Adverse events of topical ocular prostaglandin medications for glaucoma treatment: a pharmacovigilance study based on the FAERS database.

Background: As prostaglandin medications, crucial in glaucoma treatment, become more widely used, their local adverse events are increasingly observed. Objectives: To evaluate the common adverse events of four clinically commonly used prostaglandin F (FP) receptor agonists in the treatment of glaucoma in the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Design: We screened and analyzed the generic and brand names of latanoprost, bimatoprost, travoprost, and tafluprost in the FAERS database and summarized and cleaned the baseline information of subjects receiving the above-mentioned drugs. Methods: Perform descriptive statistical analysis on the baseline information of subjects using the drugs. Conduct disproportionality analysis of drug-related adverse events. The criteria for positive signals of adverse events are established by simultaneously meeting the thresholds set by four methods: the ratio of reported odds, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker. Additionally, assess the cumulative risk curves for drug-induced time of the aforementioned drugs and use one-way ANOVA to compare differences in drug-induced time across different groups. Results: The study included 1567 latanoprost, 1517 bimatoprost, 696 travoprost, and 82 tafluprost subjects. Adverse events mainly affected eye disorders, with significant issues in iris hyperpigmentation, ocular pemphigoid, corneal endothelial cell loss, periorbital fat atrophy, corneal irritation, eyelash growth, and ocular hyperemia. The time to onset varied among drugs, with latanoprost showing the longest (mean days = 344.37) and bimatoprost the shortest duration (mean days = 155.65; p < 0.001). Conclusion: Although signal detection analysis based on the FAERS database cannot establish a definitive causal relationship, our study found that FP receptor agonists used in glaucoma can cause various adverse events. Assessing their clinical suitability and potential side effects is crucial for providing personalized treatment and ensuring medication safety.

Understanding side effects of eye drops for glaucoma: a study using the FAERS database Why was the study done? Prostaglandin medications are crucial in treating glaucoma but can cause local adverse events. As the use of these medications increases, it's important to understand their common side effects. The Food and Drug Administration Adverse Event Reporting System (FAERS) is a database that contains adverse event reports, medication error reports and product quality complaints resulting in adverse events that were submitted to the Food and Drug Administration. What did the researchers do? We analyzed the FAERS database to evaluate the common adverse events of four prostaglandin medications commonly used to treat glaucoma: latanoprost, bimatoprost, travoprost, and tafluprost. What did the researchers find? The study included 1567 latanoprost users, 1517 bimatoprost users, 696 travoprost users, and 82 tafluprost users. The main adverse events affected eye disorders, with significant issues including iris hyperpigmentation, ocular pemphigoid, corneal endothelial cell loss, periorbital fat atrophy, corneal irritation, eyelash growth, and ocular hyperemia. The time to onset varied among drugs, with latanoprost showing the longest and bimatoprost the shortest duration. What do the findings mean? Although signal detection analysis from the FAERS database cannot establish a definitive causal relationship, prostaglandin medications used in glaucoma treatment can cause various ocular adverse events during long-term use. Understanding these side effects is crucial for providing personalized treatment and ensuring medication safety.

Drug-associated glaucoma: A real-world study based on the Food and Drug Administration adverse event reporting system database.

