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1.
Braz. dent. j ; 33(5): 91-99, Sep.-Oct. 2022. tab, graf
Article in English | LILACS-Express | LILACS, BBO | ID: biblio-1403785

ABSTRACT

Abstract The present study analyzed the expression of proteins involved in the sonic hedgehog signaling pathway (SHH, SMO, and GLI-1) in benign epithelial odontogenic lesions (odontogenic keratocyst - OKC, ameloblastoma - AB, and adenomatoid odontogenic tumor - AOT) in order to identify the role of these proteins in the pathogenesis of these lesions. The sample consisted of 20 OKCs, 20 ABs, and 10 AOTs. The Kruskal-Wallis, Mann-Whitney U, and Spearman's (r) tests were used for statistical analysis, with the level of significance set at 5% (p < 0.05). The membrane/cytoplasmic expression of SHH was significantly higher in AB compared to AOT (p = 0.022) and OKC (p = 0.02). No differences were found in the membrane/cytoplasmic expression of SMO between the lesions studied. Regarding GLI-1, significant differences were observed at the nuclear level for AB and OKC compared to AOT (p < 0.0001). In addition, significant positive correlations were found between cytoplasmic and nuclear GLI-1 in AB (r = 0.482; p = 0.031) and OKC (r = 0.865; p < 0.0001), and between membrane/cytoplasmic SMO and cytoplasmic GLI-1 in AOT (r = 0.667; p = 0.035) and OKC (r = 0.535; p = 0.015). The results of this study confirm the participation of the sonic hedgehog signaling pathway in the pathogenesis of the lesions studied. Overexpression of SHH in ABs and nuclear expression of GLI-1 in ABs and OKCs indicate that these proteins contribute to the more aggressive behavior of these two lesions when compared to AOT.


Resumo O presente estudo analisou a expressão de proteínas envolvidas na via de sinalização Sonic Hedgehog (SHH, SMO e GLI-1) em lesões benignas do epitélio odontogênico de comportamento biológico distintos, tais como ceratocistos odontogênicos (CO), ameloblastomas (AMB) e tumores odontogênicos adenomatoides (TOA), com o intuito de identificar o papel destas proteínas na patogênese destas lesões. A amostra foi constituída de 20 CO, 20 AMB e 10 TOA, analisada pela técnica da imuno-histoquímica de forma semiquantitativa por compartimento celular, onde foi feita uma análise da membrana e citoplasma das células nas proteínas SHH e SMO, enquanto que para a proteína GLI-1, foi feita uma análise nuclear e/ou citoplasmática. Para análise estatística, foram utilizados os testes de Kruskal-Wallis (KW), Mann-Whitney (U) e Spearman (r), com o nível de significância estabelecido em 5% (p < 0,05). Ao analisar a proteína SHH, observou-se que o AMB demonstrou expressão membranar/citoplasmática significativamente maior em comparação ao TOA (p = 0,022) e CO (p = 0,020). Com relação à análise membranar/citoplasmática da SMO, não foram identificadas diferenças entre as lesões estudadas. Para a proteína GLI-1, foram constatadas diferenças estatisticamente significativas, em nível nuclear, para o AMB e CO em comparação ao TOA (p< 0,0001). Além disso, foram observadas correlações positivas com significância estatística entre GLI-1 citoplasmático e GLI-1 nuclear para o AMB (r = 0,482; p = 0,031) e CO (r = 0,865; p< 0,0001), e entre o SMO membranar/citoplasmático e o GLI-1 citoplasmático para o TOA (r = 0,667; p = 0,035) e o CO (r = 0,535; p = 0,015). Os resultados deste estudo confirmam a participação da via de sinalização Sonic Hedgehog na patogênese das lesões estudadas e, a superexpressão de SHH em AMBs e GLI-1 nuclear em AMBs e COs, indica que estas proteínas contribuem com o comportamento biológico mais agressivo destas duas lesões quando comparado ao TOA.

2.
Article in Chinese | WPRIM | ID: wpr-940511

ABSTRACT

ObjectiveTo explore the effect of Chaishao Liujuntang on Hedgehog signaling pathway in rats with chronic atrophic gastritis (CAG) of liver depression and spleen deficiency. MethodWistar rats were randomized into normal group and modeling group. CAG with the liver depression and spleen deficiency syndrome was induced in rats in the modeling group with a compound method. After modeling, they were classified into the model group, vitacoenzyme group, Chaishao Liujuntang group, GDC-0449 (blocker) group, and Chaishao Liujuntang + GDC-0449 group. Normal group and model group were given (ig) normal saline. Vitacoenzyme and Chaishao Liujuntang group received (ig) corresponding drugs at 240 mg·kg-1·d-1 and 5.1 g·kg-1·d-1, respectively, and GDC-0449 group was treated (ip) with GDC-0449 at 50 mg·kg-1·d-1. For the Chaishao Liujuntang + GDC-0449 group, rats received GDC-0449 (ip) at 50 mg·kg-1·d-1 and Chaishao Liujuntang (ig) at 5.1 g·kg-1·d-1. The administration lasted 4 weeks. The pathological morphology of rat gastric mucosa was observed based on hematoxylin-eosin (HE) staining. mRNA and protein expression of sonic hedgehog (Shh), 12th transmembrane receptor Patched1 (Ptch1), and glioma-associated oncogene homolog 1 (Gli1) in gastric mucosa tissues was detected by real-time fluorescent quantitative polymerase chain reaction (Real-time PCR) and Western blot. Content of serum interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) was determined by enzyme-linked immunosorbent assay (ELISA). ResultCompared with normal group, the model group demonstrated decrease in gland cells, glandular atrophy, large lumen volume, plasma cell infiltration, intestinal metaplasia, decrease in the mRNA and protein expression of Shh, Ptch1, and Gli1 in gastric mucosa (P<0.01), and rise of serum IL-1β and TNF-α content (P<0.01). Compared with model group, vitacoenzyme group and Chaishao Liujuntang group showed ordered cells, alleviation of gland atrophy, and no obvious inflammatory infiltration, and GDC-0499 group and Chaishao Liujuntang + GDC-0449 showed no significant improvement. Significant rise in the mRNA and protein expression of Shh, Ptch1, and Gli1 in gastric mucosa tissues of vitacoenzyme group and Chaishao Liujuntang group (P<0.01), no significant difference in serum IL-1β content and significant decrease in TNF-α content in vitacoenzyme group (P<0.01), significant reduction in content of serum IL-1β and TNF-α in Chaishao Liujuntang group (P<0.05, P<0.01) were observed compared with those in the model group. The mRNA and protein expression of Shh, Ptch1, and Gli1 in gastric mucosa and the content of serum IL-1β and TNF-α were insignificantly different between the GDC-0449 group and Chaishao Liujuntang + GDC-0449 group. ConclusionChaishao Liujuntang can effectively improve the pathological state of gastric mucosa in CAG rats with liver depression and spleen deficiency, which may be related to the activation of Hedgehog signaling pathway and the decrease of IL-1β and TNF-α content.

