Crotoxin induces cytotoxic effects in human malignant melanoma cells in both native and detoxified forms.

Introduction: Melanoma, a highly aggressive skin cancer originating in melanocytes, poses a significant threat due to its metastatic potential. While progress has been made in treating melanoma with targeted therapies and immunotherapies, challenges persist. Crotoxin (CTX), the principal toxin in Crotalus durissus terrificus snake venom, exhibits various biological activities, including anti-tumoral effects across multiple cancers. However, its clinical use is limited by toxicity. Thus, exploring alternatives to mitigate adverse effects is crucial. Methods and Results: This study investigates the antitumoral potential of CTX in its native and in a detoxified form, in melanoma cells. Firstly, we demonstrated that detoxified CTX presented reduced phospholipase activity. Both forms proved to be more cytotoxic to SK-MEL-28 and MeWo melanoma cells than non-tumoral cells. In SK-MEL-28 cells, where cytotoxic effects were more pronounced, native and detoxified CTX induced increased necrosis and apoptosis rates. We also confirmed the apoptosis death demonstrated by the activation of caspase-3 and 7, and the formation of apoptotic bodies. Furthermore, both CTX caused cell cycle arrest at the G2/M phase, interfering with melanoma cell proliferation. Cell migration and invasion were also suppressed by both CTX. These results confirm the antitumoral potential of CTX. Discussion: The maintenance of the antiproliferative effects in the detoxified version, with reduced enzymatic activity often liked to harm effects, supports further studies to identify active parts of the molecule responsible for the interesting effects without causing substantial toxic events, contributing to the future use of CTX-derived drugs with safety and efficacy.

Combined expression of JHDM1D/KDM7A gene and long non-coding RNA RP11-363E7.4 as a biomarker for urothelial cancer prognosis.

Bladder cancer is the tenth most frequently diagnosed cancer globally. Classification of high- or low-grade tumors is based on cytological differentiation and is an important prognostic factor. LncRNAs regulate gene expression and play critical roles in the occurrence and development of cancer, however, there are few reports on their diagnostic value and co-expression levels with genes, which may be useful as specific biomarkers for prognosis and therapy in bladder cancer. Thus, we performed a marker lesion study to investigate whether gene/lncRNA expression in urothelial carcinoma tissues may be useful in differentiating low-grade and high-grade tumors. RT-qPCR was used to evaluate the expression of the JHDM1D gene and the lncRNAs CTD-2132N18.2, SBF2-AS1, RP11-977B10.2, CTD-2510F5.4, and RP11-363E7.4 in 20 histologically diagnosed high-grade and 10 low-grade tumors. A protein-to-protein interaction network between genes associated with JHDM1D gene was constructed using STRING website. The results showed a moderate (positive) correlation between CTD-2510F5.4 and CTD2132N18.2. ROC curve analyses showed that combined JHDM1D and RP11-363E7.4 predicted tumor grade with an AUC of 0.826, showing excellent accuracy. In conclusion, the results indicated that the combined expression of JHDM1D and RP11-363E7.4 may be a prognostic biomarker and a promising target for urothelial tumor therapy.

Crotoxin induces cytotoxic effects in human malignant melanoma cells in both native and detoxified forms

Introduction: Melanoma, a highly aggressive skin cancer originating in melanocytes, poses a significant threat due to its metastatic potential. While progress has been made in treating melanoma with targeted therapies and immunotherapies, challenges persist. Crotoxin (CTX), the principal toxin in Crotalus durissus terrificus snake venom, exhibits various biological activities, including anti-tumoral effects across multiple cancers. However, its clinical use is limited by toxicity. Thus, exploring alternatives to mitigate adverse effects is crucial. Methods and Results: This study investigates the antitumoral potential of CTX in its native and in a detoxified form, in melanoma cells. Firstly, we demonstrated that detoxified CTX presented reduced phospholipase activity. Both forms proved to be more cytotoxic to SK-MEL-28 and MeWo melanoma cells than non-tumoral cells. In SK-MEL-28 cells, where cytotoxic effects were more pronounced, native and detoxified CTX induced increased necrosis and apoptosis rates. We also confirmed the apoptosis death demonstrated by the activation of caspase-3 and 7, and the formation of apoptotic bodies. Furthermore, both CTX caused cell cycle arrest at the G2/M phase, interfering with melanoma cell proliferation. Cell migration and invasion were also suppressed by both CTX. These results confirm the antitumoral potential of CTX. Discussion: The maintenance of the antiproliferative effects in the detoxified version, with reduced enzymatic activity often liked to harm effects, supports further studies to identify active parts of the molecule responsible for the interesting effects without causing substantial toxic events, contributing to the future use of CTX-derived drugs with safety and efficacy.