BACKGROUND: This study aims to assess the risk of drug-associated glaucoma and track its epidemiological characteristics using real-world data. METHODS: Adverse event reports from the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to December 2023 were analysed. Disproportionality analysis and the Bayesian Confidence Propagation Neural Network algorithm were used. The study classified drugs associated with glaucoma, assessed risk levels, and compared drug-induced times across different categories. RESULTS: Eight hundred and five drugs were linked to glaucoma in the FAERS database. Disproportionality analysis identified 46 drugs with significant risk, mainly adrenergic medications (clobetasol propionate, fluocinolone acetonide), antihypertensives (hydrochlorothiazide), insulin (insulin human), anticholinergics (umeclidinium, darifenacin), VEGF inhibitors (brolucizumab, faricimab), and psychotropics (topiramate, ziprasidone). The top three high-risk drugs were clobetasol propionate, umeclidinium, and fluocinolone acetonide. The shortest drug-induced times were observed with indacaterol, salmeterol, and umeclidinium. Anticholinergic medications had the shortest drug-induced time among all categories. Females (62.5%) and the elderly (average age 63.5 ± 16.8 years) were predominantly affected. Reports of drug-associated glaucoma increased over the years. CONCLUSION: Preventing drug-associated glaucoma is more effective than treatment. Identifying the risk and drug-induced times of systemic and ophthalmic drugs can reduce occurrence risk. Clinical practitioners should be vigilant and inform patients of these risks.

Psychometric validation of the Chinese version of the dry eye-related quality-of-life score questionnaire.

AIM: To psychometrically validate the Chinese version of the dry eye-related quality-of-life score questionnaire (DEQS-CHN) among Chinese patients with dry eye. METHODS: This study involved 231 participants, including 191 with dry eye disease (DED) comprising the dry eye disease group, and 40 healthy participants forming the control group. Participants were required to complete the DEQS-CHN, and Chinese dry eye questionnaire and undergo clinical tests including the fluorescein breakup time (FBUT), corneal fluorescein staining (CFS), and Schirmer I test. To assess the internal consistency and retest reliability, Cronbach's α and the intraclass correlation coefficient (ICC) were employed. Content validity was assessed by item-level content validity index (ICV) and an average scale-level content validity index (S-CVI/Ave). Construct validity was assessed by confirmatory factor analysis. The concurrent validity was assessed by calculating correlations between DEQS-CHN and Chinese dry eye questionnaire. Discriminative validity was evaluated through non-parametric tests, with receiver operating characteristic (ROC) curve serving as conclusive indicators of the questionnaire's distinguishing capability. RESULTS: The Cronbach's α coefficients for frequency and degree of ocular symptoms, impact on daily life, and summary score were 0.736, 0.704, 0.811, 0.818, 0.861, and 0.860, respectively, and the ICC were 0.611, 0.677, 0.715, 0.769, 0.711, and 0.779, respectively. All I-CVI scores ranged from 0.833 to 1.000, with an S-CVI/Ave of 0.956. Confirmatory factor analysis results exhibited a well-fitting model consistent with the original questionnaire [χ 2/df=2.653, incremental fit index (IFI)=0.924, comparative fit index (CFI)=0.924, Tucker-Lewis index (TLI)=0.909, and root mean square error of approximation (RMSEA)=0.065]. There was a moderate positive correlation between the DEQS-CHN and the Chinese dry eye questionnaire (r 2=0.588). The dry eye group demonstrated significantly higher scores compared to the control group, and the area under the curve (AUC) value was 0.8092. CONCLUSION: The DEQS-CHN has been demonstrated as a valid and reliable instrument for assessing the impact of dry eye disease on the quality of life among Chinese individuals with DED.

Drug-Related Keratitis: A Real-World FDA Adverse Event Reporting System Database Study.

