NEMO/NF-κB signaling functions as a double-edged sword in PanIN formation versus progression to pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is marked by a dismal survival rate, lacking effective therapeutics due to its aggressive growth, late-stage diagnosis, and chemotherapy resistance. Despite debates on NF-κB targeting for PDAC treatment, no successful approach has emerged. METHODS: To elucidate the role of NF-κB, we ablated NF-κB essential modulator (NEMO), critical for conventional NF-κB signaling, in the pancreata of mice that develop precancerous lesions (KC mouse model). Secretagogue-induced pancreatitis by cerulein injections was utilized to promote inflammation and accelerate PDAC development. RESULTS: NEMO deletion reduced fibrosis and inflammation in young KC mice, resulting in fewer pancreatic intraepithelial neoplasias (PanINs) at later stages. Paradoxically, however, NEMO deletion accelerated the progression of these fewer PanINs to PDAC and reduced median lifespan. Further, analysis of tissue microarrays from human PDAC sections highlighted the correlation between reduced NEMO expression in neoplastic cells and poorer prognosis, supporting our observation in mice. Mechanistically, NEMO deletion impeded oncogene-induced senescence (OIS), which is normally active in low-grade PanINs. This blockage resulted in fewer senescence-associated secretory phenotype (SASP) factors, reducing inflammation. However, blocked OIS fostered replication stress and DNA damage accumulation which accelerated PanIN progression to PDAC. Finally, treatment with the DNA damage-inducing reagent etoposide resulted in elevated cell death in NEMO-ablated PDAC cells compared to their NEMO-competent counterparts, indicative of a synthetic lethality paradigm. CONCLUSIONS: NEMO exhibited both oncogenic and tumor-suppressive properties during PDAC development. Caution is suggested in therapeutic interventions targeting NF-κB, which may be detrimental during PanIN progression but beneficial post-PDAC development.

Advances in the study of tertiary lymphoid structures in the immunotherapy of breast cancer.

Breast cancer, as one of the most common malignancies in women, exhibits complex and heterogeneous pathological characteristics across different subtypes. Triple-negative breast cancer (TNBC) and HER2-positive breast cancer are two common and highly invasive subtypes within breast cancer. The stability of the breast microbiota is closely intertwined with the immune environment, and immunotherapy is a common approach for treating breast cancer.Tertiary lymphoid structures (TLSs), recently discovered immune cell aggregates surrounding breast cancer, resemble secondary lymphoid organs (SLOs) and are associated with the prognosis and survival of some breast cancer patients, offering new avenues for immunotherapy. Machine learning, as a form of artificial intelligence, has increasingly been used for detecting biomarkers and constructing tumor prognosis models. This article systematically reviews the latest research progress on TLSs in breast cancer and the application of machine learning in the detection of TLSs and the study of breast cancer prognosis. The insights provided contribute valuable perspectives for further exploring the biological differences among different subtypes of breast cancer and formulating personalized treatment strategies.

Marine-Derived Bisindoles for Potent Selective Cancer Drug Discovery and Development.

Marine-derived bisindoles exhibit structural diversity and exert anti-cancer influence through multiple mechanisms. Comprehensive research has shown that the development success rate of drugs derived from marine natural products is four times higher than that of other natural derivatives. Currently, there are 20 marine-derived drugs used in clinical practice, with 11 of them demonstrating anti-tumor effects. This article provides a thorough review of recent advancements in anti-tumor exploration involving 167 natural marine bisindole products and their derivatives. Not only has enzastaurin entered clinical practice, but there is also a successfully marketed marine-derived bisindole compound called midostaurin that is used for the treatment of acute myeloid leukemia. In summary, investigations into the biological activity and clinical progress of marine-derived bisindoles have revealed their remarkable selectivity, minimal toxicity, and efficacy against various cancer cells. Consequently, they exhibit immense potential in the field of anti-tumor drug development, especially in the field of anti-tumor drug resistance. In the future, these compounds may serve as promising leads in the discovery and development of novel cancer therapeutics.

