Evaluation of the healing potential of Nile tilapia skin collagen in traumatic oral ulcers in male rats.

OBJECTIVE: To evaluate the healing potential of Nile tilapia skin collagen using a rat model with experimentally induced traumatic oral ulcers. DESIGN: Male Wistar rats were segregated into three experimental groups (n = 8/group/euthanasia day). Ulcers were induced using a dermatological punch on the left buccal mucosa. The rats were then euthanized on days 1, 5, 10, 15, and 20 (ntotal=120 rats). Each group received topical treatment, 2x/day, with 1 % Nile tilapia skin collagen orabase (experimental group), only orabase (negative control), or Oncilom-A® orabase (positive control). Ulcer area, closure percentage, and body mass variation were measured. Slides were prepared for histological analysis, which included Picrosirius red staining (collagen analysis), and immunohistochemistry (platelet endothelial cell adhesion molecule, alpha-smooth muscle actin, and transforming growth factor-beta). RESULTS: On day 15, the experimental and positive control groups displayed smaller ulcer areas, a higher percentage of closure, complete re-epithelialization, superior histological repair scores, and a reduced count of polymorphonuclear cells in comparison to the negative control group (p < 0.05). Additionally, the experimental group exhibited an increased number of blood vessels, total collagen (types I and III) and expression of platelet endothelial cell adhesion molecule, alpha-smooth muscle actin, and transforming growth factor-beta relative to the negative and positive control groups (p < 0.05). By day 20, the experimental group showed a more significant weight gain compared to the other groups (p < 0.0001). CONCLUSIONS: Nile tilapia skin collagen orabase optimizes the healing of traumatic ulcers by stimulating re-epithelialization, angiogenesis, and collagenesis. Transforming growth factor-beta plays a significant role in this process.

Effect of CYB2B6 (c.516G>T), CYP2C9 (c.1075A>C) and UGT1A9 (c.98T>C) polymorphisms on propofol pharmacokinetics in patients submitted to colonoscopy: a cohort study.

BACKGROUND: The aim of this study was to investigate the effect of CYB2B6 (c.516G>T, rs3745274), CYP2C9 (c.1075A>C, rs1057910) and UGT1A9 (c.98T>C, rs72551330) polymorphisms on the pharmacokinetics of single-drug propofol in adult patients undergoing intravenous sedation. METHODS: In this prospective clinical study, a total of 124 patients undergoing anaesthesia with propofol, as a single drug, were evaluated when undergoing colonoscopy procedure. Clinical variables were obtained from the patient's anamnesis prior to performing the anaesthetic procedure, in the moment of the patient's loss of consciousness, during the colonoscopy exam (recorded every 5 min) and in the awakening time. RESULTS: Polymorphic genotypes for the rs3745274 and rs1057910 polymorphisms were associated with bispectral index, target-controlled infusion (TCI)/effector concentration of propofol and TCI/plasma concentration of propofol values. Based on multivariate analysis, it was observed that weight, age, surgery time, systolic blood pressure and the rs1057910 polymorphism corresponded to predictive values for the dose of propofol used. Weight (B = 4.807±0.897), age (B = 1.834±0.834) and duration of surgery (B = 8.164±1.624) corresponded to factors associated with increased propofol dose, while systolic blood pressure (B = -1.892±0.679) and the genotypes (AA vs CA) of the single nucleotide polymorphism (SNP) rs1057910 CYPP2C9 gene (B = -74.161±26.820) decreased the total dose of propofol used. CONCLUSION: We concluded that the rs1057910 and rs3745274 polymorphisms affect the metabolism of propofol in patients exclusively submitted to this drug. Thus, the knowledge of the polymorphic genotypes of the CYPP2C9 and CYB2B6 genes may be predictive of different metabolising phenotypes, suggesting expected behaviours of BIS parameter in the anaesthetic procedure, which contributes to safer monitoring by anaesthesiologists during the clinical intervention.