Purpose: This study aimed to assess the drug risk of drug-related keratitis and track the epidemiological characteristics of drug-related keratitis. Methods: This study analyzed data from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database from January 2004 to December 2023. A disproportionality analysis was conducted to assess drug-related keratitis with positive signals, and drugs were classified and assessed with regard to their drug-induced timing and risk of drug-related keratitis. Results: A total of 1606 drugs were reported to pose a risk of drug-related keratitis in the FAERS database, and, after disproportionality analysis and screening, 17 drugs were found to significantly increase the risk of drug-related keratitis. Among them, seven were ophthalmic medications, including dorzolamide (reporting odds ratio [ROR] = 3695.82), travoprost (ROR = 2287.27), and brimonidine (ROR = 2118.52), and 10 were non-ophthalmic medications, including tralokinumab (ROR = 2609.12), trazodone (ROR = 2377.07), and belantamab mafodotin (ROR = 680.28). The top three drugs having the highest risk of drug-related keratitis were dorzolamide (Bayesian confidence propagation neural network [BCPNN] = 11.71), trazodone (BCPNN = 11.11), and tralokinumab (BCPNN = 11.08). The drug-induced times for non-ophthalmic medications were significantly shorter than those for ophthalmic medications (mean days, 141.02 vs. 321.96, respectively; P < 0.001). The incidence of drug-related keratitis reached its peak in 2023. Conclusions: Prevention of drug-related keratitis is more important than treatment. Identifying the specific risks and timing of drug-induced keratitis can support the development of preventive measures. Translational Relevance: Identifying the specific drugs related to medication-related keratitis is of significant importance for drug vigilance in the occurrence of drug-related keratitis.

Real-World Large Sample Assessment of Drug-related Dry Eye Risk: Based on the FDA Adverse Event Reporting System Database.

PURPOSE AND DESIGN: This study aimed to evaluate the risk of drug-related dry eye using real-world data, underscoring the significance of tracing pharmacological etiology for distinct clinical types of dry eye. METHODS: Analyzing adverse event reports in the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to September 2023, we employed disproportionality analysis and the Bayesian confidence propagation neural network algorithm. The analysis involved categorizing drugs causing dry eye, assessing risk levels, and conducting segmental assessments based on the time of onset of drug-related dry eye adverse reactions. RESULTS: In the FAERS database, adverse reactions related to dry eye were linked to 1160 drugs. Disproportionality analysis identified 33 drugs with significant risk, notably in ophthalmic (brimonidine, bimatoprost), oncology (tisotumab vedotin, erdafitinib), and other medications (isotretinoin, oxymetazoline). The top three drugs with the highest risk of drug-related dry eye are isotretinoin (Bayesian confidence propagation neural network (BCPNN) = 6.88), tisotumab vedotin (BCPNN = 6.88), and brimonidine (BCPNN = 6.77). Among different categories of drugs, respiratory medications have the shortest mean onset time for drug-related dry eye, averaging 50.99 days. The prevalence skewed towards females (69.9 %), particularly in menopausal and elderly individuals (45-70 years old, mean age 54.7 ± 18.2). Reports of drug-related dry eye adverse reactions showed an annual increase. CONCLUSION: Informed clinical decision-making is crucial for preventing drug-related dry eye. Assessing the risk of dry eyes associated with both local and systemic medications helps optimize treatment and provide necessary cautionary information.

Optimization and mechanisms of proteolytic enzyme immobilization onto large-pore mesoporous silica nanoparticles: Enhanced tumor penetration.

Immobilization of proteolytic enzymes onto nanocarriers is effective to improve drug diffusion in tumors through degrading the dense extracellular matrix (ECM). Herein, immobilization and release behaviors of hyaluronidase, bromelain, and collagenase (Coll) on mesoporous silica nanoparticles (MSNs) were explored. A series of cationic MSNs (CMSNs) with large and adjustable pore sizes were synthesized, and investigated together with two anionic MSNs of different pore sizes. CMSNs4.0 exhibited the highest enzyme loading capacity for hyaluronidase and bromelain, and CMSNs4.5 was the best for Coll. High electrostatic interaction, matched pore size, and large pore volume and surface area favor the immobilization. Changes of the enzyme conformations and surface charges with pH, existence of a space around the immobilized enzymes, and the depth of the pore structures, affect the release ratio and tunability. The optimal CMSNs-enzyme complexes exhibited deep and homogeneous penetration into pancreatic tumors, a tumor model with the densest ECM, with CMSNs4.5-Coll as the best. Upon loading with doxorubicin (DOX), the CMSNs-enzyme complexes induced high anti-tumor efficiencies. Conceivably, the DOX/CMSNs4.5-NH2-Coll nanodrug exhibited the most effective tumor therapy, with a tumor growth inhibition ratio of 86.1 %. The study provides excellent nanocarrier-enzyme complexes, and offers instructive theories for enhanced tumor penetration and therapy.

