A pharmacovigilance study of drug-reduced male semen quality based on the Food and Drug Administration adverse event reporting system database.

BACKGROUND: Real-world big data studies on drug-reduced male semen quality are few and far between, with most studies based on animal trials, small scale retrospective studies, or a limited number of pre-market clinical trials. METHODS: This study aimed to identify culprit drugs that reduced male semen quality based on the United States Food and Drug Administration adverse event reporting system. The Medical Dictionary for Regulatory Activities preferred terms and standardized Medical Dictionary for Regulatory Activities queries were used to define reduced male semen quality. Adverse events related to drug-reduced male semen quality were then analyzed by disproportionality analysis using the United States Food and Drug Administration adverse event reporting system data between 2004 and 2023. RESULTS: At the preferred term level, 59 drugs with risk signals were detected to be associated with drug-reduced male semen quality, with the three most frequently reported second-level Anatomical Therapeutic Chemical groups being antineoplastic agents (n = 16, 27.12%), psychoanaleptics (n = 9, 15.25%), and psycholeptics (n = 6, 10.17%). At the standardized Medical Dictionary for Regulatory Activities queries level, the five drugs with the greatest number of cases were finasteride (845 cases, IC025 = 7.72), dutasteride (163 cases, IC025 = 7.22), tamsulosin (148 cases, IC025 = 5.99), testosterone (101 cases, IC025 = 4.08), and valproic acid (54 cases, IC025 = 2.44). Additionally, clinical information about drug-reduced male semen quality is absent from the Summary of Product Characteristics of 41 drugs in our study. CONCLUSIONS: Using the United States Food and Drug Administration adverse event reporting system database, we offer a list of drugs with risk signals for reducing male semen quality. In the future, there is still a need for more studies on drugs whose effects on male semen quality are not fully understood.

PD-1 inhibitor-based adverse events in solid tumors: A retrospective real-world study.

Background & Aims: Immune checkpoint inhibitors (ICIs) have transformed the landscape of cancer treatment, and ICI-related toxicities (i.e., immune-related adverse events (irAEs) have been reported in many clinical studies. However, the toxicity data of real-world have not been fully assessed. Methods: Patients with histologically confirmed solid tumors who had been treated with PD-1 inhibitors were included in the study. Patient data were collected from electronic medical records, including basic characteristics, data of irAEs, management and outcome. Incidences of irAEs were pooled and compared, and the risk of irAEs was also analyzed. Results: A total of 362 solid tumor patients treated with sintilimab (n = 171), camrelizumab (n = 60), toripalimab (n = 72), and pembrolizumab (n = 59) were included. In total, any grade irAEs, grade 1-2 irAEs, and grade ≥3 irAEs accounted for 47.24%, 38.67% and 8.56% of cases, reapectively. Further, 29.24% of patients discontinued immunotherapy due to irAEs, with pneumonitis being the main reason for discontinuation. By comparing the toxicity profiles between different ICIs, we found that reactive capillary haemangiomas were camrelizumab-specific. Additionally, the frequency of irAEs was association with ICIs type, the pooled incidence (standardized rate) of irAEs related to sintilimab, camrelizumab, toripalimab and pembrolizumab were 55.56% (52.81%), 48.33% (55.55%), 33.33% (29.23%) and 38.98% (38.29%), respectively. Sintilimab and camrelizumab had higher incidences of any grade and grade 1-2 than toripalimab (55.56% vs. 33.33%, p = 0.002; 48.54% vs. 25.00%, p = 0.0001) and pembrolizumab (55.56% vs. 38.98%, p = 0.0028; 48.54% vs. 25.42%, p = 0.002), while the grade ≥3 irAEs of pembrolizumab (13.56%) were approximately 1.63- to 1.93-fold higher than other ICIs, and the standardized grade ≥3 of pembrolizumab was significantly higher than that of sintilimab (13.21% vs. 7.12%, p = 0.026), especially for grade ≥3 pneumonitis. Multivariate analysis found that cumulative cycles of ICI (OR = 1.081; 95% CI: 1.023-1.142; p = 0.006), and lung cancer (OR = 1.765; 95% CI: 1.105-2.820; p = 0.017) were independent risk factors for irAEs. Conclusion: The frequency of irAEs is associated with ICI type. The pooled incidence of irAEs related to sintilimab and pneumonitis caused by pembrolizumab were higher. These data indicate the importance of having different monitoring priorities for different PD-1 inhibitors.