Linha do tempo da pele de tilápia (Oreochromis niloticus) na medicina regenerativa moderna: Da bancada ao paciente / Timeline of tilapia skin (Oreochromis niloticus) in modern regenerative medicine: From bench to patient

OBJETIVO: Descrever a trajetória de desenvolvimento dos curativos biológicos oriundos de pele de tilápia (Oreochromis niloticus) em glicerol e liofilizada para uso em cirurgias externas e, posteriormente, uma matriz proteica acelular (scaffold) para uso interno. RESULTADOS: A pele de tilapia no glicerol e liofilizada foi aplicada com sucesso em mais de 550 pacientes queimados. A pele de tilápia liofilizada obteve sucesso no tratamento de 53 mulheres em vaginoplastias, em 160 pacientes na redesignação sexual e na preparação do leito da ferida na autoenxertia em 15 portadores da Síndrome de Apert. O scaffold está sendo empregado na oftalmologia na medicina veterinária na reconstrução de córnea em 420 cães, nas duroplastias na neurocirurgia nos testes em animais, e em estudos para uso cirúrgico em 10 especialidades médicas. CONCLUSÕES: O curativo de pele de tilápia supera desafios do tratamento de queimados do Brasil. É barato, biossustentável, efetivo e reduz a dor do paciente, propiciando melhores resultados com potencial redução de custos, contribuindo para a qualidade de vida dos pacientes. O sucesso da pesquisa confirma a pele de tilápia como um novo biomaterial de grande potencial em medicina regenerativa.

OBJECTIVE: To describe the development trajectory of biological dressings made from tilapia (Oreochromis niloticus) skin in glycerol and freeze-dried for use in external surgeries and, subsequently, an acellular protein matrix (scaffold) for internal use. RESULTS: Tilapia skin in glycerol and freeze-dried was successfully applied to more than 550 burn patients. Freeze-dried tilapia skin was successful in the treatment of 53 women undergoing vaginoplasty, in 160 patients in sexual reassignment and in preparing the wound bed in self-grafting in 15 patients with Apert Syndrome. The scaffold is being used in ophthalmology, veterinary medicine in corneal reconstruction in 420 dogs, in duraplasty in neurosurgery in animal tests, and in studies for surgical use in 10 medical specialties. CONCLUSIONS: The tilapia skin dressing overcomes challenges in treating burns in Brazil. It is cheap, biosustainable, effective and reduces patient pain, providing better results with potential cost reduction, contributing to patients' quality of life. The success of the research confirms tilapia skin as a new biomaterial with great potential in regenerative medicine.

Desenvolvimento de uma matriz acelular de pele tilápia para tratamento de feridas: Um estudo experimental / Development of acellular tilapia skin matrix for wound treatment: An experimental study

OBJETIVO: Produzir um scaffold baseado em matriz extracelular (SMEC) biocompatível, atóxico e estéril, para tratamento de queimaduras e feridas. Explorou-se a utilização da pele de tilápia como alternativa, ressaltando suas propriedades semelhantes à pele humana e sua aplicação bem-sucedida em diferentes áreas médicas. MÉTODO: Descreve o processo de preparação dos SMEC de pele de tilápia, incluindo etapas de desengorduramento, descontaminação, descelularização e irradiação por raios gama a 25kGy para esterilização. São realizados testes laboratoriais para avaliar a toxicidade celular in vitro pelo método do MTT, análises histológicas com coloração de hematoxilina-eosina, análises microbiológicas e de quantificação de DNA. RESULTADOS: Destacam que os SMEC produzidos foram descelularizados de maneira eficaz, preservando a matriz extracelular e mostrando-se não citotóxicos. Além disso, a análise microbiológica evidenciou a esterilidade dos materiais após a irradiação, comprovando sua adequação para aplicação clínica. A quantificação de DNA revelou a efetividade da descelularização, reduzindo significativamente o conteúdo de DNA original do tecido. CONCLUSÕES: Foi possível o desenvolvimento de uma matriz oriunda da pele de tilápia, sendo ela não citotóxica, estéril, portadora de morfologia adequada para aplicação clínica e acelular. Assim, contribuindo para inovação da ciência brasileira.