Autophagy plays a pro-apoptotic role in arsenic trioxide-induced cell death of liver cancer.

OBJECTIVE: The effects of arsenic trioxide (As2O3) on hepatocellular carcinoma have been documented widely. Autophagy plays dual roles in the survival and death of cancer cells. Therefore, we investigated the exact role of autophagy in As2O3-induced apoptosis in liver cancer cells. METHODS: The viability of hepatoma cells was determined using the MTT assay with or without fetal bovine serum. The rate of apoptosis in liver cancer cells treated with As2O3 was evaluated using flow cytometry, Hoechst 33258 staining, and TUNEL assays. The rate of autophagy among liver cancer cells treated with As2O3 was detected using immunofluorescence, Western blot assay and transmission electron microscopy. RESULTS: Upon treatment with As2O3, the viability of HepG2 and SMMC-7721 cells was decreased in a time- and dose-dependent manner. The apoptosis rates of both liver cancer cell lines increased with the concentration of As2O3, as shown by flow cytometry. Apoptosis in liver cancer cells treated with As2O3 was also shown by the activation of the caspase cascade and the regulation of Bcl-2/Bax expression. Furthermore, As2O3 treatment induced autophagy in liver cancer cells; this finding was supported by Western blot, immunofluorescence of LC3-II and beclin 1, and transmission electron microscopy. In liver cancer cells, As2O3 inhibited the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signal pathway that plays a vital role in both apoptosis and autophagy. The PI3K activator SC-79 partially reversed As2O3-induced autophagy and apoptosis. Furthermore, inhibiting autophagy with 3-methyladenine partially reversed the negative effects of As2O3 on cell viability. Serum starvation increased autophagy and amplified the effect of As2O3 on cell death. CONCLUSION: As2O3 induces apoptosis and autophagy in liver cancer cells. Autophagy induced by As2O3 may have a proapoptotic effect that helps to reduce the viability of liver cancer cells. This study provides novel insights into the effects of As2O3 against liver cancer. Please cite this article as: Deng ZT, Liang SF, Huang GK, Wang YQ, Tu XY, Zhang YN, Li S, Liu T, Cheng BB. Autophagy plays a pro-apoptotic role in arsenic trioxide-induced cell death of liver cancer. J Integr Med. 2024; 22(3): 295-302.

Promotion of anaerobic biodegradation of azo dye RR2 by different biowaste-derived biochars: Characteristics and mechanism study by machine learning.

The addition of biochar resulted in a 31.5 % to 44.6 % increase in decolorization efficiency and favorable decolorization stability. Biochar promoted extracellular polymeric substances (EPS) secretion, especially humic-like and fulvic-like substances. Additionally, biochar enhanced the electron transfer capacity of anaerobic sludge and facilitated surface attachment of microbial cells. 16S rRNA gene sequencing analysis indicated that biochar reduced microbial species diversity, enriching fermentative bacteria such as Trichococcus. Finally, a machine learning model was employed to establish a predictive model for biochar characteristics and decolorization efficiency. Biochar electrical conductivity, H/C ratio, and O/C ratio had the most significant impact on RR2 anaerobic decolorization efficiency. According to the results, the possible mechanism of RR2 anaerobic decolorization enhanced by different types of biochar was proposed.

Emergent weak antilocalization and wide-temperature-range electronic phase diagram in epitaxial RuO2thin film.

