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OBJECTIVES: Signet ring cell carcinoma (SRCC) of the urinary bladder is a rare and highly aggressive form of bladder cancer, with no widely agreed-upon treatment strategy. The aim of this study was to identify important factors influencing patient prognosis and to assess how various treatment approaches affect survival outcomes. METHODS: A retrospective study was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) Program, including patients with bladder primary SRCC who were presented between 2000 and 2017. Univariate and multivariate Cox regression models were used to examine the impact of various factors on cancer-specific survival (CSS) and overall survival (OS). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were applied to homogenize both groups. The impact of different treatment regimens on patient CSS and OS was analyzed using the Kaplan-Meier method. RESULTS: A total of 33 cases of non-muscular invasive SRCC and 210 cases of muscular invasive SRCC were included in this study. Multivariate analysis identified race, TNM stage, and surgical method as independent variables influencing both OS and CSS. In non-muscle invasive bladder SRCC patients, radical cystectomy showed no CSS benefit compared to transurethral resection of bladder tumors (P = 0.304). For muscle invasive SRCC, patients who underwent partial cystectomy had better OS and CSS compared to those who underwent radical cystectomy (P = 0.019, P = 0.024). However, after conducting a PSM analysis, the differences between the two surgical outcomes were not statistically significant (P = 0.504, P = 0.335). Lymphadenectomy, chemotherapy, and radiation did not show any benefit to the prognosis of patients. CONCLUSION: This study identified race, TNM stage, and surgical approach as significant independent predictors for SRCC outcomes. Simple radical cystectomy and partial cystectomy proved to be effective treatments for SRCC. The optimal treatment option still needs to be supported by a number of prospective research trials.
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Carcinoma de Células en Anillo de Sello , Cistectomía , Programa de VERF , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/terapia , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/cirugía , Femenino , Masculino , Carcinoma de Células en Anillo de Sello/patología , Carcinoma de Células en Anillo de Sello/terapia , Carcinoma de Células en Anillo de Sello/mortalidad , Carcinoma de Células en Anillo de Sello/cirugía , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Cistectomía/métodos , Pronóstico , Estadificación de Neoplasias , Puntaje de Propensión , Estimación de Kaplan-Meier , AdultoRESUMEN
Background: Uric acid may play a critical role in protection against cancer by the suppression of inflammation. The association between serum uric acid (SUA) levels and prostate cancer risk is debatable yet has received little attention in the American population. Therefore, we used data from the National Health and Nutrition Examination Survey (NHANES) to determine their correlation. Methods: Using information from NHANES 1999-2010, a total of 62,160 individuals from the general population were included in this cross-sectional study. Additionally, a number of covariates were acquired. Prostate cancer was used to divide the participants into two groups: prostate cancer group (n=315) and non-prostate cancer group (n=7,545). A weighted adjusted logistic regression analysis was conducted to examine the potential correlation between SUA and prostate cancer. Results: Our study comprised a total of 7,860 participants. After full adjustment for confounders, SUA was not significantly associated with prostate cancer [odds ratio (OR) 0.91, 95% confidence interval (CI): 0.82-1.00, P=0.058]. In participants aged 60 years and above (≥60 years), a higher SUA was significantly associated with a lower risk of prostate cancer (OR 0.88, 95% CI: 0.80-0.96, P=0.003). However, among those younger than 60 years (<60 years), there was no association between SUA and prostate cancer risk (OR 1.29, 95% CI: 0.69-2.42, P=0.42). In addition, in the subgroup analysis stratified by body mass index, hypertension and diabetes, there was no significant correlation between SUA and prostate cancer. Conclusions: SUA is negatively associated with the risk of prostate cancer in older men, especially for those 60 years of age and beyond.