OBJECTIVE: To produce a biocompatible, non-toxic, and sterile scaffold based on extracellular matrix (ECM) for the treatment of burns and wounds. The utilization of tilapia skin was explored as an alternative, highlighting its similar properties to human skin and its successful application in different medical areas. METHODS: The process of preparing tilapia skin-derived ECM scaffolds is described, including steps of degreasing, decontamination, decellularization, and gamma ray irradiation at 25kGy for sterilization. Laboratory tests were conducted to assess in vitro cellular toxicity using the MTT method, histological analyses with hematoxylin-eosin staining, microbiological analyses, and DNA quantification. RESULTS: It is emphasized that the produced ECM scaffolds were effectively decellularized, preserving the extracellular matrix and demonstrating non-cytotoxicity. Furthermore, microbiological analysis evidenced the sterility of the materials after irradiation, confirming their suitability for clinical application. DNA quantification revealed the effectiveness of decellularization, significantly reducing the original DNA content of the tissue. CONCLUSIONS: The development of a tilapia skin-derived matrix was achieved, which is non-cytotoxic, sterile, possesses suitable morphology for clinical application, and is acellular. Thus, contributing to the innovation of Brazilian science.

Neovaginoplasty with tilapia fish skin: a series of eleven cases.

INTRODUCTION AND HYPOTHESIS: Mayer-Rokitansky-Küster-Hauser syndrome affects about 1 in 5000 live female births and is associated with gonadal dysgenesis and primary amenorrhea. Neovaginoplasty has been established as an appropriate treatment option for patients who have failed or denied dilation therapy. In search of accessible, economical material with low risk of complications, the team proposed the use of Nile tilapia fish skin (NTFS) as an innovative biomaterial in the neovaginoplasty procedure for vaginal agenesis management. NTFS has noninfectious microbiota, morphologic structure comparable to human skin and high in vivo bioresorption. METHODS: In this descriptive study, the method offered an anatomical and functional neovagina to 11 patients efficiently, quickly and safely. Correct post-surgical dilation is still extremely important to keep the neovagina's size > 6 cm. RESULTS: Histological and immunohistochemical analysis demonstrated the formation of a stratified squamous epithelium with strong marking for cytokeratins, FGF and EGFR, similar to healthy adult vaginal tissue. CONCLUSIONS: Since NTFS is a low cost and easily accessible biomaterial, this technique proves to be an inexpensive therapeutic possibility for the health system with excellent advantages for patients.

Effect of CYB2B6 (c.516G>T), CYP2C9 (c.1075A>C) and UGT1A9 (c.98T>C) polymorphisms on propofol pharmacokinetics in patients submitted to colonoscopy: a cohort study.

BACKGROUND: The aim of this study was to investigate the effect of CYB2B6 (c.516G>T, rs3745274), CYP2C9 (c.1075A>C, rs1057910) and UGT1A9 (c.98T>C, rs72551330) polymorphisms on the pharmacokinetics of single-drug propofol in adult patients undergoing intravenous sedation. METHODS: In this prospective clinical study, a total of 124 patients undergoing anaesthesia with propofol, as a single drug, were evaluated when undergoing colonoscopy procedure. Clinical variables were obtained from the patient's anamnesis prior to performing the anaesthetic procedure, in the moment of the patient's loss of consciousness, during the colonoscopy exam (recorded every 5 min) and in the awakening time. RESULTS: Polymorphic genotypes for the rs3745274 and rs1057910 polymorphisms were associated with bispectral index, target-controlled infusion (TCI)/effector concentration of propofol and TCI/plasma concentration of propofol values. Based on multivariate analysis, it was observed that weight, age, surgery time, systolic blood pressure and the rs1057910 polymorphism corresponded to predictive values for the dose of propofol used. Weight (B = 4.807±0.897), age (B = 1.834±0.834) and duration of surgery (B = 8.164±1.624) corresponded to factors associated with increased propofol dose, while systolic blood pressure (B = -1.892±0.679) and the genotypes (AA vs CA) of the single nucleotide polymorphism (SNP) rs1057910 CYPP2C9 gene (B = -74.161±26.820) decreased the total dose of propofol used. CONCLUSION: We concluded that the rs1057910 and rs3745274 polymorphisms affect the metabolism of propofol in patients exclusively submitted to this drug. Thus, the knowledge of the polymorphic genotypes of the CYPP2C9 and CYB2B6 genes may be predictive of different metabolising phenotypes, suggesting expected behaviours of BIS parameter in the anaesthetic procedure, which contributes to safer monitoring by anaesthesiologists during the clinical intervention.

Male-to-Female Gender-Affirming Surgery Using Nile Tilapia Fish Skin as a Biocompatible Graft.