Binary ruthenium dioxide (RuO2) has gradually attracted much attention in condensed matter physics and material sciences due to its various intriguing physical properties, such as strain-induced superconductivity, anomalous Hall effect, collinear anti-ferromagnetism, etc. However, its complex emergent electronic states and the corresponding phase diagram over a wide temperature range remain unexplored, which is critically important to understanding the underlying physics and exploring its final physical properties and functionalities. Here, through optimizing the growth conditions by using versatile pulsed laser deposition, high-quality epitaxial RuO2thin films with clear lattice structure are obtained, upon which the electronic transport is investigated, and emergent electronic states and the relevant physical properties are unveiled. Firstly, at a high-temperature range, it is the Bloch-Grüneisen state, instead of the common Fermi liquid metallic state, that dominates the electrical transport behavior. Moreover, the recently reported anomalous Hall effect is also revealed, which confirms the presence of the Berry phase in the energy band structure. More excitingly, we find that above the superconductivity transition temperature, a new positive magnetic resistance quantum coherent state with an unusual dip as well as an angel-dependent critical magnetic field emerges, which can be attributed to the weak antilocalization effect. Lastly, the complex phase diagram with multiple intriguing emergent electronic states over a wide temperature range is mapped. The results greatly promote the fundamental physics understanding of the binary oxide RuO2and provide guidelines for its practical applications and functionalities.

Study on the removal characteristics and degradation pathways of highly toxic and refractory organic pollutants in real pharmaceutical factory wastewater treated by a pilot-scale integrated process.

Introduction: Pharmaceutical wastewater frequently contains high levels of toxic pollutants. If they are discharged untreated, they pose a threat to the environment. The traditional activated sludge process and the advanced oxidation process do not sufficiently remove toxic and conventional pollutants from pharmaceutical wastewater treatment plants (PWWTPs). Methods: We designed a pilot-scale reaction system to reduce toxic organic pollutants and conventional pollutants from pharmaceutical wastewater during the biochemical reaction stage. This system included a continuous stirred tank reactor (CSTR), microbial electrolysis cells (MECs), an expanded sludge bed reactor (EGSB), and a moving bed biofilm reactor (MBBR). We used this system to further investigate the benzothiazole degradation pathway. Results and discussion: The system effectively degraded the toxic pollutants (benzothiazole, pyridine, indole, and quinoline) and the conventional chemicals (COD, NH4 +-N, TN). During the stable operation of the pilot-scale plant, the total removal rates of benzothiazole, indole, pyridine, and quinoline were 97.66, 94.13, 79.69, and 81.34%, respectively. The CSTR and MECs contributed the most to the removal of toxic pollutants, while the EGSB and MBBR contributed less to the removal of the four toxic pollutants. Benzothiazoles can be degraded via two pathways: the benzene ring-opening reaction and the heterocyclic ring-opening reaction. The heterocyclic ring-opening reaction was more important in degrading the benzothiazoles in this study. Conclusion: This study provides feasible design alternatives for PWWTPs to remove both toxic and conventional pollutants at the same time.

Effects of microplastics (MPs) and tributyltin (TBT) alone and in combination on bile acids and gut microbiota crosstalk in mice.

Microplastics (MPs) and tributyltin (TBT) are both potential environmental pollutants that enter organisms through the food chain and affect bodily functions. However, the effects and mechanisms of MPs and TBT exposure (especially the co-exposure of both pollutants) on mammals remain unclear. In this study, Ф5µm MPs (5MP) was administered alone or in combination with TBT to investigate the health risk of oral exposure in mice. All three treatments induced inflammation in the liver, altered gut microbiota composition and disturbed fecal bile acids profiles. In addition to decreasing triglyceride (TG) and increasing aspartate aminotransferase (AST) and macrophage-expressed gene 1 (Mpeg1), 5MP induced hepatic cholestasis by stimulating the expression of the cholesterol hydroxylase enzymes CYP8B1 and CYP27A1, and inhibiting multidrug resistance-associated protein 2 and 3 (MRP2, MRP3), and bile-salt export pump (BSEP) to prevent bile acids for entering the blood and bile. Correspondingly, 5MP treatment decreased 7-ketolithocholic acid (7-ketoLCA) and taurocholic acid (TCA), which were positively correlated with decreased Bacteroides and Marvinbryantia and negatively correlated with increased Bifidobacterium. In addition, TBT increased interferon γ (IFNγ) and Mpeg1 levels to induce inflammation, accompanied by decreased 7-ketoLCA, tauro-alpha-muricholic acid (T-alpha-MCA) and alpha-muricholic acid (alpha-MCA) levels, which were negatively related to Coriobacteriaceae_UCG-002 and Bifidobacterium. Co-exposure to 5MP and TBT also decreased TG and induced bile acids accumulation in the liver due to inhibited BSEP, which might be attributed to the co-regulation of decreased T-alpha-MCA and Harryflintia. In conclusion, the administration of 5MP and TBT alone and in combination could cause gut microbiome dysbiosis and subsequently alter bile acids profiles, while the combined exposure of 5MP and TBT weakened the toxic effects of 5MP and TBT alone.

