Clinical and imaging characteristics of patients with bronchogenic cysts: a single-center retrospective analysis.

BACKGROUND: Bronchogenic cysts (BCs) are rare and usually asymptomatic malformations detected during imaging examinations. We aimed to investigate the clinical and imaging characteristics of patients with BCs. METHODS: We retrospectively evaluated patients who received surgery to remove their BCs from January 2015 to January 2019. Their baseline characteristics, clinical information, and imaging results were reviewed. RESULTS: Our study included 129 patients, with 57 males and 72 females and a mean age of 42.7 years old. The most common location for BCs was the mediastinum (67 patients, 51.9%). Fewer than half of the patients (53 patients, 41.1%) reported clinical symptoms, with chest pain being the most common (16 patients, 30.2%). Neck BCs were more frequently observed in young patients (P = 0.002) and were more often associated with thyroid cancer (P = 0.007). A computed tomography scan was the most commonly used method to diagnose BCs in the lung and mediastinum, whereas ultrasound was the most commonly used diagnostic method for neck BCs. The characteristic images were well-defined, thin-wall cystic lesions in varying densities. A few lesions showed small, calcified spots along the rim or cavities. CONCLUSIONS: Although most BCs were found in the mediastinum, their locations could vary in different sex and age groups. Particular attention should be paid to young patients with BCs in the neck to rule out thyroid cancer.

S100 proteins in cardiovascular diseases.

Cardiovascular diseases have become a serious threat to human health and life worldwide and have the highest fatality rate. Therefore, the prevention and treatment of cardiovascular diseases have become a focus for public health experts. The expression of S100 proteins is cell- and tissue-specific; they are implicated in cardiovascular, neurodegenerative, and inflammatory diseases and cancer. This review article discusses the progress in the research on the role of S100 protein family members in cardiovascular diseases. Understanding the mechanisms by which these proteins exert their biological function may provide novel concepts for preventing, treating, and predicting cardiovascular diseases.

Environmentally relevant perinatal exposure to DBP accelerated spermatogenesis by promoting the glycolipid metabolism of Sertoli cells in male offspring mice.

Since Sertoli cells (SCs) play an essential role in providing energy for spermatogenesis, the present study aimed to investigate the effects of maternal exposure to plasticizer Dibutyl phthalate (DBP) on the onset of spermatogenesis in male offspring through the metabolism pathway as well as the underlying molecular mechanism. Here, pregnant mice were treated with 0 (control), 50, 250, or 500 mg/kg/day DBP in 1 mL/kg corn oil administered daily by oral gavage from gestation day (GD) 12.5 to parturition. The in vivo results showed that 50 mg/kg/day DBP exposure could promote the expression of glucose metabolism-related proteins (GLUT3, LDHA, and MCT4) in the testis of 22 days male offspring. The in vitro results demonstrated that 0.1 mM monobutyl phthalate (MBP, the active metabolite of DBP) promoted the lactate production, glucose consumption, and glycolytic flux of immature SCs, which was paralleled by the upregulated expression of glucose metabolism-related proteins (GLUT1, GLUT3, LDHA, and MCT4). On the other hand, DBP/MBP increased fatty acid (FA) uptake, FA ß-oxidation, and ATP production by promoting the expression of CD36 in immature SCs, which might accelerate the maturity of SCs to support the onset of spermatogenesis. Therefore, our findings provided a new perspective on glycolipid metabolism to explain prenatal DBP exposure leading to earlier onset of spermatogenesis in male offspring mice.

Verification of cell cycle-associated cyclin-dependent kinases facilitated prostate cancer progression by integrated bioinformatic analysis and experimental validation.