STUDY OBJECTIVE: Insufficient penile skin is common during vaginoplasty for male-to-female transition. This issue may be compensated by a scrotal skin flap, with the drawback of hair growth [1]. In recent studies, Nile tilapia skin was successfully used for the surgical management of Mayer-Rokitansky-Küster-Hauser syndrome [2,3] and vaginal stenosis [4,5]. This study aims to describe a novel technique for primary vaginoplasty in male-to-female gender-affirming surgery using Nile tilapia skin as a biocompatible graft to ensure adequate vaginal depth. DESIGN: Stepwise demonstration of the procedure with narrated video footage. SETTING: Transgender health clinic. INTERVENTIONS: A 29-year-old patient with gender dysphoria was referred to our office because of a desire for gender-affirming surgery. A physical examination revealed normal male genitalia with a 14-cm-long penis. Before surgery, approval from the institutional review board and written permission from the patient were obtained. After orchiectomy, penile disassembly, perineal dissection, and urethroplasty were performed, and a hollow Nile tilapia skin mold was prepared and sutured to the distal edge of the remaining penile skin. This structure was inverted, covering the newly created canal. The neocavity was then filled with a handmade inflatable vaginal mold, held in place by sutures in the labia majora. Finally, labiaplasty and clitoroplasty were conducted. After 7 days, the inflatable mold was removed, and the use of progressively larger dilators was initiated. After 3 weeks, a neovagina that was 16 cm long and able to accommodate the width of 2 fingers was detected. At that time, the Nile tilapia skin was completely reabsorbed into the neovaginal mucosa. There were no complications in the early postsurgical period. CONCLUSION: Nile tilapia skin, a safe, low-cost, and easy-to-use biocompatible material, may be an alternative option to scrotal skin grafts for neovaginal augmentation in primary vaginoplasty for male-to-female gender transition. However, further studies are needed to confirm this assertive.

Synthesis of PJOV56, a new quinoxalinyl-hydrazone derivative able to induce autophagy and apoptosis in colorectal cancer cells, and related compounds.

Quinoxaline derivatives are reported as antineoplastic agents against a variety of human cancer cell lines, with some compounds being submitted to clinical trials. In this work, we report the synthesis, characterization and cytotoxicity potential of a new series of quinoxalinyl-hydrazones. The most cytotoxic compound was (E)-2-[2-(2-pyridin-2-ylmethylene)hydrazinyl]quinoxaline (PJOV56) that presented a time-dependent effect against HCT-116 cells. After 48 h of incubation, PJOV56 was able to induce autophagy and apoptosis of HCT-116 cells, mediated by upregulation of Beclin 1, upregulation of LC3A/B II and activation of caspase 7. Apoptosis was induced along with G0/G1 cell cycle arrest at the highest concentration of PJOV56 (6.0 µM). Thus, PJOV56 showed a dose-dependent mode of action related to induction of autophagy and apoptosis in HCT-116 cells.

Uso da pele de tilápia do Nilo em medicina regenerativa: Status atual e perspectivas futuras / Nile tilapia fish skin use in regenerative medicine: Current status and future perspectives

OBJETIVO: O presente estudo tem como objetivo apresentar a trajetória do desenvolvimento da pele de tilápia como curativo biológico. MÉTODO: Descrição do processo de desenvolvimento da pele de tilápia como curativo biológico, desde a concepção da ideia para utilização no tratamento de queimaduras, até as perspectivas de sua utilização como scaffold em múltiplas especialidades médicas. RESULTADOS: Com o objetivo de oferecer uma alternativa segura, eficaz e de baixo custo para o tratamento de queimaduras, pesquisadores brasileiros desenvolveram um curativo biológico derivado da pele de tilápia. CONCLUSÃO: A pele de tilápia vem demonstrando um notável potencial como curativo biológico no tratamento de queimaduras e na medicina regenerativa.

OBJECTIVE: The present study aims to present the development trajectory of the tilapia skin as a biological dressing. METHODS: To describe the development process of tilapia skin as biological dressing, from the conception to the burn wounds treatment to the perspectives of its use as a scaffold in multiple medical specialties. RESULTS: In order to provide a safe, effective and low-cost alternative for the treatment of burn injuries, Brazilian researchers have recently developed a biological dressing derived from tilapia skin. CONCLUSION: The tilapia skin have been demonstrating the remarkable potential as a biological dressing in burn injuries treatment and in regenerative medicine.