An exploration of the role of Sertoli cells on fetal testis development using cell ablation strategy.

Sertoli cells (SCs) are presumed to be the center of testis differentiation because they provide both structural support and biological regulation for spermatogenesis. Previous studies suggest that SCs control germ cell (GC) count and Leydig cell (LC) development in mouse testes. However, the regulatory role of SCs on peritubular myoid (PTM) cell fate in fetal testis has not been clearly reported. Here, we employed Amh-Cre; diphtheria toxin fragment A (DTA) mouse model to selectively ablate SCs from embryonic day (E) 14.5. Results found that SC ablation in the fetal stage caused the disruption of testis cords and the massive loss of GCs. Furthermore, the number of α-smooth muscle actin-labeled PTM cells was gradually decreased from E14.5 and almost lost at E18.5 in SC ablation testis. Interestingly, some Ki67 and 3ß-HSD double-positive fetal LCs could be observed in Amh-Cre; DTA testes at E16.5 and E18.5. Consistent with this phenomenon, the messenger RNA levels of Hsd3b1, Cyp11a1, Lhr, Star and the protein levels of 3ß-HSD and P450Scc were significantly elevated by SC ablation. SC ablation appears to induce ectopic proliferation of fetal LCs although the total LC number appeared reduced. Together, these findings bring us a better understanding of SCs' central role in fetal testis development.

Treatment with 6-Gingerol Regulates Dendritic Cell Activity and Ameliorates the Severity of Experimental Autoimmune Encephalomyelitis.

SCOPE: Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disorder, with increasing incidence worldwide but unknown etiology. 6-Gingerol (6-GIN), a major dietary compound found in ginger rhizome, has immunomodulatory activity. However, its role in autoimmune diseases, as well as the underlying mechanisms, are unclear. In this study, it is evaluated if 6-GIN can effectively ameliorate the clinical disease severity of experimental autoimmune encephalomyelitis, an animal model of MS. METHODS AND RESULTS: Clinical scores of experimental autoimmune encephalomyelitis (EAE) mice are recorded daily. Inflammation of periphery and neuroinflammation of EAE mice are determined by flow cytometry analysis, ELISA, and histopathological analysis, and results show that 6-GIN significantly inhibits inflammatory cell infiltration from the periphery into the central nervous system and reduces neuroinflammation and demyelination. Flow cytometry analysis, ELISA, and quantitative PCR show that 6-GIN could suppress lipolysaccharide-induced dendritic cell (DC) activation and induce the tolerogenic DCs. Immunoblot analysis reveals that the phosphorylation of nuclear factor-κB and mitogen-activated protein kinase, two critical regulators of inflammatory signaling, are significantly inhibited in 6-GIN-treated DCs. CONCLUSION: The results of this study demonstrate that 6-GIN has significant potential as a novel anti-inflammatory agent for the treatment of autoimmune diseases such as MS via direct modulatory effects on DCs.