Crotoxin induces cytotoxic effects in human malignant melanoma cells in both native and detoxified forms

Introduction: Melanoma, a highly aggressive skin cancer originating in melanocytes, poses a significant threat due to its metastatic potential. While progress has been made in treating melanoma with targeted therapies and immunotherapies, challenges persist. Crotoxin (CTX), the principal toxin in Crotalus durissus terrificus snake venom, exhibits various biological activities, including anti-tumoral effects across multiple cancers. However, its clinical use is limited by toxicity. Thus, exploring alternatives to mitigate adverse effects is crucial. Methods and Results: This study investigates the antitumoral potential of CTX in its native and in a detoxified form, in melanoma cells. Firstly, we demonstrated that detoxified CTX presented reduced phospholipase activity. Both forms proved to be more cytotoxic to SK-MEL-28 and MeWo melanoma cells than non tumoral cells. In SK-MEL-28 cells, where cytotoxic effects were more pronounced, native and detoxified CTX induced increased necrosis and apoptosis rates. We also confirmed the apoptosis death demonstrated by the activation of caspase-3 and 7, and the formation of apoptotic bodies. Furthermore, both CTX caused cell cycle arrest at the G2/M phase, interfering with melanoma cell proliferation. Cell migration and invasion were also suppressed by both CTX. These results confirm the antitumoral potential of CTX. Discussion: The maintenance of the antiproliferative effects in the detoxified version, with reduced enzymatic activity often liked to harm effects, supports further studies to identify active parts of the molecule responsible for the interesting effects without causing substantial toxic events, contributing to the future use of CTX-derived drugs with safety and efficacy.

Combined expression of JHDM1D/KDM7A gene and long non-coding RNA RP11-363E7.4 as a biomarker for urothelial cancer prognosis

Bladder cancer is the tenth most frequently diagnosed cancer globally. Classification of high- or low-grade tumors is based on cytological differentiation and is an important prognostic factor. LncRNAs regulate gene expression and play critical roles in the occurrence and development of cancer, however, there are few reports on their diagnostic value and co-expression levels with genes, which may be useful as specific biomarkers for prognosis and therapy in bladder cancer. Thus, we performed a marker lesion study to investigate whether gene/lncRNA expression in urothelial carcinoma tissues may be useful in differentiating low-grade and high-grade tumors. RT-qPCR was used to evaluate the expression of the JHDM1D gene and the lncRNAs CTD-2132N18.2, SBF2-AS1, RP11-977B10.2, CTD-2510F5.4, and RP11-363E7.4 in 20 histologically diagnosed high-grade and 10 low-grade tumors. A protein-to-protein interaction network between genes associated with JHDM1D gene was constructed using STRING website. The results showed a moderate (positive) correlation between CTD-2510F5.4 and CTD2132N18.2. ROC curve analyses showed that combined JHDM1D and RP11-363E7.4 predicted tumor grade with an AUC of 0.826, showing excellent accuracy. In conclusion, the results indicated that the combined expression of JHDM1D and RP11-363E7.4 may be a prognostic biomarker and a promising target for urothelial tumor therapy.

ANRIL, H19 and TUG1: a review about critical long non-coding RNAs in cardiovascular diseases

Cardiovascular diseases are the leading cause of death worldwide. They are non-transmissible diseases that affect the cardiovascular system and have different etiologies such as smoking, lipid disorders, diabetes, stress, sedentary lifestyle and genetic factors. To date, lncRNAs have been associated with increased susceptibility to the development of cardiovascular diseases such as hypertension, acute myocardial infarction, stroke, angina and heart failure. In this way, lncRNAs are becoming a very promising point for the prevention and diagnosis of cardiovascular diseases. Therefore, this review highlights the most important and recent discoveries about the mechanisms of action of the lncRNAs ANRIL, H19 and TUG1 and their clinical relevance in these pathologies. This may contribute to early detection of cardiovascular diseases in order to prevent the pathological phenotype from becoming established.