Natural products as new antimitotic compounds for anticancer drug development.

Cell cycle control genes are frequently mutated in cancer cells, which usually display higher rates of proliferation than normal cells. Dysregulated mitosis leads to genomic instability, which contributes to tumor progression and aggressiveness. Many drugs that disrupt mitosis have been studied because they induce cell cycle arrest and tumor cell death. These antitumor compounds are referred to as antimitotics. Vinca alkaloids and taxanes are natural products that target microtubules and inhibit mitosis, and their derivatives are among the most commonly used drugs in cancer therapy worldwide. However, severe adverse effects such as neuropathies are frequently observed during treatment with microtubule-targeting agents. Many efforts have been directed at developing improved antimitotics with increased specificity and decreased likelihood of inducing side effects. These new drugs generally target specific components of mitotic regulation that are mainly or exclusively expressed during cell division, such as kinases, motor proteins and multiprotein complexes. Such small molecules are now in preclinical studies and clinical trials, and many are products or derivatives from natural sources. In this review, we focused on the most promising targets for the development of antimitotics and discussed the advantages and disadvantages of these targets. We also highlighted the novel natural antimitotic agents under investigation by our research group, including combretastatins, withanolides and pterocarpans, which show the potential to circumvent the main issues in antimitotic therapy.

Prognostic importance of Aurora Kinases and mitotic spindle genes transcript levels in Myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) are a heterogeneous group of clonal disease characterized by insufficiency of bone marrow, increase of apoptosis and increased risk of acute leukemia progression. Proteins related to the mitotic spindle (AURKA, AURKB, TPX2), to the mitotic checkpoint (MAD2, CDC20) and the regulation of the cell cycle (p21) are directly related to chromosomal stability and tumor development. This study aimed to evaluate the mRNA expression levels of these genes in 101 MDS patients using a real-time PCR methodology. We identified that CDC20 expression are increased in patients with dysmegakaryopoiesis (p=0.024), thrombocytopenia (p=0.000) and high-risk patients (p=0.014, 0.018) MAD2 expression are decreased in patients with 2 or 3 cytopenias (p=0.000) and neutrophil below 800/mm3. TPX2 is also overexpressed in patients presenting dysmegakaryopoiesis (p=0.009). A decrease in AURKA and AURKB expression were observed in patients with altered karyotype (p=0.000), who presented dysplasia in 3 lineages (p=0.000; 0.017) and hemoglobin inferior to 8g/dL (p=0.024). The expression of AURKA, AURKB and MAD2 (p=0.000; 0.001; 0.025) were decreased in patients with hypoplastic MDS, associated with high frequency of chromosomal alterations and high mortality rate. This study reaffirms the importance of aurora kinases and mitotic spindle genes to the pathogenesis and clinical evolution of MDS.

Natural products as new antimitotic compounds for anticancer drug development

Cell cycle control genes are frequently mutated in cancer cells, which usually display higher rates of proliferation than normal cells. Dysregulated mitosis leads to genomic instability, which contributes to tumor progression and aggressiveness. Many drugs that disrupt mitosis have been studied because they induce cell cycle arrest and tumor cell death. These antitumor compounds are referred to as antimitotics. Vinca alkaloids and taxanes are natural products that target microtubules and inhibit mitosis, and their derivatives are among the most commonly used drugs in cancer therapy worldwide. However, severe adverse effects such as neuropathies are frequently observed during treatment with microtubule-targeting agents. Many efforts have been directed at developing improved antimitotics with increased specificity and decreased likelihood of inducing side effects. These new drugs generally target specific components of mitotic regulation that are mainly or exclusively expressed during cell division, such as kinases, motor proteins and multiprotein complexes. Such small molecules are now in preclinical studies and clinical trials, and many are products or derivatives from natural sources. In this review, we focused on the most promising targets for the development of antimitotics and discussed the advantages and disadvantages of these targets. We also highlighted the novel natural antimitotic agents under investigation by our research group, including combretastatins, withanolides and pterocarpans, which show the potential to circumvent the main issues in antimitotic therapy.