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CONTEXT: In men with prostate cancer, urinary incontinence is one of the most common long-term side effects of radical prostatectomy (RP). The recovery of urinary continence in patients is positively influenced by preserving the integrity of the neurovascular bundles (NVBs). However, it is still unclear if bilateral nerve sparing (BNS) is superior to unilateral nerve sparing (UNS) in terms of post-RP urinary continence. The aim of this study is to systematically compare the differences in post-RP urinary continence outcomes between BNS and UNS. METHODS: The electronic databases of PubMed and Web of Science were comprehensively searched. The search period was up to May 31, 2023. English language articles comparing urinary continence outcomes of patients undergoing BNS and UNS radical prostatectomy were included. Meta-analyses were performed to calculate pooled relative risk (RR) estimates with 95% confidence intervals for urinary continence in BNS and UNS groups at selected follow-up intervals using a random-effects model. Sensitivity analyses were performed in prospective studies and robotic-assisted RP studies. RESULTS: A meta-analysis was conducted using data from 26,961 participants in fifty-seven studies. A meta-analysis demonstrated that BNS improved the urinary continence rate compared to UNS at all selected follow-up points. RRs were 1.36 (1.14-1.63; p = 0.0007) at ≤ 1.5 months (mo), 1.28 (1.08-1.51; p = 0.005) at 3-4 mo, 1.12 (1.03-1.22; p = 0.01) at 6 mo, 1.08 (1.05-1.12; p < 0.00001) at 12 mo, and 1.07 (1.00-1.13; p = 0.03) at ≥ 24 mo, respectively. With the extension of the follow-up time, RRs decreased from 1.36 to 1.07, showing a gradual downward trend. Pooled estimates were largely heterogeneous. Similar findings were obtained through sensitivity analyses of prospective studies and robotic-assisted RP studies. CONCLUSION: The findings of this meta-analysis demonstrate that BNS yields superior outcomes in terms of urinary continence compared to UNS, with these advantages being sustained for a minimum duration of 24 months. It may be due to the real effect of saving the nerves involved. Future high-quality studies are needed to confirm these findings.
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Tratamientos Conservadores del Órgano , Prostatectomía , Neoplasias de la Próstata , Incontinencia Urinaria , Humanos , Prostatectomía/métodos , Prostatectomía/efectos adversos , Incontinencia Urinaria/etiología , Incontinencia Urinaria/prevención & control , Masculino , Neoplasias de la Próstata/cirugía , Tratamientos Conservadores del Órgano/métodos , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/etiología , Pronóstico , Procedimientos Quirúrgicos Robotizados/métodos , Procedimientos Quirúrgicos Robotizados/efectos adversosRESUMEN
Neural style transfer is an algorithm that transfers the style of one image to another image and converts the style of the second image while preserving its content. In this paper, we propose a style transfer approach for sand painting generation based on convolutional neural networks. The proposed approach aims to improve sand painting generation via neural style transfer, which can address the problem of blurred objects. Furthermore, it can reduce background noise caused by neural style transfers. First, we segment the main objects from the content image. Subsequently, we perform close-open filtering operations on the content image to obtain smooth images. Subsequently, we perform Sobel edge detection to process the images and obtain edge maps. Based on these edge maps and the input style image, we perform neural style transfer to generate sand painting images. Finally, we integrate the generated images to obtain the final stylized sand painting image. The results show that the proposed approach yields good visual effects from sand paintings. Moreover, the proposed approach achieves better visual effects for sand painting than the previous method.
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Prostate cancer (PCa) frequently presents as a multifocal disease within a single gland. Herein, the transcriptome-wide profiles of glandular epithelial (GE) cells of four PCa tissues with various Gleason scores (GSs) are analyzed with Visium spatial transcriptomics (ST). The genetic classifications across PCa section sites generally matched the spatial patterns of histological structures with different GSs. Average inferred copy number variation (inferCNV) values gradually increased during GS development. Developing trajectories during GS upgrading were assessed, and differentially expressed genes (DEGs) during GS progression were analyzed which exhibited heterogeneity among individual patients with PCa. Several crucial genes, such as NANS, PABPC1L, PILRB, PPFIA2, and SESN3, were associated with GS upgrading. Enrichment analysis showed that biological functions, such as cadherin binding, Golgi vesicle transport, protein folding, and cell adhesion molecules were related to GS progression. In conclusion, this study provides insight into ST-based transcriptome-wide expression patterns during GS progression.