G Protein Subunit Beta 3 (GNB3) Variant Is Associated with Biochemical Changes in Brazilian Patients with Hypertension. / Variante da Subunidade Beta 3 da Proteína G ( GNB3 ) Está Associada a Alterações Bioquímicas em Pacientes Brasileiros com Hipertensão.

BACKGROUND: Central Illustration : G Protein Subunit Beta 3 (GNB3) Variant Is Associated with Biochemical Changes in Brazilian Patients with Hypertension. BACKGROUND: Genes and their variants associated with environmental factors contribute to the development of the hypertensive phenotype. The G protein beta 3 subunit gene (GNB3) is involved in the intracellular signaling process, and its variants have been related to susceptibility to arterial hypertension. OBJECTIVE: To determine the association of the GNB3 variant (rs5443:C>T) with arterial hypertension, biochemical parameters, age, and obesity in hypertensive and normotensive individuals from Ouro Preto, Minas Gerais, Brazil. METHOD: The identification of variants was performed by real-time PCR, using the TaqMan® system, in 310 samples (155 hypertensive and 155 normotensive). Biochemical analyses (renal function, lipid profile and glycemia) were performed from the serum using UV/Vis spectrophotometry and ion-selective electrode. A multiple logistic regression model was used to identify factors associated with arterial hypertension. The analysis of continuous variables with normal distribution was performed using the unpaired Student's t test; non-normal data were analyzed using Mann-Whitney. P < 0.05 was considered significant. RESULTS: The rs5443:C>T variant was not associated with arterial hypertension in the evaluated population (p = 0.88). Regarding biochemical measures, the T allele was associated with high levels of triglycerides, glucose and uric acid in hypertensive individuals (p < 0.05). CONCLUSION: These results show the importance of genetic diagnosis to prevent the causes and consequences of diseases and imply that the GNB3 rs5443:C>T variant may be associated with changes in the biochemical profile in hypertensive individuals.

ANRIL, H19 and TUG1: a review about critical long non-coding RNAs in cardiovascular diseases.

Cardiovascular diseases are the leading cause of death worldwide. They are non-transmissible diseases that affect the cardiovascular system and have different etiologies such as smoking, lipid disorders, diabetes, stress, sedentary lifestyle and genetic factors. To date, lncRNAs have been associated with increased susceptibility to the development of cardiovascular diseases such as hypertension, acute myocardial infarction, stroke, angina and heart failure. In this way, lncRNAs are becoming a very promising point for the prevention and diagnosis of cardiovascular diseases. Therefore, this review highlights the most important and recent discoveries about the mechanisms of action of the lncRNAs ANRIL, H19 and TUG1 and their clinical relevance in these pathologies. This may contribute to early detection of cardiovascular diseases in order to prevent the pathological phenotype from becoming established.

Variante da Subunidade Beta 3 da Proteína G ( GNB3 ) Está Associada a Alterações Bioquímicas em Pacientes Brasileiros com Hipertensão / G Protein Subunit Beta 3 (GNB3) Variant Is Associated with Biochemical Changes in Brazilian Patients with Hypertension

Resumo Fundamento Genes e suas variantes associadas a fatores ambientais contribuem para o desenvolvimento do fenótipo hipertenso. O gene da subunidade beta 3 da proteína G ( GNB3 ) está envolvido no processo de sinalização intracelular e suas variantes têm sido relacionadas à suscetibilidade à hipertensão arterial. Objetivo Determinar a associação da variante GNB3 (rs5443:C>T) com a hipertensão arterial, parâmetros bioquímicos, idade e obesidade em indivíduos hipertensos e normotensos de Ouro Preto, Minas Gerais. Método A identificação das variantes foi realizada por PCR em tempo real, utilizando o sistema TaqMan®, em amostras de 310 pacientes (155 hipertensos e 155 normotensos). Análises bioquímicas (função renal, perfil lipídico e glicemia) foram realizadas a partir do soro por meio de espectrofotometria UV/Vis e eletrodo íon-seletivo. Foi utilizado um modelo de regressão logística múltipla para identificar fatores associados à hipertensão arterial. A análise das variáveis contínuas com distribuição normal foi realizada usando o teste t de Student não pareado; dados não normais foram analisados usando o teste de Mann-Whitney. Valores de p < 0,05 foram considerados significativos. Resultados A variante rs5443:C>T não esteve associada à hipertensão arterial na população avaliada (p = 0,88). Em relação às medidas bioquímicas, o alelo T esteve associado a níveis elevados de triglicerídeos, glicose e ácido úrico em indivíduos hipertensos (p < 0,05). Conclusão Os presentes resultados mostram a importância do diagnóstico genético para prevenir as causas e consequências de doenças e sugerem que a variante GNB3 rs5443:C>T pode estar associada a alterações no perfil bioquímico em indivíduos hipertensos.