GATA4 is a negative regulator of contractility in mouse testicular peritubular myoid cells

Reduced contractility of the testicular peritubular myoid (PTM) cells may contribute to human male subfertility or infertility. Transcription factor GATA4 in Sertoli and Leydig cells is essential for murine spermatogenesis, but limited attention has been paid to the potential role of GATA4 in PTM cells. In primary cultures of mouse PTM cells, siRNA knockdown of GATA4 increased the contractile activity, while GATA4 overexpression significantly attenuated the contractility of PTM cells using a collagen gel contraction assay. Using RNA sequencing and qRT-PCR, we identified a set of genes that exhibited opposite expressional alternation between Gata4 siRNA vs nontargeting siRNA-treated PTM cells and Gata4 adenovirus vs control adenovirus-treated PTM cells. Notably, ion channels, smooth muscle function, cytokines and chemokines, cytoskeleton, adhesion and extracellular matrix were the top four enriched pathways, as revealed by cluster analysis. Natriuretic peptide type B (NPPB) content was significantly upregulated by GATA4 overexpression in both PTM cells and their culture supernatant. More importantly, the addition of 100 µM NPPB could abolish the promoting effect of Gata4 silencing on PTM cell contraction. Taken together, we suggest that the inhibitory action of GATA4 on PTM cell contraction is mediated at least partly by regulating genes belonging to smooth muscle contraction pathway (e.g. Nppb).

A miR-125b/CSF1-CX3CL1/tumor-associated macrophage recruitment axis controls testicular germ cell tumor growth.

Tumor growth is modulated by crosstalk between cancer cells and the tumor microenvironment. Recent advances have shown that miRNA dysfunction in tumor cells can modulate the tumor microenvironment to indirectly determine their progression. However, this process is poorly understood in testicular germ cell tumors (TGCTs). We reported here that miR-125b was repressed in TGCT samples by epigenetic modifications rather than genetic alternations. Furthermore, miR-125b overexpression significantly alleviated the tumor growth in two NCCIT human embryonic carcinoma xenograft models in vivo, whereas miR-125b did not stimulate autonomous tumor cell growth in vitro. Notably, forced expression of miR-125b in NCCIT embryonic carcinoma cells decreased the abundance of host tumor-associated macrophages (TAMs) within tumor microenvironment. Selective deletion of host macrophages by clodronate abolished the anti-tumoral ability of miR-125b in xenograft models. By RNA profiling, Western blot and luciferase reporter assay, we further observed that miR-125b directly regulated tumor cell-derived chemokine CSF1 and CX3CL1, which are known to control the recruitment of TAMs to tumor sites. Lastly, we found that one set of miRNAs, which are under the regulation of miR-125b, might convergently target CSF1/CX3CL1 in NCCIT cells using miRNA profiling. These findings uncover the anticancer effect of miR-125b via mediating tumor-stroma crosstalk in xenograft models of TGCTs and raise the possibility of targeting miR-125b as miRNA therapeutics.

Cyclin B2 can compensate for Cyclin B1 in oocyte meiosis I.

Mammalian oocytes are arrested at the prophase of the first meiotic division for months and even years, depending on species. Meiotic resumption of fully grown oocytes requires activation of M-phase-promoting factor (MPF), which is composed of Cyclin B1 and cyclin-dependent kinase 1 (CDK1). It has long been believed that Cyclin B1 synthesis/accumulation and its interaction with CDK1 is a prerequisite for MPF activation in oocytes. In this study, we revealed that oocyte meiotic resumption occurred in the absence of Cyclin B1. Ccnb1-null oocytes resumed meiosis and extruded the first polar body. Without Cyclin B1, CDK1 could be activated by up-regulated Cyclin B2. Ccnb1 and Ccnb2 double knockout permanently arrested the oocytes at the prophase of the first meiotic division. Oocyte-specific Ccnb1-null female mice were infertile due to failed MPF activity elevation and thus premature interphase-like stage entry in the second meiotic division. These results have revealed a hidden compensatory mechanism between Cyclin B1 and Cyclin B2 in regulating MPF and oocyte meiotic resumption.

