes

Caneguim, Breno Henrique; Cerri, Paulo Sérgio; Spolidório, Luís Carlos; Miraglia, Stefania; Sasso-Cerri, Estela

doi:10.1159/000322901

Cited by 7 publications

(12 citation statements)

References 82 publications

(59 reference statements)

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“…Thus, caspase‐3 immunolabelling and ultrastructural features are used for the identification of apoptotic cell death (Caneguim et al. ; Faloni et al. ; Longhini et al.…”

Section: Discussionmentioning

confidence: 99%

“…However, it has been reported that the TUNEL method should be combined with other markers to obtain a definitive identification of apoptotic cells (Danial & Korsmeyer, 2004;Cerri, 2005;Cerri & Katchburian, 2005). Thus, caspase-3 immunolabelling and ultrastructural features are used for the identification of apoptotic cell death (Caneguim et al 2011;Faloni et al 2012;Longhini et al 2013;Beltrame et al 2015). Strong immunolabelling for caspase-3 was observed in the cells of lamina propria, primarily in the mucosal penetration stage of the eruptive process, i.e., in the 16-day-old rats.…”

Section: Discussionmentioning

confidence: 99%

“…Caspases constitute a family of proteases that are involved in the complex and orchestrated cascade of molecular events that control cell death by apoptosis (Danial & Korsmeyer, 2004;Lockshin & Zakeri, 2004;Connolly et al 2014). Caspase-3 is an executor caspase (Green & Amarante-Mendes, 1998;Demon et al 2009;Khalil et al 2014) that is widely used as a marker of apoptosis (Huppertz et al 1999;Caneguim et al 2011;Faloni et al 2012;Longhini et al 2013). In addition, ultrastructural analysis of the lamina propria revealed cells with irregular nuclei with tortuous and conspicuous masses of condensed chromatin, which is typical of apoptosis (Cerri et al 2000;Cerri & Katchburian, 2005;Caneguim et al 2011;Longhini et al 2013;Beltrame et al 2015).…”

Section: Discussionmentioning

confidence: 99%

“…) and seems to play a key role in apoptotic cell death; therefore, it is considered to be a marker of apoptosis (Green, ; Gown & Willingham, ; Caneguim et al. ; Faloni et al. ).…”

Section: Introductionmentioning

confidence: 99%

“…Caspase enzymes are divided into two groups based on the timing of their involvement in the apoptotic processes: initiator caspases (such as caspase-1, -2, -4, -5, -8, -9, -10, -11 and -12) or executor caspases (such as caspase-3, -6 and -7) (Hyman & Yuan, 2012;Parrish et al 2013). Caspase-3 is activated by a variety of apoptotic signals including initiator caspases (Stennicke et al 1998) and seems to play a key role in apoptotic cell death; therefore, it is considered to be a marker of apoptosis (Green, 2000;Gown & Willingham, 2002;Caneguim et al 2011;Faloni et al 2012). Caspases are responsible for the cleavage of several structural proteins such as cytoplasmic cytoskeletal proteins, the degradation of nuclear proteins, and the activation of nucleases that lead to DNA fragmentation (Shi, 2002;Brentnall et al 2013).…”

Section: Introductionmentioning

confidence: 99%

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Apoptosis and reduced microvascular density of the lamina propria during tooth eruption in rats

2015

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During tooth eruption, structural and functional changes must occur in the lamina propria to establish the eruptive pathway. In this study, we evaluate the structural changes that occur during lamina propria degradation and focus these efforts on apoptosis and microvascular density. Fragments of maxilla containing the first molars from 9-, 11-, 13- and 16-day-old rats were fixed, decalcified and embedded in paraffin. The immunohistochemical detection of vascular endothelial growth factor (VEGF), caspase-3 and MAC387 (macrophage marker), and the TUNEL method were applied to the histological molar sections. The numerical density of TUNEL-positive cells and VEGF-positive blood vessel profiles were also obtained. Data were statistically evaluated using a one-way anova with the post-hoc Kruskal-Wallis or Tukey test and a significance level of P ≤ 0.05. Fragments of maxilla were embedded in Araldite for analysis under transmission electron microscopy (TEM). TUNEL-positive structures, fibroblasts with strongly basophilic nuclei and macrophages were observed in the lamina propria at all ages. Using TEM, we identified processes of fibroblasts or macrophages surrounding partially apoptotic cells. We found a high number of apoptotic cells in 11-, 13- and 16-day-old rats. We observed VEGF-positive blood vessel profiles at all ages, but a significant decrease in the numerical density was found in 13- and 16-day-old rats compared with 9-day-old rats. Therefore, the establishment of the eruptive pathway during the mucosal penetration stage depends on cell death by apoptosis, the phagocytic activity of fibroblasts and macrophages, and a decrease in the microvasculature due to vascular cell death. These data point to the importance of vascular rearrangement and vascular neoformation during tooth eruption and the development of oral mucosa.