3.
Article in Chinese | WPRIM | ID: wpr-932429

ABSTRACT

Objective:To investigate the expression levels and clinical significance of glioma-associated oncogene homolog 1 (GLI1) and sonic hedgehog signaling molecule (Shh) in the malignant transformation of ovarian endometriosis (EM).Methods:The expressions of GLI1 and Shh were detected by real-time reverse transcription (RT)-polymerase chain reaction (PCR) and EnVision method in 50 cases of ovarian EM tissues, 35 cases of atypical endometriosis (aEM) and 50 cases of endometriosis-associated ovarian cancer (EAOC). The expression differences of two molecular markers in the malignant transformation of ovarian EM were compared, and the relationships between two molecular markers and the clinicopathological features and prognosis of EAOC were analyzed.Results:(1) RT-PCR showed that the expression levels of GLI1 mRNA in EM, aEM and EAOC group were 1.77±0.40, 3.54±0.44, and 7.80±0.24, respectively. The expression levels of Shh mRNA were 0.95±0.21, 3.14±0.35, and 5.41±0.31, respectively. GLI1 and Shh mRNA in EAOC group were significantly higher than those in EM and aEM group (all P<0.01), and there were statistically significant differences between EM and aEM group (all P<0.01). The percentages of GLI1 in ovarian EM, aEM and EAOC were 32% (16/50), 57% (20/35), and 66% (33/50), respectively, meanwhile, the positive expression rates of Shh were 20% (10/50), 49% (17/35), and 54% (27/50), respectively (all P<0.01). GLI1 mRNA expression was positively correlated with Shh mRNA expression in EAOC tissues ( r=0.721, P<0.01). The expressions of GLI1 protein were proportionated to Shh protein in EAOC tissues ( r=0.608, P=0.001). (2) The expression of GLI1 was significantly related to the International Federation of Gynecology and Obstetrics (FIGO) stage, cancer antigen 125 (CA 125) levels, lymph node metastasis, and Platinum resistance in EAOC patients (all P<0.05). The expression of Shh were related to FIGO stage and lymph node metastasis in EAOC patients (all P<0.05). Logistic regression analysis showed that GLI1 expression was an independent risk factor for poor prognosis in EAOC patients ( P<0.05). Kaplan-meier survival analysis showed that the overall survival rate of EAOC patients with high GLI1 expression and low GLI1 expression was 12.1% and 35.3%, respectively, with statistical significance ( χ2=10.73, P<0.01). The overall survival rate of EAOC patients with high and low expression of Shh protein was 11.1% and 30.4%, in which there was statistically significant difference ( χ2=3.96, P=0.047). Conclusion:GLI1 and Shh are highly associated with the malignant transformation of ovarian EM, which may play a role in promoting malignant degeneration of ovarian EM, and the high expression of GLI1 and Shh indicates a poor prognosis in EAOC patients.