Anti-polyphenol oxidase properties of total flavonoids from young loquat fruits: inhibitory activity and mechanism.

This study investigated anti-polyphenol oxidase activity and mechanism of purified total flavonoids (PTF) from young loquat fruits. PTF remarkably inhibited the activity of polyphenol oxidase (PPO) with an IC50 value of 21.03 ± 2.37 µg/mL. Based on enzyme kinetics, PTF was found to be a potent, mixed-type, and reversible inhibitor of PPO. The fluorescence intensity of PPO was quenched by PTF through forming a PTF-PPO complex in a static procedure. Therefore, this study authenticated PTF as an efficient PPO inhibitor, which would contribute to their utilization in food industry.

Eriodictyol Inhibits Proliferation, Metastasis and Induces Apoptosis of Glioma Cells via PI3K/Akt/NF-κB Signaling Pathway.

Glioma is the most common type of malignant brain tumor. Due to its highly aggressive and metastatic features, glioma is associated with poor prognosis and a lack of effective treatments. Eriodictyol, a natural flavonoid compound, has been reported to possess anti-inflammatory and antioxidant effects. However, the anti-tumor effects of eriodictyol and the underlying mechanisms have rarely been reported. In this study, we found that eriodictyol has anti-tumor activity in lung, colon, breast, pancreas, and liver cancer, and most significantly in glioma cell lines. Eriodictyol dose- and time-dependently suppresses cell proliferation, migration, and invasion in U87MG and CHG-5 glioma cells. In addition, eriodictyol induces apoptosis in U87MG and CHG-5 cells, as evaluated by flow cytometry, immunofluorescence, and Western blot. Furthermore, eriodictyol downregulates the phosphoinositide 3-kinase (PI3K)/Akt/NF-κB signaling pathway in a concentration-dependent manner. Moreover, the effects of eriodictyol on the apoptosis of glioma cells are enhanced by LY294002 (a PI3K inhibitor) and reversed by 740 Y-P (a PI3K agonist). In a mouse xenograft model, eriodictyol not only dramatically suppressed tumor growth but also induced apoptosis in tumor cells. In summary, our data illustrate that eriodictyol effectively inhibits proliferation and metastasis and induces apoptosis of glioma cell lines, which might be a result of the blockade of the PI3K/Akt/NF-κB signaling pathway.

Optimization of extraction of loquat flowers polyphenolics and its antioxidant and anti-polyphenol oxidase properties.

In this study, the conditions of extraction of loquat flowers polyphenolics were optimized through response surface methodology (RSM). Proper extraction conditions were: solid to liquid ratio 1 g per 50 mL and ethanol concentration 50% at 61°C for 9 min. Furthermore, the antioxidant and anti-polyphenol oxidase (PPO) activity of purified total polyphenolics (PTP) were investigated. PTP displayed strong antioxidant activity with IC50 values of 126.3 ± 8.9, 162.4 ± 6.3 and 94.97 mg ascorbic acid equivalent/g dry weight (mg AAE/d.w.) for ABTS, DPPH, and FRAP assays. In addition, PTP has a substantial inhibitory activity on PPO (IC50 = 115 ± 9.2 µg/mL). From the kinetics analysis, it was proved to be a reversible and mixed-type inhibitor of PPO with KI and KIS values of 76.77 µg/mL and 227.86 µg/mL, respectively. Further, the molecular mechanism underlying the inhibition of PPO by PTP was investigated by molecular docking techniques. The results showed that PTP units could form interaction with the catalytic pocket of PPO through the interaction with amino acid residues in the enzyme active center. The antioxidant activities of PTP together with its effect on PPO activity provide a strong starting point for their practical usage in the food industry.

Retinoic acid receptor α facilitates human colorectal cancer progression via Akt and MMP2 signaling.