Abstract Background Genes and their variants associated with environmental factors contribute to the development of the hypertensive phenotype. The G protein beta 3 subunit gene (GNB3) is involved in the intracellular signaling process, and its variants have been related to susceptibility to arterial hypertension. Objective To determine the association of the GNB3 variant (rs5443:C>T) with arterial hypertension, biochemical parameters, age, and obesity in hypertensive and normotensive individuals from Ouro Preto, Minas Gerais, Brazil. Method The identification of variants was performed by real-time PCR, using the TaqMan® system, in 310 samples (155 hypertensive and 155 normotensive). Biochemical analyses (renal function, lipid profile and glycemia) were performed from the serum using UV/Vis spectrophotometry and ion-selective electrode. A multiple logistic regression model was used to identify factors associated with arterial hypertension. The analysis of continuous variables with normal distribution was performed using the unpaired Student's t test; non-normal data were analyzed using Mann-Whitney. P < 0.05 was considered significant. Results The rs5443:C>T variant was not associated with arterial hypertension in the evaluated population (p = 0.88). Regarding biochemical measures, the T allele was associated with high levels of triglycerides, glucose and uric acid in hypertensive individuals (p < 0.05). Conclusion These results show the importance of genetic diagnosis to prevent the causes and consequences of diseases and imply that the GNB3 rs5443:C>T variant may be associated with changes in the biochemical profile in hypertensive individuals.

Discovery of a new dihydroeugenol-chalcone hybrid with cytotoxic and anti-migratory potential: A dual-action hit for cancer therapeutics.

Cancer still represents a serious public health problem and one of the main problems related to the worsening of this disease is the ability of some tumors to develop metastasis. In this work, we synthesized a new series of chalcones and isoxazoles derived from eugenol and analogues as molecular hybrids and these compounds were evaluated against different tumor cell lines. This structural pattern was designed considering the cytotoxic potential already known for eugenol, chalcones and isoxazoles. Notably, chalcones 7, 9, 10, and 11 displayed significant activity (4.2-14.5 µM) against two cancer cell lines, surpassing the potency of the control drug doxorubicin. The reaction of chalcones with hydroxylamine hydrochloride provided the corresponding isoxazoles that were inactive against these cancer cells. The dihydroeugenol chalcone 7 showed the most promising results, demonstrating higher potency against HepG2 (CC50: 4.2 µM) and TOV-21G (CC50: 7.2 µM). Chalcone 7 was also three times less toxic than doxorubicin considering HepG2 cells, with a selectivity index greater than 11. Further investigations including clonogenic survival, cell cycle progression and cell migration assays confirmed the compelling antitumoral potential of chalcone 7, as it reduced long-term survival due to DNA fragmentation, inducing cell death and inhibiting HepG2 cells migration. Moreover, in silico studies involving docking and molecular dynamics revealed a consistent binding mode of chalcone 7 with metalloproteinases, particularly MMP-9, shedding light on its potential mechanism of action related to anti-migratory effects. These significant findings suggest the inclusion of compound 7 as a promising candidate for future studies in the field of cancer therapeutics.

Cytotoxic effect of crotoxin on cancer cells and its antitumoral effects correlated to tumor microenvironment: A review.

Cancer is the second leading cause of death worldwide, and despite the effort of standard treatments, the search for new tools against this disease is necessary. Importantly, it is known that the tumor microenvironment plays a crucial role in tumor initiation, progression, and response to therapies. Therefore, studies of potential drugs that act on these components are as critical as studies regarding antiproliferative substances. Through the years, studies of several natural products, including animal toxins, have been conducted to guide the development of medical compounds. In this review, we present the remarkable antitumor activities of crotoxin, a toxin from the rattlesnake Crotalus durissus terrificus, highlighting its effects on cancer cells and in the modulation of relevant elements in the tumor microenvironment as well as the clinical trials conducted with this compound. In summary, crotoxin acts through several mechanisms of action, such as activation of apoptosis, induction of cell cycle arrest, inhibition of metastasis, and decrease of tumor growth, in different tumor types. Crotoxin also modulates tumor-associated fibroblasts, endothelial cells, and immune cells, which contribute to its antitumoral effects. In addition, preliminary clinical studies confirm the promising results of crotoxin and support its potential future use as an anticancer drug.