4.
Article in Chinese | WPRIM | ID: wpr-930513

ABSTRACT

Objective:To investigate the role of nuclear transcription factor Gli1/Gli2 of the sonic hedgehog (Shh) signaling pathway in the hepatic epithelial mesenchymal transition (EMT) of biliary atresia mice caused by Rhesus rotavirus (RRV) infection.Methods:The biliary atresia model in mice was generated by RRV infection.Mice were divided into normal group, model group, Gli1 overexpression group, Gli1 shRNA group, Gli2 overexpression group and Gli2 shRNA group.Real-time fluorescence quantitative polymerase chain reaction and Western blot were used to detect the mRNA and protein expressions of regulatory factors for EMT (Snail/Slug) and characteristic cytokines of EMT [Vimentin, α-smooth muscle actin(α-SMA), E-cadherin] in mouse liver tissues.Additionally, hematoxylin-eosin staining and Masson staining were performed to calculate the percentage of liver fibrous tissue expression area.The data were analyzed by One- Way ANOVA and LSD- t test. Results:The relative mRNA expression of Snail, Slug, Vimentin, α-SMA and E-cadherin in Gli2 overexpression group, Gli2 shRNA group and model group were 15.13±3.40, 5.48±0.46, 8.78±1.06, 12.40±2.18 and 3.06±0.53; 3.73±1.16, 5.62±1.75, 3.56±1.06, 3.88±1.16 and 10.51±1.83; 8.13±1.27, 5.32±0.98, 5.05±0.98, 4.02±0.77 and 5.12±1.60.Compared with those of the model group, mRNA levels of Snail, Vimentin and α-SMA were significantly higher in Gli2 overexpression group, while that of E-cadherin was significantly lower( t=4.53, 5.29, 8.12, -2.13; all P<0.05); compared with those of the model group, mRNA levels of Snail and Vimentin in Gli2 shRNA group significantly decreased, while that of E-cadherin significantly increased( t=-2.86, -2.12, 5.62; all P<0.05). In Gli2 overexpression group, Gli2 shRNA group and model group, the protein levels of Snail, Slug, Vimentin, α-SMA and E-cadherin were 2.02±0.39, 0.31±0.08, 0.95±0.17, 1.07±0.17 and 0.42±0.06; 0.53±0.13, 0.40±0.18, 0.20±0.04, 0.28±0.07 and 1.09±0.31; 0.70±0.15, 0.42±0.22, 0.64±0.13, 0.81±0.11 and 0.42±0.09.Compared with those of the model group, protein levels of Snail, Vimentin and α-SMA were significantly higher in Gli2 overexpression group( t=12.71, 4.28, 3.70; all P<0.05); compared with those of the model group, protein levels of Vimentin and α-SMA in Gli2 shRNA group significantly decreased, while that of E-cadherin significantly increased( t=-6.14, -7.57, 5.96; all P<0.05). However, no significant change trend were detected in expression levels of characteristic cytokines of EMT between Gli1 overexpression group and Gli1 shRNA group.The area percentage of liver fiber expression in normal group, model group, Gli1 overexpression group, Gli1 shRNA group, Gli2 overexpression group and Gli2 shRNA group were (1.03±0.58)%, (33.02±11.39)%, (39.81±5.67)%, (26.06±1.29)%, (49.81±8.57)% and (17.55±0.66)%, respectively.Besides, in terms of percentage of area expressed in liver fiber tissue, the Gli2 overexpression group and Gli2 shRNA group were statistically significant compared with the model group( t=3.21, -2.96; all P<0.05), while the Gli1 overexpression group and Gli1 shRNA group were not statistically significant compared with the model group (all P>0.05). Conclusions:The Shh signaling pathway plays an important role in liver fibrosis in mice with biliary atresia.Gli2, a key transcription factor of Shh signaling pathway, can significantly regulate liver EMT process in mice with biliary atresi.

5.
Asian Journal of Andrology ; (6): 238-242, 2022.
Article in English | WPRIM | ID: wpr-928542

ABSTRACT

Cilium, an organelle with a unique proteome and organization, protruding from the cell surface, generally serves as a force generator and signaling compartment. During ciliogenesis, ciliary proteins are synthesized in cytoplasm and transported into cilia by intraflagellar transport (IFT) particles, where the inner counterparts undergo reverse trafficking. The homeostasis of IFT plays a key role in cilial structure assembly and signaling transduction. Much progress has been made on the mechanisms and functions of IFT; however, recent studies have revealed the involvement of IFT particle subunits in organogenesis and spermatogenesis. In this review, we discuss new concepts concerning the molecular functions of IFT protein IFT25 and how its interactions with other IFT particle subunits are involved in mammalian development and fertility.


Subject(s)
Animals , Biological Transport , Carrier Proteins/metabolism , Cilia/metabolism , Flagella/metabolism , Male , Mammals/metabolism , Organogenesis , Proteins/metabolism , Signal Transduction
6.
Journal of Clinical Hepatology ; (12): 334-341, 2022.
Article in Chinese | WPRIM | ID: wpr-920880

ABSTRACT

Objective To investigate the intervention effect of GDC-0449, a hedgehog signaling pathway inhibitor, on rats with liver fibrosis induced by carbon tetrachloride (CCl 4 ) combined with 2-acetylaminofluorene (2-AAF). Methods A total of 18 female Fisher344 rats were randomly divided into normal group, CCl 4 /2-AAF group, and GDC-0449 group, with 6 rats in each group. The rats in the CCl 4 /2-AAF group and the GDC-0449 group were given subcutaneously injected 30% CCl 4 -olive oil solution at a dose of 2 mL/kg twice a week for 6 weeks to induce liver fibrosis; since week 7, in addition to the injection of CCl 4 -olive oil solution, the rats in these two groups were given 2-AAF (100 mg/kg/d) by gavage, and the rats in the GDC-0449 group were given GDC-0449 (25 mg/kg/d) by gavage, while those in the normal group were given an equal volume of olive oil solution by injection and normal saline by gavage. All rats were sacrificed at the end of week 9, and related samples were collected. HE staining and sirius red (SR) staining were used to observe the changes in liver histopathology and collagen deposition, and the semi-quantitative analysis of SR-positive area and Ishak score were used to evaluate fibrosis degree; the alkaline hydrolysis method was used to measure the level of hydroxyproline (Hyp) in liver tissue; immunohistochemistry, Western blot, and qRT-PCR were used to measure the expression of α-smooth muscle actin (α-SMA), type Ⅰ collagen (Col-Ⅰ), type Ⅳ collagen (Col-Ⅳ), cytokeratin 19 (CK19), cytokeratin 7 (CK7), the epithelial cell adhesion molecule Epcam, and the hedgehog signaling pathway in liver tissue; double immunofluorescence staining was used to observe the colocalization of CK19 and the oval cell marker OV6. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t -test was used for further comparison between two groups. Results Compared with the normal group, the CCl 4 /2-AAF group had marked inflammatory cell aggregation and collagen deposition in liver tissue, with the formation of a pseudolobular structure, as well as significant increases in Hyp level and collagen positive area ratio in liver tissue ( P < 0.05), Ishak score ( P < 0.05), and the expression of α-SMA, Col-Ⅰ, Col-Ⅳ, Epcam, CK19, CK7, the transmembrane transporter Smoothened (Smo), Hedgehog ligand Desert Hedgehog (Dhh), the Indian Hedgehog membrane-binding receptor Patched (Ptch2), and glioma-related oncogenes Gli1, Gli2, and Gli3 (all P < 0.05); double immunofluorescence staining showed that CK19-positive cells also expressed OV6 in the liver tissue of rats in the CCl 4 /2-AAF group, with a significant increase compared with the normal group. Compared with the CCl 4 /2-AAF group, the GDC-0449 group had significant reductions in inflammatory cell aggregation and collagen deposition in liver tissue, Hyp level and collagen positive area ratio in liver tissue ( P < 0.05), Ishak score ( P < 0.05), and the expression of α-SMA, Epcam, CK19, CK7, Smo, Ptch2, Gli1, Gli2, and Gli3 (all P < 0.05); double immunofluorescence staining showed a significant reduction in the number of cells with co-expression of OV6 and CK19 in liver tissue. Conclusion The Hedgehog signaling pathway inhibitor GDC-0449 can significantly inhibit the progression of liver fibrosis induced by CCl 4 /2-AAF in rats, possibly by inhibiting hepatic stellate cell activation, collagen deposition, activation and proliferation of hepatic progenitor cells, and differentiation of hepatic progenitor cells into biliary epithelial cells.