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Nephrolithiasis is highly prevalent and associated with the increased risk of kidney cancer. The tumor suppressor von Hippel-Lindau (VHL) is critical for renal cancer development, however, its role in kidney stone disease has not been fully elucidated until now. Here we reported VHL expression was upregulated in renal epithelial cells upon exposure to crystal. Utilizing Vhl+/mu mouse model, depletion of VHL exacerbated kidney inflammatory injury during nephrolithiasis. Conversely, overexpression of VHL limited crystal-induced lipid peroxidation and ferroptosis in a BICD2-depdendent manner. Mechanistically, VHL interacted with the cargo adaptor BICD2 and promoted itsd K48-linked poly-ubiquitination, consequently resulting in the proteasomal degradation of BICD2. Through promoting STAT1 nuclear translocation, BICD2 facilitated IFNγ signaling transduction and enhanced IFNγ-mediated suppression of cystine/glutamate antiporter system Xc-, eventually increasing cell sensitivity to ferroptosis. Moreover, we found that the BRAF inhibitor impaired the association of VHL with BICD2 through triggering BICD2 phosphorylation, ultimately causing severe ferroptosis and nephrotoxicity. Collectively, our results uncover the important role of VHL/BICD2/STAT1 axis in crystal kidney injury and provide a potential therapeutic target for treatment and prevention of renal inflammation and drug-induced nephrotoxicity.
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Carcinoma de Células Renales , Neoplasias Renales , Nefrolitiasis , Animales , Ratones , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Riñón/patología , Neoplasias Renales/metabolismo , Carcinoma de Células Renales/metabolismo , Nefrolitiasis/metabolismoRESUMEN
OBJECTIVES: The association of migraine with the risk of certain cancer has been reported. The aim of this pilot study was to examine the associations between migraine and the onset of head and neck cancers (HNC). MATERIALS AND METHODS: A total of 1755 individuals were identified through a nationwide population-based cohort registry in Taiwan between 2000 and 2013. The primary end point variable was new-onset head and neck cancers in patients with migraine versus non-migraine controls. Cox proportional hazard regression was used to derive the risk of HNC. Subgroup analyses were performed to determine subpopulations at risk of migraine-associated HNC. Sub-outcome analyses were carried out to provide the subtypes of migraine-associated HNC. Propensity score matching was utilized to validate the findings. RESULTS: A total of four patients out of 351 patients with migraine and seven out of 1404 non-migraine controls developed HNC. The incidence of HNC was higher in patients with migraine than that in non-migraine controls (108.93 vs. 48.77 per 100,000 person-years) (adjusted hazard ratio, aHR = 2.908, 95% CI = 0.808-10.469; p = 0.102). The risk of HNC in patients with migraine with aura (aHR = 5.454, 95% CI = 0.948-26.875; p = 0.264) and without aura (aHR = 2.777, 95% CI = 0.755-8.473; p = 0.118) was revealed. The incidence of non-nasopharyngeal HNC secondary to migraine (112.79 per 100,000 person-years) was higher than that of nasopharyngeal cancer secondary to migraine (105.33 per 100,000 person-years). CONCLUSION: A higher incidence of HNC was observed in a small sample of patients with migraine, especially in those with migraine with aura. Migraine-associated HNC included non-nasopharyngeal HNC. Studies with a larger sample are needed to confirm the finding of the high risk of HNC in people with migraine.
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Background: Racial/ethnic disparities in prostate cancer are reported in the United States (US). However, long-term trends and contributors of racial/ethnic disparities in all-cause and cause-specific death among patients with prostate cancer remain unclear. We analysed the trends and contributors of racial/ethnic disparities in prostate cancer survivors according to the cause of death in the US over 25 years. Methods: In this retrospective, population-based longitudinal cohort study, we identified patients diagnosed with first primary prostate cancer between 1995 and 2019, with follow-up until Dec 31, 2019, using population-based cancer registries' data from the Surveillance, Epidemiology, and End Results (SEER) Program. We calculated the cumulative incidence of death for each racial/ethnic group (Black, white, Hispanic, Asian or Pacific Islander [API], and American Indian or Alaska Native [AI/AN] people), by diagnostic period and cause of death. We quantified absolute disparities using rate changes for the 5-year cumulative incidence of death between racial/ethnic groups and diagnostic periods. We estimated relative (Hazard ratios [HR]) racial/ethnic disparities and the percentage of potential factors contributed to racial/ethnic disparities using Cox regression models. Findings: Despite a decreasing trend in the cumulative risk of death across five racial/ethnic groups, AI/AN and Black patients consistently had the highest rate of death between 1995 and 2019 with an adjusted HR of 1.48 (1.40-1.58) and 1.40 (1.38-1.42) respectively. The disparities in all-cause mortality between AI/AN and white patients increased over time, with adjusted HR 1.32 (1.17-1.49) in 1995-1999 and 1.95 (1.53-2.49) in 2015-2019. Adjustment of stage at diagnosis, initial treatment, tumor grade, and household income explained 33% and 24% of the AI/AN-white and Black-white disparities in all-cause death among patients with prostate cancer. Interpretation: The enduring racial/ethnic disparities in patients with prostate cancer, call for new interventions to eliminate health disparities. Our study provides important evidence and ways to address racial/ethnic inequality. Funding: National Key R&D Program of China, National Natural Science Foundation of China, Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support, the Open Research Fund from Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Key Projects of Philosophy and Social Sciences Research, Ministry of Education of China.