LncRNA JHDM1D-AS1 Is a Key Biomarker for Progression and Modulation of Gemcitabine Sensitivity in Bladder Cancer Cells.

Long non-coding RNAs are frequently found to be dysregulated and are linked to carcinogenesis, aggressiveness, and chemoresistance in a variety of tumors. As expression levels of the JHDM1D gene and lncRNA JHDM1D-AS1 are altered in bladder tumors, we sought to use their combined expression to distinguish between low-and high-grade bladder tumors by RTq-PCR. In addition, we evaluated the functional role of JHDM1D-AS1 and its association with the modulation of gemcitabine sensitivity in high-grade bladder-tumor cells. J82 and UM-UC-3 cells were treated with siRNA-JHDM1D-AS1 and/or three concentrations of gemcitabine (0.39, 0.78, and 1.56 µM), and then submitted to cytotoxicity testing (XTT), clonogenic survival, cell cycle progression, cell morphology, and cell migration assays. When JHDM1D and JHDM1D-AS1 expression levels were used in combination, our findings indicated favorable prognostic value. Furthermore, the combined treatment resulted in greater cytotoxicity, a decrease in clone formation, G0/G1 cell cycle arrest, morphological alterations, and a reduction in cell migration capacity in both lineages compared to the treatments alone. Thus, silencing of JHDM1D-AS1 reduced the growth and proliferation of high-grade bladder-tumor cells and increased their sensitivity to gemcitabine treatment. In addition, the expression of JHDM1D/JHDM1D-AS1 indicated potential prognostic value in the progression of bladder tumors.

Resveratrol induces the production of reactive oxygen species, interferes with the cell cycle, and inhibits the cell migration of bladder tumour cells with different TP53 status.

Resveratrol is a polyphenolic compound whose antitumor activity has been demonstrated in several types of cancer. However, there are few studies on its molecular mechanisms of action in bladder cancer. Therefore, we aimed to evaluate resveratrol activity in bladder tumour cells with different TP53 gene status. Cytotoxicity, cell proliferation, reactive oxygen species (ROS) production, cell migration, mutagenicity, and CDH1, CTNNBIP1, HAT1, HDAC1, MYC, and SMAD4 gene expression were evaluated. An increase in ROS after resveratrol treatment was accompanied by reduced cell viability and proliferation in all cell lines. In TP53 wild-type cells, the inhibition of cell migration was accompanied by CDH1 and SMAD4 modulation. In TP53 mutated cells, cell migration inhibition with CDH1 and CTNNB1P1 upregulation was observed. In conclusion, resveratrol has antiproliferative effect in bladder tumour cells and its mechanism of action occurred through ROS production, interference with cell cycle, and inhibition of cell migration, independent of TP53 status.

Angiotensin-converting enzyme gene (ACE) polymorphisms are associated with dysregulation of biochemical parameters in hypertensive patients.

INTRODUCTION: The genetic component, including genes and their variants, plays a significant role in the pathophysiology of arterial hypertension (AH). Thus, clinical, epidemiological and genetic studies have been carried out to improve the understanding of disease mechanisms, improve diagnostic quality and contribute to prevention. OBJECTIVE: To determine the association of risk factors, biochemical parameters and different ACE gene polymorphisms with AH. METHOD: The case-control study was carried out in the population of Ouro Preto, Brazil. The subjects answered a questionnaire containing clinical and sociodemographic data. The ACE gene polymorphisms rs4291, rs4363 and rs4335 were evaluated by real time-polymerase chain reaction (real-time PCR) in 310 people (155 hypertensive and 155 normotensive patients), in addition to biochemical parameters. A multivariate logistic regression model was used to identify factors associated with AH. Analysis of continuous variables was performed using the Kruskal-Wallis test to assess significance between groups and Dunn's post-test for multiple comparisons. RESULTS: The results showed that AH was associated with age, education, smoking, obesity and high levels of triglycerides, sodium, glucose and uric acid. Regarding the biochemical parameters, in hypertensive patients, the rs4363 and rs4335 polymorphisms were associated with high levels of triglycerides, urea and glucose; the rs4291 polymorphism was associated with elevated urea and glucose levels. No association was detected between SNPs and HA. CONCLUSION: AH was associated with socioeconomic status, lifestyle habits and biochemical parameters. ACE polymorphisms may have influenced the levels of triglycerides, urea and glucose in hypertensive patients.