7.
Braz. j. biol ; 82: e244581, 2022. tab, graf
Article in English | LILACS, VETINDEX | ID: biblio-1278490

ABSTRACT

Abstract Due to the urbanization and human invasion of the natural environments, great changes have been occurred on the food composition and feeding ecology of several animals especially those are sharing human his habitat in fields, wadis and gardens. The desert hedgehogs Paraechinus aethiopicus populations inhabiting different localities in Saudi Arabia were studied by using stomach contents analysis between February 2015 and October 2019. Precise analysis of stomach contents of 55 hedgehogs showed that the food of P. aethiopicus is highly diverse and highly influenced with effect of human on the environment including cooked rice, insects, plant materials, eggshells, worms, garbage and remnants of mammals and birds. Diet composition showed seasonal variations that are apparently associated with changes in the availability of different food items. The present results clearly showed that P. aethiopicus is an omnivorous mammal, capable of adapting to a great variety of dietary compositions in the study sites.


Resumo Devido à urbanização e invasão humana dos ambientes naturais, grandes mudanças têm ocorrido na composição alimentar e ecologia alimentar de vários animais, especialmente aqueles que estão compartilhando seu hábitat humano em campos, wadis e jardins. As populações de ouriços-do-deserto Paraechinus aethiopicus que habitam diferentes localidades na Arábia Saudita foram estudadas usando análise de conteúdo estomacal entre fevereiro de 2015 e outubro de 2019. A análise precisa do conteúdo estomacal de 55 ouriços mostrou que a alimentação de P. aethiopicus é altamente diversa e altamente influenciada com efeito de humanos no meio ambiente, incluindo arroz cozido, insetos, materiais vegetais, cascas de ovo, vermes, lixo e restos de mamíferos e pássaros. A composição da dieta apresentou variações sazonais que aparentemente estão associadas a mudanças na disponibilidade de diferentes itens alimentares. Os presentes resultados mostraram claramente que P. aethiopicus é um mamífero onívoro, capaz de se adaptar a uma grande variedade de composições dietéticas nos locais de estudo.


Subject(s)
Animals , Ecosystem , Hedgehogs , Saudi Arabia , Ecology , Feeding Behavior
8.
Braz. J. Pharm. Sci. (Online) ; 58: e20354, 2022. graf
Article in English | LILACS | ID: biblio-1403749

ABSTRACT

Abstract Colorectal cancer (CRC) one of the leading cause of cancer-related deaths worldwide. With the presently available knowledge on CRC, it is understood that the underlying is a complex process. The complexity of CRC lies in aberrant activation of several cellular signaling pathways that lead to activation and progression of CRC. In this context, recent studies have pointed towards the role of developmental pathways like; hedgehog (HH), wingless-related integration site (WNT/ß-catenin) and Notch pathways that play a crucial role in maintenance and homeostasis of colon epithelium. Moreover, the deregulation of these signaling pathways has also been associated with the pathogenesis of CRC. Therefore, in the search for better therapeutic options, these pathways have emerged as potential targets. The present review attempts to highlight the role of HH, WNT/ß-catenin and Notch pathways in colon carcinogenesis


Subject(s)
Colorectal Neoplasms/pathology , Pathogenesis, Homeopathic/classification , Colonic Neoplasms/pathology , Comprehension , Carcinogenesis
9.
J. Bras. Patol. Med. Lab. (Online) ; 58: e4452022, 2022. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1375699

ABSTRACT

ABSTRACT Introduction Hepatocellular carcinoma (HCC) is the most common primary malignant neoplasm in the liver. HCC develops gradually from multiple stages that control proliferation and apoptosis. In hepatocarcinogenesis, multiple signaling pathways were already described, such as the Hedgehog pathway (Hh). However, few studies have investigated the expression of Hh proteins as a potential prognostic factor in human HCC. This study aimed to investigate the expression of the Shh protein in HCC and to correlate with clinical and morphological prognostic characteristics of the tumor. Methods Immunohistochemical expression of Shh protein in tumor and cirrhotic parenchyma was performed in 36 HCC samples from patients who underwent liver transplantation at Clinical Hospital - UFMG. Correlation between the Shh tumor expression and etiology, number of nodules, size of the nodules, levels of alpha-fetus-protein (AFP), MELD score, tumor differentiation, and vascular invasion were performed. Results In our study, Shh protein labeling gradually increased from the normal to the cirrhotic and neoplastic parenchyma. Degree of tumor differentiation and vascular invasion were correlated with high Shh protein expression (p = 0.014 and p = 0.003, respectively). The other variables did not show a statistically significant correlation with Shh labeling. Conclusion Hedgehog pathway has importance in hepatocarcinogenesis. The immunohistochemical study of the Hh signaling pathway may have a promising role as a prognostic factor for HCC, especially due to the positive correlation between the Shh expression and the degree of tumor differentiation and invasion vascular.