Regulation of blood-testis barrier assembly in vivo by germ cells.

The assembly of the blood-testis barrier (BTB) during postnatal development is crucial to support meiosis. However, the role of germ cells in BTB assembly remains unclear. Herein, KitW/KitWV mice were used as a study model. These mice were infertile, failing to establish a functional BTB to support meiosis due to c-Kit mutation. Transplantation of undifferentiated spermatogonia derived from normal mice into the testis of KitW/KitWV mice triggered functional BTB assembly, displaying cyclic remodeling during the epithelial cycle. Also, transplanted germ cells were capable of inducing Leydig cell testosterone production, which could enhance the expression of integral membrane protein claudin 3 in Sertoli cells. Early spermatocytes were shown to play a vital role in directing BTB assembly by expressing claudin 3, which likely created a transient adhesion structure to mediate BTB and cytoskeleton assembly in adjacent Sertoli cells. In summary, the positive modulation of germ cells on somatic cell function provides useful information regarding somatic-germ cell interactions.-Li, X.-Y., Zhang, Y., Wang, X.-X., Jin, C., Wang, Y.-Q., Sun, T.-C., Li, J., Tang, J.-X., Batool, A., Deng, S.-L., Chen, S.-R., Cheng, C. Y., Liu, Y.-X. Regulation of blood-testis barrier assembly in vivo by germ cells.

Role of WNT signaling in epididymal sperm maturation.

PURPOSE: Spermatozoa maturation, a process required for spermatozoa to acquire progressive motility and the ability to fertilize ova, primarily occurs in the caput and corpus of the epididymis. Despite considerable efforts, the factor(s) promoting epididymal sperm maturation remains unclear. Recently, WNT signaling has been implicated in epididymal sperm maturation. METHODS: To further investigate WNT signaling function in epididymal sperm maturation, we generated Wntless conditional knockout mice (Wls cKO), Wls flox/flox ; Lcn5-Cre. RESULTS: In these mice, WNTLESS (WLS), a conserved membrane protein required for all WNT protein secretion, was specifically disrupted in the principal cells of the caput epididymidis. Immunoblot analysis showed that WLS was significantly reduced in the caput epididymidis of Wls cKO mice. In the caput epididymidis of Wls cKO mice, WNT 10A and WNT 2b, which are typically secreted by the principal cells of the caput epididymis, were not secreted. Interestingly, sperm motility analysis showed that the WLS deficiency in the caput epididymidis had no effect on sperm motility. Moreover, fertility tests showed that Wls cKO male mice had normal fertility. CONCLUSION: These results indicate that the disruption of WLS in principal cells of the caput epididymidis inhibits WNT protein secretion but has no effect on sperm motility and male fertility, suggesting that WNT signaling in the caput epididymidis may be dispensable for epididymal sperm maturation in mice.

[Summary and prospect of medicinal plant active substances in regulation of p65 nuclear translocation].

As the most important nuclear transcription factors in the cells, NF-κB is involved in many intracellular signaling pathways and transcription and regulation of genetic information. The signal transduction pathways mainly include the activation of IκB kinase, degradation of IκB protein and the nuclear translocation of p65. p65 trans-nuclear binding with DNA is the key for NF-κB to play a role. Abnormal activation of NF-κB is a major factor in the induction of oxidative stress, inflammation, cancer and so on. Therefore, maintaining the balance of NF-κB activity and regulating the nuclear translocation of p65 have great significance for further research on related subjects. In this paper, the regulation effects of the main active substances of medicinal plants (such as polyphenols, saponins, and alkaloids) on p65 nuclear translocation and the upstream pathway of NF-κB were discussed, expecting to provide reference for the development of natural active substances for functional food.