Arctigenin Induces Apoptosis in Melanoma Cells by Reducing the Expression of BCL-2 and VEGF.

BACKGROUND: To investigate the biological effects of arctigenin on B16-F10 melanoma cells in vitro and to explore its mechanism. METHODS: B16-F10 melanoma cells in vitro were treated with the blank control solution and arctigenin solution of different concentrations, respectively. Cell proliferation and apoptosis were analyzed using the CCK-8 assay and cell loss assay, and the effect of arctigenin on melanoma cell proliferation was evaluated. Western blot was used to analyze the expression of BCL-2 protein and vascular endothelial growth factor (VEGF) in the cells of different groups and to explore the mechanism of action of arctigenin. RESULTS: The proliferation rate of B16-F10 melanoma cells treated with arctigenin solutions was significantly lower than that of the blank control group (P < .05), and the proliferation rate decreased with increasing concentration of arctigenin. The apoptosis rate of B16-F10 melanoma cells treated with arctigenin solutions was significantly higher than that of the blank control group (P < .05), and the apoptosis rate increased with increasing concentration of arctigenin. The expression levels of BCL-2 and VEGF in B16-F10 melanoma cells treated with arctigenin solutions were significantly lower than those in the blank control group (P < .05), and the expression levels decreased as the concentration of arctigenin increased. CONCLUSIONS: Arctigenin can inhibit the proliferation and promote the apoptosis of melanoma cells, and the mechanism may be associated with decreasing the expression of BCL-2 and VEGF in melanoma cells.

The Notch1/Hes1 pathway regulates Neuregulin 1/ErbB4 and participates in microglial activation in rats with VPA-induced autism.

The core clinical characteristics of autism, which is a neurodevelopmental disease, involve repetitive behavior and impaired social interactions. Studies have shown that the Notch and Neuregulin1 (NRG1) signaling pathways are abnormally activated in autism, but the mechanism by which these two signaling pathways interact to contribute to the progression of autism has not been determined. Our results suggest that the levels of Notch1, Hes1, NRG1, and phosphorylated ErbB4 in the cerebellum (CB), hippocampus (HC), and prefrontal cortex (PFC) were increased in rats with valproic acid (VPA)-induced autism compared to those in the Con group. However, 3, 5-difluorophenyl-L-alanyl-L-2-phenylglycine tert-butyl (DAPT), which is a Notch pathway inhibitor, ameliorated autism-like behavioral abnormalities and decreased the protein levels of NRG1 and phosphorylated ErbB4 in rats with VPA-induced autism; these results demonstrated that the Notch1/Hes1 pathway could participate in the pathogenesis of autism by regulating the NRG1/ErbB4 signaling pathway. Studies have shown that the Notch pathway regulates microglial differentiation and activation during the onset of neurological disorders and that microglia affect autism-like behavior via synaptic pruning. Therefore, we hypothesized that the Notch1/Hes1 pathway could regulate the NRG1/ErbB4 pathway and thus participate in the development of autism by regulating microglial functions. The present study showed that AG1478, which is an ErbB4 inhibitor, ameliorated the autism-like behaviors in a VPA-induced autism rat model, reduced abnormal microglial activation, and decreased NRG1 and Iba-1 colocalization; however, AG1478 did not alter Notch1/Hes1 activity. These results demonstrated that Notch1/Hes1 may participate in the microglial activation in autism by regulating NRG1/ErbB4, revealing a new mechanism underlying the pathogenesis of autism.

Insights on Antitumor Activity and Mechanism of Natural Benzophenanthridine Alkaloids.