RESUMO Introdução O carcinoma hepatocelular (CHC) é a neoplasia maligna primária mais comum no fígado. O CHC se desenvolve gradualmente a partir de múltiplos estágios que controlam a proliferação e a apoptose. Na hepatocarcinogênese, múltiplas vias de sinalização já foram descritas, como a via Hedgehog (Hh). No entanto, poucos estudos investigaram a expressão de proteínas Hh como um potencial fator prognóstico no CHC humano. Este estudo teve como objetivo investigar a expressão da proteína Shh no CHC e correlacionar com características prognósticas clínicas e morfológicas do tumor. Métodos A expressão imuno-histoquímica da proteína Shh em tumor e parênquima cirrótico foi realizada em 36 amostras de CHC de pacientes submetidos a transplante hepático no Hospital das Clínicas - UFMG. Correlação entre a expressão e etiologia do tumor Shh, número de nódulos, tamanho dos nódulos, níveis de proteína alfa-feto (AFP), pontuação MELD, diferenciação tumoral e invasão vascular foram realizadas. Resultados Em nosso estudo, a marcação da proteína Shh aumentou gradualmente do parênquima normal para o cirrótico e neoplásico. Grau de diferenciação tumoral e invasão vascular foram correlacionados com alta expressão da proteína Shh (p = 0,014 ep = 0,003, respectivamente). As demais variáveis não apresentaram correlação estatisticamente significativa com a marcação de Shh. Conclusão A via Hedgehog tem importância na hepatocarcinogênese. O estudo imuno-histoquímico da via de sinalização Hh pode ter um papel promissor como fator prognóstico para CHC, principalmente devido à correlação positiva entre a expressão de Shh e o grau de diferenciação tumoral e invasão vascular.

10.
An. bras. dermatol ; 96(6): 712-716, Nov.-Dec. 2021. tab
Article in English | LILACS | ID: biblio-1355629

ABSTRACT

Abstract Background: The treatment of advanced periocular basal cell carcinomas becomes a challenge as surgery may involve highly mutilating procedures. Vismodegib is the first selective hedgehog inhibitor approved for the treatment of locally advanced tumors or metastatic disease. Objective: Analyze the results of treatment with vismodegib for advanced periocular basal cell carcinomas in a real-life setting of a reference center between 2014 and 2020. Methods: Retrospective longitudinal study. The patient's demographic profile, comorbidities, tumor characteristics, and treatment outcomes were analyzed. Results: A total of 13 patients were included. Median follow-up and treatment duration were 15.9 and 10.5 months, respectively. Objective clinical response rate was 76.9%: 30.8% had a complete response and 46.2% a partial response. The median duration of response was 13 months. Progressive disease was observed in 38.5% of cases, with a median of 19 months after the beginning of treatment. Eighty-four percent of the patients had at least one adverse event, and 61.54% needed to interrupt treatment temporarily or permanently to increase tolerability. Study limitations: Being a retrospective study in a real-life setting, the evaluation of objective clinical response was subjective to physician appreciation. Conclusion: Vismodegib is a safe and effective treatment for locally advanced basal cell carcinoma. To prevent recurrences, the drug should be used continually when tolerated. The role of neoadjuvant vismodegib before surgery is being investigated and might add an important step in searching for a definitive treatment for these cases.


Subject(s)
Humans , Carcinoma, Basal Cell/drug therapy , Neoplasms/drug therapy , Pyridines , Retrospective Studies , Longitudinal Studies , Hedgehog Proteins , Anilides , Neoplasm Recurrence, Local/drug therapy
11.
Int. j. morphol ; 39(5)oct. 2021.
Article in English | LILACS-Express | LILACS | ID: biblio-1385493

ABSTRACT

SUMMARY: The rabbit is considered an ideal animal model for studies that describe abnormalities in the testicles due to the similar morphogenetic mechanisms of sexual development and diseases commonly found in humans. The aim of this study was to determine the male sexual differentiation of the New Zealand rabbit (Oryctolagus cuniculus) through development. The gestational age was estimated and classified as 9, 12, 14, 16, 18, 20, 23 and 28 gestational days. The morphological and sexual determination were performed by histological analysis of the reproductive tract in the embryos and fetuses (9-28 days) as well as by immunohistochemistry- Desert hedgehog-Dhh- (testis-specific protein on Y chromosome- 16, 20, 23 days and adult rabbits). Gonads were observed from the 14th day in an undifferentiated stage and with homogeneous aspect. Sexual differentiation was observed from the 16th day with presence of cells forming gonadal cords and Dhh+ cells in the gonadal parenchyma. From the 18th gestational day testicular cords were observed, which evolved into organized seminiferous tubules. The formation of the efferent ducts and ductus deferens and epididymis was observed on the 20th and 23rd days, respectively. The differentiation of the external genitalia occurred from the 23rd days from the anogenital distance and was identified to identify the penile structures. In summary, the features of the sexual differentiation were determined by observation of the Dhh+ protein in embryos from the 16th day to adulthood, and the morphological particularities observed from the 18th gestational day, determined by differentiation of the external genitalia from the 23rd day.