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Prostate cancer (PCa) is a pernicious tumor with high heterogeneity, which creates a conundrum for making a precise diagnosis and choosing an optimal treatment approach. Multiparametric magnetic resonance imaging (mp-MRI) with anatomical and functional sequences has evolved as a routine and significant paradigm for the detection and characterization of PCa. Moreover, using radiomics to extract quantitative data has emerged as a promising field due to the rapid growth of artificial intelligence (AI) and image data processing. Radiomics acquires novel imaging biomarkers by extracting imaging signatures and establishes models for precise evaluation. Radiomics models provide a reliable and noninvasive alternative to aid in precision medicine, demonstrating advantages over traditional models based on clinicopathological parameters. The purpose of this review is to provide an overview of related studies of radiomics in PCa, specifically around the development and validation of radiomics models using MRI-derived image features. The current landscape of the literature, focusing mainly on PCa detection, aggressiveness, and prognosis evaluation, is reviewed and summarized. Rather than studies that exclusively focus on image biomarker identification and method optimization, models with high potential for universal clinical implementation are identified. Furthermore, we delve deeper into the critical concerns that can be addressed by different models and the obstacles that may arise in a clinical scenario. This review will encourage researchers to design models based on actual clinical needs, as well as assist urologists in gaining a better understanding of the promising results yielded by radiomics.
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Inteligencia Artificial , Neoplasias de la Próstata , Masculino , Humanos , Imagen por Resonancia Magnética/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Medicina de Precisión , Estudios RetrospectivosRESUMEN
N-cadherin (cadherin-2 [CDH2]) is widely known as the promoter of prostate cancer (PCa) invasion and castration resistance. However, the biological mechanism of N-cadherin in PCa progression is unclear. In this study, we overexpressed N-cadherin in LNCaP cells and downregulated N-cadherin in PC3 cells by lentiviral transduction. Then, differentially expressed genes (DEGs) and dysregulated biological functions were investigated through RNA sequencing (RNA-seq) analyses. We found 13 long noncoding RNA (lncRNA) transcripts, 72 messenger RNA (mRNA) transcripts, and 3 integrated genes were dysregulated by N-cadherin. In the disease enrichment, bone cancer, and neurodegenerative and nervous system diseases were associated with N-cadherin in the circular RNA (circRNA; PC3 versus [vs.,/] LNCaP [PC3/LNCaP] comparison) and DEG analysis (LNCaP_oe_CDH2 vs. LNCaP_oe_NC [LNCaP_oe_CDH2/NC] comparison). Epigenetic reprogramming, such as nucleic acid binding, and chromatin and histone modifications, was enriched in Gene Ontology (GO) analysis (DEGs in LNCaP_oe_CDH2/NC and PC3_sh_NC/CDH2, and host genes of circRNA in PC3/LNCaP). Transcriptional misregulation in cancer, post-translational protein modification, gene expression, and generic transcription pathways were dysregulated in the pathway enrichment analysis (host genes of circRNA in PC3/LNCaP, and DEGs in LNCaP_oe_CDH2/NC and PC3_sh_NC/CDH2). Verifying DEGs through TCGA-PRAD dataset revealed six oncogenes (ARHGEF1, GRAMD1A, GTF2H4, MAPK8IP3, POLD1, and PTBP1) that were commonly upregulated by N-cadherin and in advanced PCa stages. In summary, we identified several oncogenes and biological functions associated with N-cadherin expression in PCa cells. N-cadherin may trigger epigenetic reprogramming in PCa cells to promote tumor progression.