Introduction: Cell cycle-associated cyclin-dependent kinases (ccCDKs) are essential regulators known to control cell division and facilitate tumorigenesis and progression. However, there is currently no comprehensive study of distinct ccCDKs in prostate cancer (PCa). The purpose of this study was to determine the value of ccCDK expression in predicting the prognosis of patients with PCa and to identify the gene functions of ccCDK in PCa. Methods: The UALCAN databases were analyzed to examine the expression of CDKs in prostate cancer. The Human Protein Atlas was used to verify the expression of CDKs online. Then, we assessed the prognostic values of CDKs using GEPIA. GeneMANIA and Metascape analyses were used to predict biological functions. We analyzed the mutation of CDKs by cBioPortal. The TIMER database was used to evaluate the correlation of CDKs and immune infiltration. The expression of CDKs in tissue was examined through quantitative real-time polymerase chain reaction. After that, we focused on CDK3 and identified the expression of CDK3 by immunohistochemistry and western blot. The functions of CDK3 in C4-2 cell proliferation were determined by CCK-8 assays. C4-2 cells were tested for their ability to invade and migrate through transwell and wound healing assays. Results: The results showed that CDK1/3/4/5/6/16 was expressed at relatively higher levels in PCa tissues than in normal tissues. Patients with low expression of CDK1/3/5/16 exhibited significantly better disease-free survival than those with high expression. ccCDKs were enriched in the IL-18 signaling pathway and correlated with the infiltration of immune cells in PCa. Moreover, our cohort study data verified that there were significantly higher expression of CDK1/3/5/16 in PCa tissues compared to benign prostate hyperplasia tissues, and CDK3 was remarkably associated with a shorter progression-free survival for biochemical recurrence in PCa patients. CDK3 was positively expressed in PCa cells and tissues, and functional experiments demonstrated that silencing CDK3 inhibited PCa cell proliferation, migration, and invasion. Conclusions: Our study provides new evidence of ccCDKS in promoting PCa progression and implies that CDK3 may serve as an oncogene in PCa and may be valuable in the prognosis of biochemical recurrence in PCa patients.

Evaluation of NOTCH family genes' expression and prognostic value in prostate cancer.

Background: Abnormal regulation of the NOTCH signaling pathway in prostate cancer (PCa) can promote tumorigenesis, progression, and T cell exhaustion. However, there has not been a comprehensive analysis of NOTCH family genes (NOTCHs) as potential therapeutic targets and prognostic biomarkers for PCa patients. Methods: NOTCHs expressions in various types of cancer tissues and normal adjacent tissues in the TIMER and UALCAN database were screened. Immunohistochemistry (IHC) and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) were applied to validate the expression pattern of NOTCHs in clinical samples. The relationships of NOTCHs expression and clinicopathologic parameters or disease-free survival (DFS) were evaluated via GEPIA2 and UALCAN. A proteins network was built using STRING and GeneMANIA. Additionally, NOTCHs mutation status was analyzed by cBioportal. Finally, we used GDSC and TIMER to investigate NOTCH signaling-related drugs and immune cell infiltration. Results: The transcriptional levels of NOTCH1 and NOTCH4 in PCa tissues were significantly lower than in normal tissues, which was further validated in clinical patients' tissue samples. Furthermore, NOTCH1, NOTCH3, and NOTCH4 expressions in PCa were associated with worse DFS. Interestingly, there was a significant positive correlation between NOTCHs and androgen receptor (AR), but not with AR-related genes (KLK3 and TMPRSS2). Finally, we found that NOTCHs expressions were remarkably associated with infiltration of B cells, CD8+/CD4+ T cells, macrophages, neutrophils, and dendritic cells, which indicated that NOTCHs mutation status might be a potential therapeutic target for -tinib antineoplastic drugs. Conclusions: The expression and mutation of NOTCH1-4 in PCa were associated with disease progression, prognosis, immune cell infiltration, and drug sensitivity.

Maternal DBP exposure promotes synaptic formation in offspring by activating astrocytes via the AKT/NF-κB/IL-6/JAK2/STAT3 signaling pathway.