RESUMEN: El conejo se considera un modelo animal ideal para estudios que describen anomalías a nivel testícular debido a que presenta mecanismos morfogenéticos similares al desa- rrollo sexual y enfermedades que se encuentran comúnmente en los seres humanos. El objetivo de este estudio fue determinar la diferenciación sexual masculina del conejo de Nueva Zelanda (Oryctolagus cuniculus) a través del desarrollo. La edad gestacional se estimó y clasificó en 9, 12, 14, 16, 18, 20, 23 y 28 días gestacionales. La determinación morfológica y sexual se realizó mediante análisis histológico del tracto reproductivo en los embriones y fetos (9 - 28 días) así como mediante inmunohistoquímica -Desert hedgehog-Dhh- (proteína testicular específica en el cromosoma Y- 16, 20, 23 días y conejos adultos). Las gónadas se observaron a partir del día 14 en un estadio indiferenciado y con aspecto homogéneo. Se observó diferenciación sexual a partir del día 16 con presencia de células formadoras de cordones gonadales y células Dhh+ en el parénquima gonadal. A partir del día 18 de gestación se observaron cordones testiculares, que evolucionaron a túbulos seminíferos organizados. La formación de los conductos eferentes, deferentes y del epidídimo se observó a los 20 y 23 días, respectivamente. La diferenciación de los genitales externos ocurrió a partir del día 23 desde la distancia anogenital y se utilizó para identificar las estructuras del pene. En conclusión, las características de la diferenciación sexual se determinaron mediante la observación de la proteína Dhh en embriones desde el día 16 hasta la edad adulta, y las particularidades morfológicas observadas a partir del día 18 de gestación, determinadas por diferenciación de los genitales externos a partir del día 23.

12.
Int. j. morphol ; 39(4)ago. 2021.
Article in English | LILACS-Express | LILACS | ID: biblio-1385450

ABSTRACT

SUMMARY: In testicular differentiation, somatic cells must adopt a specific destiny towards sustentacular, peritubular and interstitial cells, being fundamental for the morphogenesis of seminiferous tubules, mediated by morphogens such as Desert Hedgehog (DHH), insulin-like growth factor-1 (IGF-1) and fibroblastic growth factor 2 (FGF-2). Its alteration could be related to failures in the development mechanisms, such as those caused by valproic acid (VPA), which can be reversed with vitamin E (VE). The objective of the study was to evaluate the epithelial-mesenchymal transition (EMT) in the testicular development of mice exposed to VPA and VE. 12 groups of pregnant female mice were formed that were separated by days post-coital (dpc) at 12.5 dpc, 17.5 dpc and 6 weeks postnatal, each one subdivided into 4 groups of 5 pregnant women each. Subgroups received different treatments from the beginning to the end of gestation orally: 600 mg/kg of VPA, 600 mg/kg of VPA and 200 IU of VE, 200 IU of VE and the control group 0.3 mL of 0.9% physiological solution. Immunohistochemistry was performed for the detection of DHH, IGF-1 and FGF-2. Immunolocalization of DHH was observed in all stages, with more evident significant differences in integrated optical density (IOD) and percentage of immunoreaction area at 6 weeks postnatal, being lower in the VPA group. In IGF-1, lower intensity and distribution of immunostaining was observed in the fetal and pubertal stages in the VPA groups, a similar situation with FGF-2, but only evident at 17.5 dpc, with significant differences. These results demonstrate that VPA can alter EMT between somatic cells in testicular development, with VE being an agent capable of attenuating this process.


RESUMEN: En la diferenciación testicular, es necesario que las células somáticas adopten un destino específico hacia células sustentaculares, peritubulares e intersticiales, siendo fundamental para la morfogénesis de los túbulos seminíferos, mediado por morfógenos como Desert Hedgehog (DHH), Factor de Crecimiento Fibroblástico 2 (FGF-2) y Factor de Crecimiento símil a Insulina (IGF-1). Su alteración se podría relacionar a fallas en los mecanismos de desarrollo, como los que ocasiona el ácido valproico (VPA), los cuales pueden ser revertidos con la vitamina E (VE). El objetivo de estudio fue evaluar la transición epitelio-mesenquimática (EMT) en el desarrollo testicular de ratones expuestos a VPA y VE. Se conformaron 12 grupos de ratones hembra gestantes que se separaron por días post-coital (dpc) a los 12.5 dpc, 17.5 dpc y 6 semanas post-natal, cada uno subdividido en 4 grupos de 5 gestantes cada uno. Cada subgrupo recibió diferentes tratamientos desde el inicio hasta el término de la gestación vía oral: 600 mg/kg de VPA, 600 mg/kg de VPA y 200 UI de VE, 200 UI de VE y el grupo control 0,3 mL de solución fisiológica 0,9%. Se realizó técnica inmunohistoquímica para la detección de DHH, IGF-1 y FGF-2. Se observó la inmunolocalización de DHH en todos los estadios, con diferencias significativas más evidentes en la densidad óptica integrada (IOD) y porcentaje de área de inmunoreacción a las 6 semanas post-natal, siendo menor en el grupo VPA. En IGF-1, se observó en la etapa fetal y puberal menor intensidad y distribución de la marcación en los grupos VPA, situación similar con la inmunomarcación de FGF-2, pero sólo evidenciándose a los 17.5 dpc, con diferencias significativas. Estos resultados demuestran que el VPA puede alterar la EMT entre las células somáticas en el desarrollo testicular, siendo la VE un agente capaz de atenuar este proceso.