Purpose: Retinoic acid α (RARα) is overexpressed in various tumors and facilitates cancer progression. Although RARα has been shown to facilitate colorectal cancer (CRC) progression, more efforts to characterize mechanisms of RARα in CRC are needed in order to develop better target-based drugs for tumor therapy. Methods: RARα expression in CRC was assessed by IHC. EdU, QPCR, Western blotting, dual-luciferase reporter assay and ChIP were performed to explore the role of RARα in CRC and the mechanism involoved. Results: Here, we show an overexpression of RARα in 73.5% (i.e., 25 of 34 human CRC specimens). RARα knockdown decreased cell proliferation, migration, and invasion. Such phenotypic manifestations can be correlated to lowered activation of Akt and expression of PCNA (proliferating cell nuclear antigen) as well as MMP2 (matrix metallopeptidase). Mechanistically, RARα facilitates CRC growth through Akt signaling activation to cause levels of PCNA to be upregulated. Furthermore, RARα promotes migration and invasion of CRC cells by directly recruiting the MMP2 promoter to enhance the expression of MMP2. Conclusions: These findings demonstrate that CRC carcinogenesis is promoted by RARα via an enhanced Akt signaling and by increasing MMP2 transcription. CRC therapy can examine the use of RARα as a prospective molecular target.

Oncogenic retinoic acid receptor γ knockdown reverses multi-drug resistance of human colorectal cancer via Wnt/ß-catenin pathway.

Retinoic acid receptor γ (RARγ), a unique member of the nuclear receptor superfamily, plays an important role in the progression of several cancers such as hepatocellular carcinoma, esophageal cancer, and cholangiocarcinoma. However, little is known about the regulatory mechanism of the RARγ expression in colorectal cancer (CRC) progression. In the present study, we found that RARγ was frequently overexpressed in human CRC specimens and CRC cell lines, and it mainly resided in the cytoplasm in CRC specimens. Tissue microarrays showed that RARγ indicated vital clinical significance in CRC. RARγ knockdown neither affected CRC cell proliferation nor blocked the cell cycle of CRC cells. However, RARγ knockdown increased the sensitivity of CRC cells to chemotherapeutics through downregulation of multi-drug resistance 1(MDR1). Further studies suggested that RARγ knockdown resulted in downregulation of MDR1, in parallel with suppression of the Wnt/ß-catenin pathway. Moreover, a significantly positive association between RARγ and MDR1 was demonstrated in CRC tissue microarrays. Collectively, these results suggested that overexpression of RARγ contributed to the multidrug chemoresistance of CRC cells, at least in part due to upregulation of MDR1 via activation of the Wnt/ß-catenin pathway, indicating that RARγ might serve as a potential therapeutic target for chemoresistant CRC patients.

Oncogenic retinoic acid receptor α promotes human colorectal cancer growth through simultaneously regulating p21 transcription and GSK3ß/ß-catenin signaling.

Retinoic acid receptor α (RARα) plays important roles in the progression of several cancers such as leukemia, breast cancer, and lung cancer. In this study, we demonstrated that RARα protein was frequently overexpressed in human CRC specimens and CRC cell lines. RARα knockdown decreased cell survival, proliferation, and colony formation in vitro and tumorigenic potential in nude mice. Specifically, RARα knockdown inhibited cell cycle progression at G1 phase through upregulation of cell cycle inhibitor p21, and downregulation of cyclinD1. Furthermore, RARα was directly recruited to the p21 promoter to inhibit the expression of p21. Simultaneously, RARα contributed to the progression of CRC cells in part due to upregulation of cyclinD1 via activation of GSK3ß/ß-catenin pathway. Molecular mechanism studies revealed RARα interacted with GSK3ß and led to decreased expression of GSK3ß at ser9, followed by increased ß-catenin expression. Taken together, our results signified the importance of RARα in CRC and demonstrated that RARα promotes CRC progression through suppressing p21 transcription and enhancing GSK3ß/ß-catenin signaling. RARα might become a potential molecular target for the treatment of CRC.

Positive feedback loop of IL-1ß/Akt/RARα/Akt signaling mediates oncogenic property of RARα in gastric carcinoma.