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Neoplasias de la Próstata , ARN Circular , Humanos , Masculino , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Proteína de Unión al Tracto de Polipirimidina/genética , Proteína de Unión al Tracto de Polipirimidina/metabolismo , Neoplasias de la Próstata/metabolismo , ARN MensajeroRESUMEN
BACKGROUND: Neoadjuvant chemotherapy followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). However, treatment outcomes are suboptimal. Camrelizumab, a PD-1 blockade, has shown benefits in several tumors. This study aimed to investigate the efficacy and safety of neoadjuvant camrelizumab in combination with gemcitabine plus cisplatin (GC) followed by RC for MIBC patients. METHODS: This was a multi-center, single-arm study that enrolled MIBC patients with a clinical stage of T2-4aN0-1M0, and scheduled for RC. Patients received three 21-day cycles of camrelizumab 200 mg on day 1, gemcitabine 1000 mg/m2 on day 1 and 8, and cisplatin 70 mg/m2 on day 2, followed by RC. The primary endpoint was pathologic complete response (pCR, pT0N0). RESULTS: From May 2020 to July 2021, 43 patients were enrolled and received study medications at nine centers in China. Three of them were deemed ineligible and excluded from efficacy analysis but included in safety analysis. In total 10 patients were unevaluable as they declined RC (two due to adverse events [AEs] and eight due to patient's willingness). Among 30 evaluable patients, 13 patients (43.3%) achieved pCR, and 16 patients (53.3%) achieved pathologic downstaging. No AEs leading to death were observed. The most common AEs were anemia (69.8%), decreased white blood cell count (65.1%), and nausea (65.1%). Immune-related AEs were all grade 1 or 2. Pathologic response was not correlated with PD-L1 expression status or tumor mutation burden. Individual genes as a biomarker for pathologic response were not identified. CONCLUSIONS: Neoadjuvant treatment with camrelizumab and GC regimen demonstrated preliminary anti-tumor activity for MIBC patients with manageable safety profiles. The study met its primary endpoint, and the following randomized trial is ongoing.
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Cisplatino , Neoplasias de la Vejiga Urinaria , Humanos , Cisplatino/uso terapéutico , Gemcitabina , Terapia Neoadyuvante/efectos adversos , Neoplasias de la Vejiga Urinaria/patología , Desoxicitidina/uso terapéutico , Cistectomía , Músculos/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Invasividad NeoplásicaAsunto(s)
Hipertensión Pulmonar , Retinopatía de la Prematuridad , Recién Nacido , Humanos , Retinopatía de la Prematuridad/complicaciones , Retinopatía de la Prematuridad/diagnóstico , Retinopatía de la Prematuridad/tratamiento farmacológico , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiología , Recien Nacido Prematuro , Inhibidores de la Angiogénesis/uso terapéutico , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Inyecciones Intravítreas , Bevacizumab/uso terapéuticoRESUMEN
Background: Epigenetic reprogramming through dysregulated histone lysine methylation (HLM) plays a crucial role in prostate cancer (PCa) progression. This study aimed to comprehensively evaluate HLM modification patterns in PCa microenvironment infiltration. Materials and methods: Ninety-one HLM regulators in The Cancer Genome Atlas (TCGA) dataset were analyzed using bioinformatics. Differentially expressed genes (DEGs) and survival analyses were performed using TCGA-PRAD clinicopathologic and follow-up information. Consensus clustering analysis divided patients into subgroups. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the DEGs. Tumor mutation burden (TMB) and tumor microenvironment (TME) cell infiltration were evaluated in different HLM clusters. Quantitative real-time PCR (qPCR) analysis assessed HLM regulators in clinical PCa tissues. Results: The tumor vs. normal (TN), Gleason score (GS) > 7 vs. GS < 7, pathological T stage (pT) = 2 vs. pT = 3, and TP53 mutation vs. wild-type comparisons using TCGA-PRAD dataset revealed 3 intersecting HLM regulators (EZH2, NSD2, and KMT5C) that were consistently upregulated in advanced PCa (GS > 7, pT3, HR > 1, and TP53 mutation) (P < 0.05) and verified in clinical PCa tissues. Consensus clustering analysis revealed three distinct HLM modification patterns (HLMclusters). However, no significant differences in recurrence-free survival (RFS) rates were found among the groups (P > 0.05). We screened 189 HLM phenotype-related genes that overlapped in the pairwise comparisons of HLMclusters and P < 0.01 in the Cox regression analysis. Three distinct subgroups (geneClusters) were revealed based on the 189 genes, in which cluster A involved the most advanced PCa (PSA > 10, T3-4, GS8-10, and biochemical recurrence) and the poorest RFS. The HLM score (HLMscore) was calculated by principal component analysis (PCA) of HLM phenotype-related genes that have positive predictive value for RFS (P < 0.001) and immune therapy responses (in the CTLA4-positive and -negative responses accompanied by a PD1-negative response). Conclusion: We comprehensively evaluated HLM regulators in the PCa microenvironment using TCGA-PRAD, revealing a nonnegligible role of HLM patterns in PCa complexity and heterogeneity. Elucidating the effects of HLM regulators in PCa may enhance prognostics, aggressiveness assessments, and immunotherapy strategies.