It has been demonstrated that activated astrocytes in the hypothalamus could disrupt GnRH secretion in offspring after maternal di-n-butyl phthalate (DBP) exposure, indicating that the effect of DBP on astrocyte activation and crosstalk between astrocytes and neurons is still worthy of further investigation. In this study, pregnant mice were intragastrically administered DBP dissolved in corn oil from gestational days (GD) 12.5-21.5. Maternal DBP exposure resulted in hippocampal astrocyte activation, abnormal synaptic formation, and reduced autonomic and exploratory behavior in offspring on postnatal day (PND) 22. Further studies identified that mono-n-butyl phthalate (MBP) induced astrocyte activation and proliferation by activating the AKT/NF-κB/IL-6/JAK2/STAT3 signaling pathway. Moreover, upregulated thrombospondin 1 (TSP1) in activated astrocytes regulated synaptic-related protein expression. This study highlights the neurotoxicity of maternal DBP exposure to offspring, which provides new insights into identifying potential molecular targets for the treatment of diseases related to neurological development disorders in children.

The positive regulation loop between NRF1 and NONO-TFE3 fusion promotes phase separation and aggregation of NONO-TFE3 in NONO-TFE3 tRCC.

TFE3 gene fusions often place TFE3 under the control of a more active promoter and cause overexpression of the TFE3 proteins in renal cell carcinoma associated with Xp11.2 translocations (Xp11.2 tRCC). The purpose of this study was to investigate the transcriptional regulation and aggregation mechanism of NONO-TFE3 in NONO-TFE3 tRCC. In this study, we found that the nuclear aggregation of NONO-TFE3 fusion was significantly more than that of intact TFE3 or PRCC-TFE3 fusion. We observed that NONO fragment mediated-phase separation promoted stabilization and aggregation of NONO-TFE3 fusion. Meantime, we revealed that the positive regulation loop between NONO-TFE3 and NRF1 increased mitochondrial biosynthesis and metabolism in NONO-TFE3 tRCC. Therefore, the present study raises the possibility that mitochondrial metabolism is potentially a fruitful arena for NONO-TFE3 tRCC therapy.

Microcystin-leucine arginine induced the apoptosis of GnRH neurons by activating the endoplasmic reticulum stress resulting in a decrease of serum testosterone level in mice.

Microcystin-leucine arginine (MC-LR) is a kind of toxin produced by cyanobacterial, resulting in decrease of testosterone levels in serum and leading to impaired spermatogenesis. Gonadotropin-releasing hormone (GnRH) neurons play crucial roles in the regulation of testosterone release. Meanwhile, it has been demonstrated that MC-LR is capable of entering the GnRH neurons and inducing apoptosis. Nevertheless, the molecular mechanism of MC-LR induced apoptosis of GnRH neurons remains elusive. In present study, we found that MC-LR inhibited the cell viability of GT1-7 cells. In addition, we discovered apoptosis of GnRH neurons and GT1-7 cells treated with MC-LR. And increased intracellular ROS production and the release of intracellular Ca2+ were all observed following exposure to MC-LR. Furthermore, we also found the endoplasmic reticulum stress (ERs) and autophagy were activated by MC-LR. Additionally, pretreatment of the ERs inhibitor (4-Phenyl butyric acid) reduced the apoptotic rate of GT1-7 cells comparing with MC-LR exposure alone. Comparing with MC-LR treatment alone, apoptotic cell death was increased by pretreatment of GT1-7 cells with an autophagy inhibitor (3-methyladenine). Together, our data implicated that the treatment of MC-LR induced the apoptosis of GnRH neurons by activating the ERs resulting in a decrease of serum testosterone level in mice. Autophagy is a protective cellular process which was activated by ER stress and thus protected cells from apoptosis upon MC-LR exposure.

In utero exposure to DBP stimulates release of GnRH by increasing the secretion of PGE2 in the astrocytes of the hypothalamus in the offspring mice.