Abnormal expression and function of retinoic acid receptor α (RARα) have been reported to be associated with various cancers including acute promyelocytic leukemia and hepatocellular carcinoma. However, the role and the mechanism of RARα in gastric carcinoma (GC) were unknown. Here, the expression of RARα was frequently elevated in human GC tissues and cell lines, and its overexpression was closely correlated with tumor size, lymph node metastasis and clinical stages in GC patients. Moreover, RARα overexpression was related with pathological differentiation. Functionally, RARα knockdown inhibited the proliferation and metastasis of GC cells, as well as enhanced drug susceptibility both in vitro and in vivo. Additionally, RARα knockdown suppressed GC progression through regulating the expression of cell proliferation, cell cycle, invasion and drug resistance associated proteins, such as PCNA, CyclinB1, CyclinD2, CyclinE, p21, MMP9 and MDR1. Mechanistically, the above oncogenic properties of RARα in GC were closely associated with Akt signaling activation. Moreover, overexpression of RARα was induced by IL-1ß/Akt signaling activation, which suggested a positive feedback loop of IL-1ß/Akt/RARα/Akt signaling in GC. Taken together, we demonstrated that RARα was frequently elevated in GC and exerted oncogenic properties. It might be a potential molecular target for GC treatment.

Upregulation of retinoic acid receptor-ß reverses drug resistance in cholangiocarcinoma cells by enhancing susceptibility to apoptosis.

Retinoic acid receptor ß (RARß), a known tumor suppressor gene, is frequently silenced in numerous malignant types of tumor. Recent reports have demonstrated that loss of RARß expression may be responsible, in part, for the drug resistance observed in clinical trials. However, little is known about the role of RARß in regulating drug sensitivity in patients with cholangiocarcinoma (CCA) with a high risk of mortality and poor outcomes. In the present study, low RARß expression was observed in the majority of CCA tissues investigated (28/33, 84.8%). In addition, the CCA cell line QBC939, which exhibits low RARß expression, was found to be significantly resistant to chemotherapeutic agents compared with SK­ChA­1, MZ­ChA­1 and Hccc9810 CCA cell lines, which exhibit high RARß expression. Furthermore, upregulation of RARß significantly enhanced the sensitivity of QBC939 cells to common chemotherapeutic agents both in vitro and in vivo. Upregulation of RARß was shown to increase the expression of proapoptotic genes bax, bak and bim, in addition to caspase­3 activity, and decrease the expression of antiapoptotic genes bcl­2, bcl­xL and mcl­1. As a result, CCA cells were more susceptible to caspase­dependent apoptosis. Taken together, these data suggest that RARß upregulation rendered CCA cells more sensitive to chemotherapeutic agents by increasing the susceptibility of cells to caspase-dependent apoptosis. These results support the hypothesis that RARß may be an ideal chemosensitization target for the treatment of patients with drug-resistant CCA.

IL-1ß induced RXRα overexpression through activation of NF-κB signaling in gastric carcinoma.

BACKGROUND: Abnormal expression of Retinoid X Receptor α (RXRα) seems to be a frequent incident in a variety of cancers. However, the expression pattern and the mechanisms in gastric carcinoma (GC) remain unclear. METHODS: In GC tissues and cell lines, the expression levels of RXRα mRNA and protein were detected by Q-PCR and Western blot, respectively; the localization of RXRα was evaluated by immunohistochemistry (IHC) or immunocytochemistry (ICC). The effect of IL-1ß on RXRα expression and localization was detected by Western blot and ICC. Nuclear factor-κB (NF-κB) pathway was assessed via Western blot. RESULTS: RXRα expression was markedly elevated at both mRNA and protein levels in GC tissues and cell lines (all P<0.05). The abnormal overexpression of RXRα was predominantly visualized in cytoplasm. IL-1ß significantly induced cytoplasmic expression of RXRα in a time-dependent manner. Co-incubation with IL-1ß enhanced phospho-IKKα (p-IKKα) expression and this effect could be inhibited by the specific inhibitor for NF-κB (all P<0.01). CONCLUSIONS: IL-1ß upregulated RXRα through activation of NF-κB signaling and these suggested a possible clinic significance of retinoid receptor expression in the diagnosis and treatment of GC.

Retinoid X receptor α enhances human cholangiocarcinoma growth through simultaneous activation of Wnt/ß-catenin and nuclear factor-κB pathways.