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“…Thus, caspase‐3 immunolabelling and ultrastructural features are used for the identification of apoptotic cell death (Caneguim et al. ; Faloni et al. ; Longhini et al.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…) and seems to play a key role in apoptotic cell death; therefore, it is considered to be a marker of apoptosis (Green, ; Gown & Willingham, ; Caneguim et al. ; Faloni et al. ).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Apoptosis and reduced microvascular density of the lamina propria during tooth eruption in rats

2015

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Immunosuppressants and Male Reproduction

Drobnis

Nangia

2017

Advances in Experimental Medicine and Biology

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Prolonged use of immunosuppressant medications is occasionally seen in infertile men with chronic inflammatory conditions; autoimmune disorders; or an organ or hematopoietic stem cell transplant. Chronic inflammation impacts negatively on male reproductive endpoints, so immunosuppressant therapy can produce improvements. Corticosteroids have been used to treat antisperm antibodies and even as an empirical treatment for male infertility in general. Trials of these methods have provided mixed results on semen quality and fertility, with improvement, no change and negative effects reported by different investigators. In a substantial number of observational studies, patients on long-term therapy with prednisone for chronic inflammatory disease, testosterone levels were lower compared to untreated controls, though randomized controlled trials have not been conducted. Similarly decreases in testosterone have been reported in men receiving corticosteroids to minimize transplant rejection; however, most were treated with multiple immunosuppressive medications that may have contributed to this effect. A large number of trials of healthy men treated with corticosteroids have shown some disruption in reproductive hormone levels, but other studies reported no effect. Studies in monkeys, rats (at human equivalent dose), cattle, sheep, and horses have shown endocrine disruption, including low testosterone with dexamethasone treatment. Of the cytostatic immunosuppressives, which have high potential for cellular damage, cyclophosphamide has received the most attention, sometimes lowering sperm counts significantly. Methotrexate may decrease sperm numbers in humans and has significant negative impacts in rodents. Other chemotherapeutic drugs used as immunosuppressants are likely to impact negatively on male fertility endpoints, but few data have been collected. The TNF-α Inhibitors have also received little experimental attention. There is some evidence that the immunophilin modulators: cyclosporine, sirolimus, and everolimus cause endocrine disruption and semen quality impairment. As we review in this chapter, results in experimental species are concerning, and well-designed studies are lacking for the effects of these medications on reproductive endpoints in men.

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The antineoplastic busulphan impairs peritubular and Leydig cells, and vitamin B12 stimulates spermatogonia proliferation and prevents busulphan-induced germ cell death

Sasso-Cerri

Oliveira

Santi

et al. 2017

Biomedicine & Pharmacotherapy

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Busulphan (Bu), an alkylating agent used for bone marrow and spermatogonial stem cell transplantation (SSCT), impairs Sertoli (SC) cells, which are necessary for the spermatogonial stem cell (SSC) homing during transplantation. As Leydig (LC) and peritubular myoid (PMC) cells are essential for SC support and maintenance of spermatogonial niche, we evaluated the impact of Bu on the LC and PMC structural integrity. Vitamin B (B) has demonstrated beneficial effects against drug-induced testicular changes; thus, we also examined whether this vitamin is able to stimulate spermatogonia mitotic activity and prevent Bu-induced germ cell death. Rats received 10mg/kg of Bu in the 1st and 4th days, and daily B supplementation during Bu treatment and for 6days after the last injection of Bu (Bu-6d), totaling 10days of treatment. Other animals received the same treatment as Bu-6d, and B supplementation (Bu+7dB) or saline (Bu+7dS) for 7 more days, totaling 17days of treatment. Serum testosterone levels were measured. In the historesin-embedded testis sections, the seminiferous tubule and epithelial areas were measured, and the number of spermatogonia and PMC was quantified. Actin and 17β-HSD6 immunofluorescence was detected, and the number of TUNEL-positive LC and germ cells was computed. In Bu-6d, PMC number reduced, and a weak actin immunoexpression and death in these cells was observed. The testosterone levels reduced, and the interstitial tissue showed a weak 17β-HSD6 immunoexpression and increased number of TUNEL-positive LC. In Bu+7dB, the number of spermatogonia was higher than in Bu-6d and Bu+7dS, and the number of TUNEL-positive germ cells was significantly lower than in Bu+7dS. Bu exerts a harmful impact on PMC and LC, reducing the testosterone levels. Vitamin B prevents significantly Bu-induced germ cell death and stimulates spermatogonia proliferation, being a useful strategy for the enrichment of SSC in vitro and an adjuvant therapy for spermatogenesis recovery in oncologic patients.

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Immunosuppressant Prograf® (Tacrolimus) Induces Histopathological Disorders in the Peritubular Tissue of Rat Testes

Cited by 7 publications

References 82 publications

Apoptosis and reduced microvascular density of the lamina propria during tooth eruption in rats

Apoptosis and reduced microvascular density of the lamina propria during tooth eruption in rats

Immunosuppressants and Male Reproduction

The antineoplastic busulphan impairs peritubular and Leydig cells, and vitamin B12 stimulates spermatogonia proliferation and prevents busulphan-induced germ cell death

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