Benzophenanthridine alkaloids are a class of isoquinoline compounds, which are widely found in the plants of papaveraceae, corydalis, and rutaceae. Biological activities and clinical studies have shown that benzophenanthridine alkaloids have inhibitory effects on many cancers. Considering that the anticancer activities and mechanisms of many natural benzophenanthridine alkaloids have been discovered in succession, the purpose of this paper is to review the anticancer effects of benzophenanthridine alkaloids and explore the application potential of these natural products in the development of antitumor drugs. A literature survey was carried out using Scopus, Pubmed, Reaxys, and Google Scholar databases. This review summarizes and analyzes the current status of research on the antitumor activity and antitumor mechanism of natural products of benzophenanthridine from different sources. The research progress of the antitumor activity of natural products of benzophenanthridine from 1983 to 2023 was reviewed. The antitumor activities of 90 natural products of benzophenanthridine and their related analogues were summarized, and the results directly or indirectly showed that natural products of benzophenanthridine had the effects of antidrug-resistant tumor cell lines, antitumor stem cells, and inducing ferroptosis. In conclusion, benzophenanthridine alkaloids have inhibitory effects on a variety of cancers and have the potential to counteract tumor resistance, and they have great application potential in the development of antitumor drugs.

The Notch1/Hes1 signaling pathway affects autophagy by adjusting DNA methyltransferases expression in a valproic acid-induced autism spectrum disorder model.

As a pervasive neurodevelopmental disease, autism spectrum disorder (ASD) is caused by both hereditary and environmental elements. Research has demonstrated the functions of the Notch pathway and DNA methylation in the etiology of ASD. DNA methyltransferases DNMT3 and DNMT1 are responsible for methylation establishment and maintenance, respectively. In this study, we aimed to explore the association of DNA methyltransferases with the Notch pathway in ASD. Our results showed Notch1 and Hes1 were upregulated, while DNMT3A and DNMT3B were downregulated at the protein level in the prefrontal cortex (PFC), hippocampus (HC) and cerebellum (CB) of VPA-induced ASD rats compared with Control (Con) group. However, the protein levels of DNMT3A and DNMT3B were augmented after treatment with 3,5-difluorophenacetyl-L-alanyl-S-phenylglycine-2-butyl ester (DAPT), suggesting that abnormal Notch pathway activation may affect the expression of DNMT3A and DNMT3B. Besides, our previous findings revealed that the Notch pathway may participate in development of ASD by influencing autophagy. Therefore, we hypothesized the Notch pathway adjusts autophagy and contributes to ASD by affecting DNA methyltransferases. Our current results showed that after receiving the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-Aza-2'dc), the VPA + DAPT+5-Aza-2'dc (V + D + Aza) group exhibited reduced social interaction ability and increased stereotyped behaviors, and decreased expression of DNMT3A, DNMT3B and autophagy-related proteins, but did not show changes in Notch1 and Hes1 protein levels. Our results indicated that the Notch1/Hes1 pathway may adjust DNMT3A and DNMT3B expression and subsequently affect autophagy in the occurrence of ASD, providing new insight into the pathogenesis of ASD.

Exploring the Potential Molecular Mechanism of Sijunzi Decoction in the Treatment of Non-Segmental Vitiligo Based on Network Pharmacology and Molecular Docking.

Background: Non-segmental vitiligo is a common decolorized skin disease. The purpose of this study was to reveal the active components of Sijunzi decoction (SJZD) and the target genes for the treatment of non-segmental vitiligo. Methods: Based on TCMSP and GEO databases, effective components and targets of SJZD in the treatment of non-segmental vitiligo were revealed by network pharmacology. GO and KEGG were used to analyze the biological functions of SJZD targets. The Cytoscape-cytoHubba plugin was used to identify hub target genes. SsGSEA method was used to analyze the infiltration level of immune cells in non-segmental vitiligo. Molecular docking was performed to predict the interaction between active compounds and hub target genes. Finally, real-time PCR detection was also performed. Results: It was found that 104 active compounds may be effective ingredients in the treatment of non-segmental vitiligo. These 104 compounds acted on 42 differentially expressed target genes. KEGG analysis showed that target genes were significantly enriched in immune-related pathways such as MAPK and TNF signaling pathways. A total of 6 hub target genes (AKT1, CASP3, PPARG, SIRT1, TNF and TP53) were identified using the Cytoscape-cytoHubba plugin. Molecular docking showed that active compounds quercetin, kaempferol, formononetin and naringenin had good binding to hub target genes. We also found that Type 2 T helper cells, CD56bright natural killer cell and CD56dim natural killer cell infiltration levels were abnormal in non-segmental vitiligo and correlated with AKT1. Conclusion: The results of this study indicate that quercetin, kaempferol, formononetin and naringenin in SJZD may play an important role in the treatment of non-segmental vitiligo by acting on AKT1, CASP3, PPARG, SIRT1, TNF and TP53 to regulate immune cell infiltration and multiple signaling pathways.