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Objective: Benign prostatic hyperplasia (BPH) is the most common urological disease in elderly men. The transforming growth factor beta 1 (TGFß1) plays an important role in the proliferation and differentiation of BPH stroma. However, it is not clear yet which important pathways and key genes are the downstream of TGFß1 acting on prostatic stromal cells. Methods: GSE132714 is currently the newer, available, and best high-throughput sequencing data set for BPH disease and includes the largest number of BPH cases. We examined the TGFß1 expression level in BPH and normal prostate (NP) by analyzing the GSE132714 data set as well as carrying out immunohistochemistry of 15 BPH and 15 NP samples. Primary prostatic stromal cells (PrSCs) were isolated from five fresh BPH tissues. RNA sequencing and bioinformatics analysis were used to reveal important pathways and hub genes associated with TGFß1 stimulation on PrSCs. Results: TGFß1 was upregulated in BPH stroma compared to NP stroma. A total of 497 genes (244 upregulated and 253 downregulated) were differentially expressed in PrSCs with and without TGFß1 stimulation. The Gene Ontology revealed that differentially expressed genes (DEGs) were mainly enriched in progesterone secretion, interleukin-7 receptor binding, and CSF1-CSF1R complex. The Wnt signaling pathway, PI3K-Akt signaling pathway, JAK-STAT signaling pathway, and Hippo signaling pathway were screened based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. FN1, SMAD3, CXCL12, VCAM1, and ICAM1 were selected as hub genes according to the degree of connection from the protein-protein interaction (PPI) network. Conclusion: This study sheds some new insights into the role of TGFß1 in BPH stroma and provides some clues for the identification of potential downstream mechanisms and targets.
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Diabetes is commonly treated with glucagon-like peptide-1 receptor (GLP-1R) agonists including liraglutide and others. However, liraglutide was found to raise plasma glucose levels in normal rats. The current study aims to determine how liraglutide causes this contentious condition in rats, both normal and diabetic. An adrenalectomy was performed to investigate the relationship between steroid hormone and liraglutide. To investigate the effect of central liraglutide infusion on blood glucose in rats, rats were intracerebroventricularly administrated with liraglutide with or without HPA axis inhibitors such as berberine and dexamethasone. The results showed that a single injection of liraglutide caused a temporary increase in blood glucose in healthy rats. Another GLP-1R agonist, Exendin-4 (Ex-4), increased blood sugar in a manner similar to that of liraglutide. The effects of liraglutide were also blocked by guanethidine pretreatment and vanished in normal rats with adrenalectomy. Additionally, central infusion of liraglutide via intracerebroventricular (icv) injection into normal rats also causes a temporary increase in blood glucose that was blocked by GLP-1R antagonists or the inhibitors such as berberine and dexamethasone. Similarly, central liraglutide treatment causes temporary increases in plasma glucose, adrenocorticotropic hormone (ACTH), and cortisol levels, which were reversed by inhibitors for the hypothalamic-pituitary-adrenal (HPA) axis. In normal rats, the temporary glucose-increasing effect of liraglutide was gradually eliminated during consecutive daily treatments, indicating tolerance formation. Additionally, liraglutide and Ex-4 cross-tolerance was also discovered in normal rats. Liraglutide was more effective in diabetic rats than in normal rats in activating GLP-1R gene expression in the isolated adrenal gland. Interestingly, the effect of liraglutide on glycemic control varied depending on whether the rats were diabetic or not. In normal rats, bolus injection of liraglutide, such as Ex-4, may stimulate the HPA axis, resulting in hyperglycemia. The cross-tolerance of liraglutide and Ex-4 provided a novel perspective on GLP-1R activation.