Retinoid X receptor α (RXRα) plays important roles in the malignancy of several cancers such as human prostate tumor, breast cancer, and thyroid tumor. However, its exact functions and molecular mechanisms in cholangiocarcinoma (CCA), a chemoresistant carcinoma with poor prognosis, remain unclear. In this study we found that RXRα was frequently overexpressed in human CCA tissues and CCA cell lines. Downregulation of RXRα led to decreased expression of mitosis-promoting factors including cyclin D1and cyclin E, and the proliferating cell nuclear antigen, as well as increased expression of cell cycle inhibitor p21, resulting in inhibition of CCA cell proliferation. Furthermore, RXRα knockdown attenuated the expression of cyclin D1 through suppression of Wnt/ß-catenin signaling. Retinoid X receptor α upregulated proliferating cell nuclear antigen expression through nuclear factor-κB (NF-κB) pathways, paralleled with downregulation of p21. Thus, the Wnt/ß-catenin and NF-κB pathways account for the inhibition of CCA cell growth induced by RXRα downregulation. Retinoid X receptor α plays an important role in proliferation of CCA through simultaneous activation of Wnt/ß-catenin and NF-κB pathways, indicating that RXRα might serve as a potential molecular target for CCA treatment.

ß-escin reverses multidrug resistance through inhibition of the GSK3ß/ß-catenin pathway in cholangiocarcinoma.

AIM: To develop a safe and effective agent for cholangiocarcinoma (CCA) chemotherapy. METHODS: A drug combination experiment was conducted to determine the effects of ß-escin in combination with chemotherapy on CCA cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was performed to determine the effects of ß-escin and common chemotherapeutics on the proliferation of human CCA cells (QBC939, Sk-ChA-1, and MZ-ChA-1). Immunocytochemistry was used to detect the expression of P-glycoprotein (P-gp) protein. Luciferase reporter assay was used to detect the activation of the Wnt/ß-catenin pathway. The protein levels of P-gp, pS9-GSK3ß, pT216-GSK3ß, GSK3ß, ß-catenin, and p-ß-catenin were further confirmed by western blotting. RESULTS: The drug sensitivity of QBC939 and QBC939/5-fluorouracil (5-FU) cells to 5-FU, vincristine sulfate (VCR), or mitomycin C was significantly enhanced by ß-escin compared with either agent alone (P<0.05). In addition, the combination of ß-escin (20 µmol/L) with 5-FU and VCR was synergic with a combination index<1. Further investigation found that the mRNA and protein expression of P-gp was down-regulated by ß-escin. Moreover, ß-escin induced GSK3ß phosphorylation at Tyr-216 and dephosphorylation at Ser-9, resulting in phosphorylation and degradation of ß-catenin. Interestingly, activation of the GSK3ß/ß-catenin pathway induced by Wnt3a resulted in up-regulation of P-gp, which was effectively abolished by ß-escin, indicating that ß-escin down-regulated P-gp expression in a GSK3ß-dependent manner. CONCLUSION: ß-escin was a potent reverser of P-gp-dependent multidrug resistance, with said effect likely being achieved via inhibition of the GSK3ß/ß-catenin pathway and thus suggesting a promising strategy of developing combination drugs for CCA.

Oncogenic activity of retinoic acid receptor γ is exhibited through activation of the Akt/NF-κB and Wnt/ß-catenin pathways in cholangiocarcinoma.

Aberrant expression and function of retinoic acid receptor γ (RARγ) are often involved in the progression of several cancers. However, the role of RARγ in cholangiocarcinoma (CCA), chemoresistant bile duct carcinoma with a poor prognosis, remains unclear. In the present study, we found that RARγ was frequently overexpressed in human CCA specimens. Its overexpression was associated with poor differentiation, lymph node metastasis, high serum carbohydrate antigen 19-9 level, and poor prognosis of CCA. Downregulation of RARγ reduced CCA cell proliferation, migration, invasion, and colony formation ability in vitro and tumorigenic potential in nude mice. RARγ knockdown resulted in upregulation of cell cycle inhibitor P21, as well as downregulation of cyclin D1, proliferating cell nuclear antigen, and matrix metallopeptidase 9, in parallel with suppression of the Akt/NF-κB pathway. Furthermore, overexpression of RARγ contributed to the multidrug chemoresistance of CCA cells, at least in part due to upregulation of P glycoprotein via activation of the Wnt/ß-catenin pathway. Molecular mechanism studies revealed that RARγ interacted with ß-catenin and led to ß-catenin nuclear translocation. Taken together, our results suggested that RARγ plays an important role in the proliferation, metastasis, and chemoresistance of CCA through simultaneous activation of the Akt/NF-κB and Wnt/ß-catenin pathways, serving as a potential molecular target for CCA treatment.