RESUMEN

BACKGROUND: The testis-specific isoform of angiotensin-converting enzyme (tACE) is exclusively expressed in germ cells during spermatogenesis. Although the exact role of tACE in male fertility is unknown, it clearly plays a critical function in spermatogenesis. The dipeptidase domain of tACE is identical to the C-terminal catalytic domain of somatic ACE (sACE). Bradykinin potentiating peptides (BPPs) from snake venoms are the first natural sACE inhibitors described and their structure-activity relationship studies were the basis for the development of antihypertensive drugs such as captopril. In recent years, it has been showed that a number of BPPs - including BPP-10c - are able to distinguish between the N- and C-active sites of sACE, what is not applicable to captopril. Considering the similarity between tACE and sACE (and since BPPs are able to distinguish between the two active sites of sACE), the effects of the BPP-10c and captopril on the structure and function of the seminiferous epithelium were characterized in the present study. BPP-10c and captopril were administered in male Swiss mice by intraperitoneal injection (4.7 µmol/kg for 15 days) and histological sections of testes were analyzed. Classification of seminiferous tubules and stage analysis were carried out for quantitative evaluation of germ cells of the seminiferous epithelium. The blood-testis barrier (BTB) permeability and distribution of claudin-1 in the seminiferous epithelium were analyzed by hypertonic fixative method and immunohistochemical analyses of testes, respectively. RESULTS: The morphology of seminiferous tubules from animals treated with BPP-10c showed an intense disruption of the epithelium, presence of atypical multinucleated cells in the lumen and degenerated germ cells in the adluminal compartment. BPP-10c led to an increase in the number of round spermatids and total support capacity of Sertoli cell in stages I, V, VII/VIII of the seminiferous epithelium cycle, without affecting BTB permeability and the distribution of claudin-1 in the seminiferous epithelium. Interestingly, no morphological or morphometric alterations were observed in animals treated with captopril. CONCLUSIONS: The major finding of the present study was that BPP-10c, and not captopril, modifies spermatogenesis by causing hyperplasia of round spermatids in stages I, V, and VII/VIII of the spermatogenic cycle.

RESUMEN

Background The testis-specific isoform of angiotensin-converting enzyme (tACE) is exclusively expressed in germ cells during spermatogenesis. Although the exact role of tACE in male fertility is unknown, it clearly plays a critical function in spermatogenesis. The dipeptidase domain of tACE is identical to the C-terminal catalytic domain of somatic ACE (sACE). Bradykinin potentiating peptides (BPPs) from snake venoms are the first natural sACE inhibitors described and their structure-activity relationship studies were the basis for the development of antihypertensive drugs such as captopril. In recent years, it has been showed that a number of BPPs - including BPP-10c - are able to distinguish between the N- and C-active sites of sACE, what is not applicable to captopril. Considering the similarity between tACE and sACE (and since BPPs are able to distinguish between the two active sites of sACE), the effects of the BPP-10c and captopril on the structure and function of the seminiferous epithelium were characterized in the present study. BPP-10c and captopril were administered in male Swiss mice by intraperitoneal injection (4.7 mol/kg for 15 days) and histological sections of testes were analyzed. Classification of seminiferous tubules and stage analysis were carried out for quantitative evaluation of germ cells of the seminiferous epithelium. The blood-testis barrier (BTB) permeability and distribution of claudin-1 in the seminiferous epithelium were analyzed by hypertonic fixative method and immunohistochemical analyses of testes, respectively. Results The morphology of seminiferous tubules from animals treated with BPP-10c showed an intense disruption of the epithelium, presence of atypical multinucleated cells in the lumen and degenerated germ cells in the adluminal compartment. BPP-10c led to an increase in the number of round spermatids and total support capacity of Sertoli cell in stages I, V, VII/VIII of the seminiferous epithelium cycle, without affecting BTB permeability and the distribution of claudin-1 in the seminiferous epithelium. Interestingly, no morphological or morphometric alterations were observed in animals treated with captopril. Conclusions The major finding of the present study was that BPP-10c, and not captopril, modifies spermatogenesis by causing hyperplasia of round spermatids in stages I, V, and VII/VIII of the spermatogenic cycle.

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Micrurus snake bites can cause death by muscle paralysis and respiratory arrest, few hours after envenomation.The specific treatment for coral snake envenomation is the intravenous application of heterologous antivenom and, inBrazil, it is produced by horse immunization with a mixture of M. corallinus and M. frontalis venoms, snakes that inhabit theSouth and Southeastern regions of the country. However, this antivenom might be inefficient, considering the existence ofintra- and inter-specific variations in the composition of the venoms. Therefore, the aim of the present study was toinvestigate the toxic properties of venoms from nine species of Micrurus: eight present in different geographic regions ofBrazil (M. frontalis, M. corallinus, M. hemprichii, M. spixii, M. altirostris, M. surinamensis, M. ibiboboca, M. lemniscatus) and one(M. fulvius) with large distribution in Southeastern United States and Mexico. This study also analyzed the antigenic crossreactivityand the neutralizing potential of the Brazilian coral snake antivenom against these Micrurus venoms

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The genus Bothrops spp. is responsible for 90% of envenomation by snakes in Brazil, andthe standard treatment for snakebites is the antivenom therapy. The anti-bothropic serumproduced by Butantan Institute is prepared by the hyperimmunization of horses witha pool of venoms from Bothrops alternatus, Bothrops jararaca, Bothrops jararacussu, Bothropsmoojeni and Bothrops neuwiedi. In this study, the biochemical and biological characteristicsof the venoms from nineteen snakes of the genus Bothrops, responsible for human accidentsin Brazil, were analysed. Venoms, particularly from Crotalidae and Viperidae snakes,are rich sources of serine proteases and metalloproteases and the ability of the Braziliananti-bothropic serum to neutralize the proteolytic activity of these venoms were alsotested. The results obtained here show the existence of a large range of variation in thecomposition and activities in Bothrops spp. toxins and demonstrate that the anti-bothropicserum is not able to fully neutralize the toxic activities of all analysed venoms. Thesesuggest that for the preparation of a fully effective therapeutic anti-bothropic serum, othervenoms should be included in the immunization mixture.

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