Di-n-butyl phthalate (DBP), the most commonly used plasticizer and typical endocrine disrupting chemicals (EDCs), has shown its characteristics of causing reproductive and developmental toxicity in males, while the neuroendocrine toxicity induced by DBP exposure in utero and the mechanism beneath still remain unclear. Here, the pregnant mice were treated with corn oil (control) or DBP at three different doses by oral gavage during gestational days (GD) 12.5-21.5. The results showed that in utero exposure to DBP induced a significant increase of gonadotropin releasing hormone (GnRH) content in serum, as well as activation and proliferation of astrocytes in the hypothalamus of offspring male mice on postnatal day (PND) 22. However, in in vitro study, mono-n-butyl phthalate (MBP), the metabolite of DBP, could not increase the release of GnRH after GnRH neurons were exposed to MBP. Further studies identified that MBP-mediated activation and proliferation of astrocytes resulted in increased secretion of prostaglandin E2 (PGE2), which might be responsible for the increased release of GnRH from GnRH neurons. This study highlights the neuroendocrine toxicity of current plasticizer DBP exposure, laying the foundation for identifying potential molecular targets for related diseases.

Exposure of DBP in gestation induces inflammation of testicular Sertoli cells in progeny by activating NLRP3 inflammasomes.

Di-n-butyl phthalate (DBP), as one of the environmental chemicals, can cause male reproductive decline including testicular hypoplasia and impairments of spermatogenesis. Testicular inflammation is positively related to decline in male reproductive function. However, whether exposure to DBP in utero can cause testicular inflammation in progeny has not been studied. In this study, we established an animal model and observed that DBP exposure during gestation induced testicular inflammation in progeny with the increased expression of pro-inflammatory cytokines and chemokines including tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1) and CXC chemokine ligand-10 (CXCL-10), representing the activation of the nuclear factor kappa B (NF-κB). However, NF-κB was activated within 1 h in Sertoli cells (SCs) when exposed to MBP (a metabolite of DBP) in vitro. Meanwhile, we detected increased expression of inflammatory NLR family pyrin domain containing 3 (NLRP3), resulting from Pellino2-mediated NLRP3 inflammasome priming. Further, we confirmed that the activation of the NLRP3/caspase-1/IL-1ß canonical inflammasome pathway induced secretion of inflammatory factors of SCs and immune response, and INF39 (an inhibitor of NLRP3) could inhibit the inflammation in vitro. Collectively, these findings indicated that NLRP3 inflammasomes played key roles in DBP-induced inflammation in testicular SCs.

The mechanism of Oatp1a5-mediated microcystin-leucine arginine entering into GnRH neurons.

Microcystin-leucine arginine (MC-LR) enters into gonadotropin-releasing hormone (GnRH) neurons and induces decline of serum GnRH levels resulting in male reproductive toxicity via hypothalamic-pituitary-testis axis. The organic anion transporting polypeptide 1a5 (Oatp1a5) is a critical transporter for the uptake of MC-LR by GnRH neurons. However, the underlying molecular mechanisms of the transport process are still elusive. In this study, we found that the transmembrane domains 2, 8, and 9 played important roles in transporting function of Oatp1a5. In addition, our data demonstrated that N-linked glycosylation was involved in the transport of MC-LR by Oatp1a5. Moreover, we showed that N-linked glycosylation sites Asn483 and Asn492 were vital for the transport function of Oatp1a5. In summary, the study furthered our understanding of mechanisms that the uptake of MC-LR by GnRH neurons and laid a theoretical foundation for preventing MC-LR from injuring male reproductive health.

MiR-301b-3p/3584-5p enhances low-dose mono-n-butyl phthalate (MBP)-induced proliferation by targeting Rasd1 in Sertoli cells.

To investigate the possible molecular mechanism of low concentration plasticizer mono-n-butyl phthalate (MBP) -induced juvenile Sertoli cells (SCs) proliferation, we evaluated global alterations of miRNA and mRNA expression in rat SCs treated with 0.1mM MBP. Microarray analysis revealed that miR-3584-5p and miR-301b-3p were up-regulated and their common target gene Dexamethasone-induced Ras-related protein 1 (Rasd1) was down-regulated. Further work suggested that SCs proliferation induced by low concentration MBP in vitro might be mediated by Rasd1 regulating ERK1/2 signaling pathway. The present study is first to investigate the effect of low-dose MBP on SCs proliferation and may enhance our understanding on the modes of action of low concentration MBP on male reproductive system. We hope the results will contribute to explain the causes of precocious puberty and testicular tumors induced by exogenous chemicals.