G protein subunit Beta 3 (GNB3) variant is associated with biochemical changes in brazilian patients with Hypertension

Background: Genes and their variants associated with environmental factors contribute to the development of the hypertensive phenotype. The G protein beta 3 subunit gene (GNB3) is involved in the intracellular signaling process, and its variants have been related to susceptibility to arterial hypertension. Objective: To determine the association of the GNB3 variant (rs5443:C>T) with arterial hypertension, biochemical parameters, age, and obesity in hypertensive and normotensive individuals from Ouro Preto, Minas Gerais, Brazil. Method: The identification of variants was performed by real-time PCR, using the TaqMan® system, in 310 samples (155 hypertensive and 155 normotensive). Biochemical analyses (renal function, lipid profile and glycemia) were performed from the serum using UV/Vis spectrophotometry and ion-selective electrode. A multiple logistic regression model was used to identify factors associated with arterial hypertension. The analysis of continuous variables with normal distribution was performed using the unpaired Student’s t test; non-normal data were analyzed using Mann Whitney. P < 0.05 was considered significant. Results: The rs5443:C>T variant was not associated with arterial hypertension in the evaluated population (p = 0.88). Regarding biochemical measures, the T allele was associated with high levels of triglycerides, glucose and uric acid in hypertensive individuals (p < 0.05). Conclusion: These results show the importance of genetic diagnosis to prevent the causes and consequences of diseases and imply that the GNB3 rs5443:C>T variant may be associated with changes in the biochemical profile in hypertensive individuals.

G protein subunit Beta 3 (GNB3) variant is associated with biochemical changes in brazilian patients with hypertension

Fundamento Genes e suas variantes associadas a fatores ambientais contribuem para o desenvolvimento do fenótipo hipertenso. O gene da subunidade beta 3 da proteína G ( GNB3 ) está envolvido no processo de sinalização intracelular e suas variantes têm sido relacionadas à suscetibilidade à hipertensão arterial. Objetivo Determinar a associação da variante GNB3 (rs5443:C>T) com a hipertensão arterial, parâmetros bioquímicos, idade e obesidade em indivíduos hipertensos e normotensos de Ouro Preto, Minas Gerais. Método A identificação das variantes foi realizada por PCR em tempo real, utilizando o sistema TaqMan®, em amostras de 310 pacientes (155 hipertensos e 155 normotensos). Análises bioquímicas (função renal, perfil lipídico e glicemia) foram realizadas a partir do soro por meio de espectrofotometria UV/Vis e eletrodo íon-seletivo. Foi utilizado um modelo de regressão logística múltipla para identificar fatores associados à hipertensão arterial. A análise das variáveis contínuas com distribuição normal foi realizada usando o teste t de Student não pareado; dados não normais foram analisados usando o teste de Mann-Whitney. Valores de p < 0,05 foram considerados significativos. Resultados A variante rs5443:C>T não esteve associada à hipertensão arterial na população avaliada (p = 0,88). Em relação às medidas bioquímicas, o alelo T esteve associado a níveis elevados de triglicerídeos, glicose e ácido úrico em indivíduos hipertensos (p < 0,05). Conclusão Os presentes resultados mostram a importância do diagnóstico genético para prevenir as causas e consequências de doenças e sugerem que a variante GNB3 rs5443:C>T pode estar associada a alterações no perfil bioquímico em indivíduos hipertensos.