13.
Article in English | WPRIM | ID: wpr-876436

ABSTRACT

@#Introduction: Hedgehog (HH) pathway is an important signalling cascade for growth and patterning during embryonic development. Constitutive activation of Hedgehog pathway can be found in various types of malignancies including medulloblastoma, basal cell carcinoma, gastrointestinal, breast, pancreatic, prostate cancer and leukaemia. Little is known about the expression and role of Hedgehog signalling in bladder cancer. Materials and Methods: The purpose of this study was to investigate the immunohistochemical expression of SMO in 112 bladder cancer cases and determine their association with demographic and clinicopathological parameters. Bladder cancer tissues were obtained from the Hospital Kuala Lumpur. Results: SMO was expressed in the cytoplasm of all cases of bladder cancer. 6 cases (5.4%) showed low expression, while 106 cases (94.6%) showed high expression. Positive expression of SMO protein was correlated with a few variables which include grade and stage of tumour, lymph node metastasis and distant metastasis. SMO expression showed statistically significant association with higher grade (p=0.001) and higher stage (p=0.042) of bladder cancer. SMO expression also showed borderline association with lymph node metastasis (p=0.056). Conclusion: These findings indicate that SMO expression may be a poor prognostic marker in bladder cancer.

14.
Article in Chinese | WPRIM | ID: wpr-909607

ABSTRACT

OBJECTIVE To investigate the inhibition and mechanism of berberine on human colorectal cancer HCT116 cells through canonical Hedgehog signaling pathway. METHODS The effect of berberine on cell morphology was observed by microscopy. MTT colorimetric assay, cell scratch experiment, colony formation assay and Hoechest/PI staining were utilized to detect the activities of berberine on cell viability, cell migration and cell apoptosis. Flow cytome?try was applied to examine the cell apoptosis. The effects of berberine on caspase-3 and caspase-9 were detected by caspase activity detection kit. The expressions of Hedgehog signaling pathway-related proteins SHH, GLI1, PTCH1, SMO, SUFU, apoptosis-related proteins Bax and Bcl-2 as well as cell cycle-related proteins cyclin D1 were detected by Western blotting. Additionally, quantitative real time RT-PCR was employed to assess the mRNA expression levels of Hedgehog signaling pathway-related genes SHH, GLI1, PTCH1, SMO, SUFU, apoptosis-related genes Bax and Bcl-2 as well as cell cycle-related genes cyclin D1. RESULTS Berberine sharply altered the morphology of human colorectal cancer HCT116 cells, demonstrated by that migration ability of HCT116 cells was reduced significantly and the nuclei were densely stained. Berberine could induce apoptosis in a dose-dependent manner. The activities of caspase-3 and caspase-9 were increased prominently. The expression levels of Hedgehog signaling pathway-related protein SUFU and apoptosis-related protein Bax were augmented substantially. The expression levels of Hedgehog signaling pathway-related proteins SHH, GLI1, PTCH1, SMO, apoptosis-related protein Bcl-2 as well as cell cycle-related genes cyclin D1 were markedly lessened. Besides, the mRNA expression levels of Hedgehog signaling pathway-related gene SUFU and apoptosis-related gene Bax were augmented substantially. The mRNA expression levels of Hedgehog signaling path?way-related genes SHH, GLI1, PTCH1, SMO, apoptosis-related gene Bcl-2 as well as cell cycle-related gene cyclin D1 were markedly lessened. CONCLUSION Berberine, which is the main component of coptidis rhizoma, can remarkably restrain the growth and proliferation, promote apoptosis of human colorectal cancer cells HCT116, and the underlying mechanism may be involved in suppressing the activity of the Hedgehog signaling pathway.

15.
Article in Chinese | WPRIM | ID: wpr-909590

ABSTRACT

OBJECTIVE To identify the inhibitory effect of ursolic acid on the colorectal cancer HCT116 cells in vitro and in vivo, and to explore the underlying mechanism. METHODS The smoothened (SMO) gene-silenced human colorectal cancer HCT116hSMO- cell line was established by transfection with the lentivirus carrying SMO shRNA. The cytotoxic effect of ursolic acid on HCT116hSMO-cells was determined by MTT assay. The effect of ursolic acid on the migration of HCT116hSMO- cells was studied by wound healing assay. The effect of ursolic acid on apoptosis of HCT116hSMO-cells was explored by Hoechst33342/PI double staining and flow cytometry. The effects of ursolic acid on the expressions of apoptotic marker gene Bcl-2, Bax, caspase-3 and caspase-9 were measured by real-time quantitative RT-PCR (RT-qPCR) and Western blotting (WB) analysis. RT-qPCR and WB were used to examine the relationship between GLI1, c-Myc expression and PI3K/Akt pathway to further investigate the mechanism of GLI1 activation in HCT116hSMO- cells. The effects of ursolic acid on the expressions of GLI1, p-Akt, Akt, c-Myc, SHH and SUFU of nonca?nonical Hedgehog pathway were evaluated by RT-qPCR and WB assays. Xenograft nude mouse model bearing HCT116hSMO- cells was established and intraperitoneally treated with ursolic acid to investigate the effect on tumor growth in vivo. The body weight and tumor size of mice were assessed regularly every 2 d. The effect of ursolic acid on the apoptosis of tumor tissue was determined by TUNEL assay. The expressions of Bcl-2, Bax, GLI1, p-Akt, Akt, c-Myc, SHH, SUFU mRNA and proteins were measured by RT-qPCR and WB. The levels of Bcl-2, Bax, GLI1, p-Akt, c-Myc and SHH proteins in tumor tissues were also evaluated by immunohistochemistry. RESULTS Ursolic acid significantly inhibited the growth and migration of HCT116hSMO-cells in vitro, compared with the control (P<0.05). Meanwhile, ursolic acid also induced apoptosis of HCT116hSMO- cells in vitro (P<0.05). Furthermore, SC79 (Akt activator) enhanced the expressions of p-Akt, GLI1 and c-Myc, which could be abolished by ursolic acid, and the effect was equal to Akt inhibitor LY294002. The expressions of Bcl-2, GLI1, p-Akt, c-Myc, SHH mRNA and proteins were reduced by ursolic acid, while the levels of Bax and SUFU were increased. Ursolic acid could inhibit the growth and induce the apoptosis of colorectal cancer xeno?graft in vivo. Similarly, lower levels of Bcl-2, GLI1, p-Akt, c-Myc and SHH, and higher expression of Bax and SUFU were noted in ursolic acid-treated mice. CONCLUSION Ursolic acid can inhibit the growth and induce apoptosis of HCT116hSMO- cells both in vitro and in vivo. And the mechanism is related to the suppression of PI3K/Akt-mediated noncanonical Hedgehog signaling pathway.