TNF-α-induced NF-κB activation promotes myofibroblast differentiation of LR-MSCs and exacerbates bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease of unknown cause. It has been reported that both lung resident mesenchymal stem cells (LR-MSCs) and tumor necrosis factor-α (TNF-α) play important roles in the development of pulmonary fibrosis. However, the underlying connections between LR-MSCs and TNF-α in the pathogenesis of pulmonary fibrosis are still elusive. In this study, we found that the pro-inflammatory cytokine TNF-α and the transcription factor nuclear factor kappa B (NF-κB) p65 subunit were both upregulated in bleomycin-induced fibrotic lung tissue. In addition, we discovered that TNF-α promotes myofibroblast differentiation of LR-MSCs through activating NF-κB signaling. Interestingly, we also found that TNF-α promotes the expression of ß-catenin. Moreover, we demonstrated that suppression of the NF-κB signaling could attenuate myofibroblast differentiation of LR-MSCs and bleomycin-induced pulmonary fibrosis which were accompanied with decreased expression of ß-catenin. Our data implicates that inhibition of the NF-κB signaling pathway may provide a therapeutic strategy for pulmonary fibrosis, a disease that warrants more effective treatment approaches.

Effects of In Utero Exposure to Di-n-Butyl Phthalate on Testicular Development in Rat.

Humans are inevitably exposed to ubiquitous phthalate esters (PAEs). In utero exposure to di-n-butyl phthalate (DBP) induces abnormal development of the testis and reproductive tract in male offspring, which correspond closely with the human condition of testicular dysgenesis syndrome (TDS)-like syndrome. However, the underlying mechanisms have not been elucidated in detail. In this study, pregnant rats were orally exposed to either corn oil (controls) or DBP at three different doses by gavage during Gestational Days 12.5-21.5. Pathological examinations were performed for toxicity evaluation. Proliferation and apoptosis related proteins (ras related dexamethasone induced 1 (Rasd1), mitogen-activated protein kinase kinases1/2 (MEK1/2), Bcl-2, and Bax) were measured for mechanisms exploration. The results showed that different doses of DBP caused male developmental and reproductive toxicity in rats, including the decrease of anogenital distance (AGD), the histological damage of testis, and apoptosis of seminiferous tubule cells. Our data suggested that DBP played chronic and continuous toxic roles on male reproductive system by disrupting expression of Rasd1 and MEK1/2 as well as Bcl-2/Bax ratio. Further research is warranted.

A novel schiff base zinc coordination compound inhibits proliferation and induces apoptosis of human osteosarcoma cells.

Various kinds of schiff base metal complexes have been proven to induce apoptosis of tumor cells. However, it remains largely unknown whether schiff base zinc complexes induce apoptosis in human cancer cells. Here, we synthesized a novel schiff base zinc coordination compound (SBZCC) and investigated its effects on the growth, proliferation and apoptosis of human osteosarcoma MG-63 cells. A novel SBZCC was synthesized by chemical processes and used to treat MG-63 cells. The cell viability was determined by CCK-8 assay. The cell cycle progression, mitochondrial membrane potential and apoptotic cells were analyzed by flow cytometry. The apoptosis-related proteins levels were determined by immunoblotting. Treatment of MG-63 cells with SBZCC resulted in inhibition of cell proliferation and cell cycle arrest at G1 phase. Moreover, SBZCC significantly reduced the mitochondrial membrane potential and induced apoptosis, accompanied with increased Bax/Bcl-2 and FlasL/Fas expression as well as caspase-3/8/9 cleavage. Our results demonstrated that the synthesized novel SBZCC could inhibit the proliferation and induce apoptosis of MG-63 cells via activating both the mitochondrial and cell death receptor apoptosis pathways, suggesting that SBZCC is a promising agent for the development as anticancer drugs.