Cytotoxic effect of crotoxin on cancer cells and its antitumoral effects correlated to tumor microenvironment: A review

Cancer is the second leading cause of death worldwide, and despite the effort of standard treatments, the search for new tools against this disease is necessary. Importantly, it is known that the tumor microenvironment plays a crucial role in tumor initiation, progression, and response to therapies. Therefore, studies of potential drugs that act on these components are as critical as studies regarding antiproliferative substances. Through the years, studies of several natural products, including animal toxins, have been conducted to guide the development of medical compounds. In this review, we present the remarkable antitumor activities of crotoxin, a toxin from the rattlesnake Crotalus durissus terrificus, highlighting its effects on cancer cells and in the modulation of relevant elements in the tumor microenvironment as well as the clinical trials conducted with this compound. In summary, crotoxin acts through several mechanisms of action, such as activation of apoptosis, induction of cell cycle arrest, inhibition of metastasis, and decrease of tumor growth, in different tumor types. Crotoxin also modulates tumor-associated fibroblasts, endothelial cells, and immune cells, which contribute to its antitumoral effects. In addition, preliminary clinical studies confirm the promising results of crotoxin and support its potential future use as an anticancer drug.

LncRNA JHDM1D-AS1 is a key biomarker for progression and modulation of gemcitabine sensitivity in bladder cancer cells

Long non-coding RNAs are frequently found to be dysregulated and are linked to carcinogenesis, aggressiveness, and chemoresistance in a variety of tumors. As expression levels of the JHDM1D gene and lncRNA JHDM1D-AS1 are altered in bladder tumors, we sought to use their combined expression to distinguish between low-and high-grade bladder tumors by RTq-PCR. In addition, we evaluated the functional role of JHDM1D-AS1 and its association with the modulation of gemcitabine sensitivity in high-grade bladder-tumor cells. J82 and UM-UC-3 cells were treated with siRNA-JHDM1D-AS1 and/or three concentrations of gemcitabine (0.39, 0.78, and 1.56 µM), and then submitted to cytotoxicity testing (XTT), clonogenic survival, cell cycle progression, cell morphology, and cell migration assays. When JHDM1D and JHDM1D-AS1 expression levels were used in combination, our findings indicated favorable prognostic value. Furthermore, the combined treatment resulted in greater cytotoxicity, a decrease in clone formation, G0/G1 cell cycle arrest, morphological alterations, and a reduction in cell migration capacity in both lineages compared to the treatments alone. Thus, silencing of JHDM1D-AS1 reduced the growth and proliferation of high-grade bladder-tumor cells and increased their sensitivity to gemcitabine treatment. In addition, the expression of JHDM1D/JHDM1D-AS1 indicated potential prognostic value in the progression of bladder tumors.

Modulation of non-coding RNAs by natural compounds as a potential therapeutical approach in oral cancer: A comprehensive review.

Oral cancer is a disease with high incidence and mortality worldwide, and its treatment still needs to be improved. The search for new therapies using natural products is strongly supported, given the wide chemical range of these compounds. In addition, phytochemicals can exert antitumor activities by several mechanisms of action, including the modulation of non-coding RNAs. Thus, in this review, we discussed the role of non-coding RNAs, including circular RNAs, microRNAs, and long non-coding RNAs, in oral cancer and presented their potential as treatment targets using natural products. Some natural products capable of being used to treat oral cancer have been suggested.

Sodium butyrate-loaded nanoparticles coated with chitosan for the treatment of neovascularization in age-related macular degeneration: Ocular biocompatibility and antiangiogenic activity.

Sodium butyrate-loaded nanoparticles coated chitosan (NaBu-loaded nanoparticles/CS) were developed to treat the choroidal neovascularization in wet age-related macular degeneration (AMD). The nanoparticles were produced by double emulsification and solvent evaporation technique, optimized by experimental statistical design, characterized by analytical methods, investigated in terms of in vitro and in vivo ocular biocompatibility, and evaluated as an antiangiogenic system in vivo. The NaBu-loaded nanoparticles/CS were 311.1 ± 3.1 nm in diameter with a 0.208 ± 0.007 polydispersity index; had a +56.3 ± 2.6 mV zeta potential; showed a 92.3 % NaBu encapsulation efficiency; and sustained the drug release over 35 days. The NaBu-loaded nanoparticles/CS showed no toxicity to human retinal pigment epithelium cells (ARPE-19 cells); was not irritant to the chorioallantoic membrane (CAM); did not interfere in the integrity of the retinal layers of rat's eyes, as detected by the Optical Coherence Tomography and histopathology; and inhibited the angiogenesis in CAM assay. The NaBu-loaded nanoparticles/CS could be a therapeutic alternative to limit the neovascularization in AMD.