16.
Acta Pharmaceutica Sinica B ; (6): 1148-1157, 2021.
Article in English | WPRIM | ID: wpr-881190

ABSTRACT

As one of the most lethal diseases, pancreatic cancer shows a dismal overall prognosis and high resistance to most treatment modalities. Furthermore, pancreatic cancer escapes early detection during the curable period because early symptoms rarely emerge and specific markers for this disease have not been found. Although combinations of new drugs, multimodal therapies, and adjuvants prolong survival, most patients still relapse after surgery and eventually die. Consequently, the search for more effective treatments for pancreatic cancer is highly relevant and justified. As a newly re-discovered mediator of gasotransmission, hydrogen sulfide (H

17.
Acta Pharmaceutica Sinica B ; (6): 609-620, 2021.
Article in English | WPRIM | ID: wpr-881159

ABSTRACT

The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon-

18.
Acta Pharmaceutica Sinica B ; (6): 488-504, 2021.
Article in English | WPRIM | ID: wpr-881149

ABSTRACT

Medulloblastoma (MB) is a common yet highly heterogeneous childhood malignant brain tumor, however, clinically effective molecular targeted therapy is lacking. Modulation of hedgehog (HH) signaling by epigenetically targeting the transcriptional factors GLI through bromodomain-containing protein 4 (BRD4) has recently spurred new interest as potential treatment of HH-driven MB. Through screening of current clinical BRD4 inhibitors for their inhibitory potency against glioma-associated oncogene homolog (GLI) protein, the BRD4 inhibitor

19.
Acta Pharmaceutica Sinica B ; (6): 55-70, 2021.
Article in English | WPRIM | ID: wpr-881124

ABSTRACT

Cancer stem cells (CSCs) are a subpopulation of cancer cells with functions similar to those of normal stem cells. Although few in number, they are capable of self-renewal, unlimited proliferation, and multi-directional differentiation potential. In addition, CSCs have the ability to escape immune surveillance. Thus, they play an important role in the occurrence and development of tumors, and they are closely related to tumor invasion, metastasis, drug resistance, and recurrence after treatment. Therefore, specific targeting of CSCs may improve the efficiency of cancer therapy. A series of corresponding promising therapeutic strategies based on CSC targeting, such as the targeting of CSC niche, CSC signaling pathways, and CSC mitochondria, are currently under development. Given the rapid progression in this field and nanotechnology, drug delivery systems (DDSs) for CSC targeting are increasingly being developed. In this review, we summarize the advances in CSC-targeted DDSs. Furthermore, we highlight the latest developmental trends through the main line of CSC occurrence and development process; some considerations about the rationale, advantages, and limitations of different DDSs for CSC-targeted therapies were discussed.

20.
Article in English | WPRIM | ID: wpr-880634

ABSTRACT

OBJECTIVES@#Silence of SET domain containing lysine methyltransferase 7 (SET7) alleviates myocardial tissue injury caused by ischemia-reperfusion. But the effects of SET7 on angiotensin II (Ang II)-induced myocardial fibroblast proliferation and the collagen synthesis are not clear. The purpose of this study was to explore the effect of SET7 on the proliferation and collagen synthesis of myocardial fibroblasts and its mechanisms.@*METHODS@#Myocardial fibroblasts were isolated and identified by immunofluorescence. Myocardial fibroblasts were randomly divided into 4 groups: a control group (cells were normally cultured), an Ang II group (cells were treated with 100 nmol/L Ang II for 24 h), a siCtrl group (cells were transfected with siRNA control and were then treated with 100 nmol/L Ang II for 24 h), and a siSET7 group (cells were transfected with siRNA SET7 and were then treated with 100 nmol/L Ang II for 24 h). Cell counting kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assay were used to evaluate cell proliferation. Real-time PCR was used to detect the mRNA levels of SET7, collagen I, collagen III, and α-smooth muscle actin (α-SMA). Western blotting was used to detect the protein expression of SET7, collagen I, collagen III, α-SMA, sonic hedgehog (Shh), ptched1 (Ptch1), and glioma-associated oncogene homolog 1 (Gli1).@*RESULTS@#Fluorescence microscopy showed positive vimentin staining, and myocardial fibroblasts were in good condition. As compared to the control group, the mRNA and protein levels of SET7 in the Ang II group were significantly upregulated; cell proliferation rate and EdU fluorescence intensity in the Ang II group were significantly increased; the mRNA and protein levels of collagen I, collagen III, and α-SMA were significantly upregulated (all @*CONCLUSIONS@#Silence of SET7 gene inhibits Ang II-induced proliferation and collagen synthesis of myocardial fibroblasts. Shh signaling pathway may be involved in this process.


Subject(s)
Angiotensin II/pharmacology , Cell Proliferation , Cells, Cultured , Collagen/genetics , Fibroblasts , Hedgehog Proteins
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