Comparison of clinical safety and efficacy of ultrasound-guided local lauromacrogol injection versus uterine artery embolization in the treatment of caesarean scar pregnancy: a systematic review and meta-analysis.

BACKGROUND: The aim of this systematic review and meta-analysis was to introduce the relatively novel method of ultrasound-guided local lauromacrogol injection (USG-LLI) followed by dilatation and curettage for caesarean scar pregnancy (CSP) and to investigate the clinical safety and efficacy between uterine artery embolization (UAE) and USG-LLI in the treatment of CSP. METHODS: The relevant literature and articles about USG-LLI, UAE and CSP published in eight electronic databases were searched to extract the primary outcomes for the selected articles. Review Manager Software(RevMan) V.5.2 was used for quantitative data synthesis and data analysis. Forest plots, sensitivity analysis and bias analysis were also performed on the included articles. RESULTS: Of 10 studies included in our search, 623 patients were in the USG-LLI group and 627 patients were in the UAE groups. There were no significant differences between the two groups in terms of success rate, blood loss and time to human chorionic gonadotropin (hCG) normalization. However, USG-LLI group patients than UAE group patients had a shorter duration of hospital stay (mean difference [MD] = -1.97; 95% confidence intervals [CI] -2.63 to -1.31; P < 0.05; I2 = 95%), shorter restored menses (MD = -4.84; 95%CI -5.78 to -3.90; P < 0.05; I2 = 95%), and lower complication rates [odds ratio(OR) = 0.21; 95%CI:0.15 to 0.30; P < 0.05]; and cheaper on expenses of hospitalization (MD = -8028.29; 95%CI -10,311.18 to -5745.40; P < 0.05; I2 = 100%). CONCLUSIONS: The results demonstrate that USG-LLI is comparable in curative effect and success rates with UAE in the therapy of CSP, but patients in the USG-LLI group seem to have fewer complications rates, shorter duration of hospital stays and lower costs.

Dynamic Changes in Serum Cytokine Profile in Rats with Severe Acute Pancreatitis.

Background and Objectives: Most published research has only investigated a single timepoint after the onset of severe acute pancreatitis (SAP), meaning that they have been unable to observe the relationship between the dynamic changes in cytokines and SAP progression. In this study, we attempted to reveal the relationship between dynamic changes in cytokine expression levels and SAP disease progression and the relationship between cytokines, using continuous large-scale cytokine detection. Materials and Methods: Seventy rats were randomly assigned to control (Con), sham operation (SO) and SAP groups. The SAP group was randomly allocated to five subgroups at 3, 6, 9, 12 and 15 h after the operation. In the SAP group, 5% sodium taurocholate was injected retrograde into the pancreatic bile duct. Animals in the SO group received a similar incision, a turning over of the pancreas. Control animals did not receive any treatment. We observed the survival, ascites fluid amount, pancreatic histopathological scores and serum amylase activity of SAP rats. We used the cytokine microarray to simultaneously detect 90 cytokines and the dynamic changes in one experiment and to analyze the correlation between cytokine expression and disease progression. Results: The mortality of SAP rats increased with an increase in time. Serum amylase activity, pancreatic histopathological scores and ascites fluid amount were time-dependent. Compared with normal rats, 69 cytokines in SAP rats were significantly changed for at least one timepoint, and 49 cytokines were significantly changed at different timepoints after SAP induction. The changes in inflammatory cytokines were significantly upregulated at 6 and 9 h and 12 h and then significantly decreased. Conclusions: The trend of cytokine expression in SAP rats was not consistent with the disease progression. The cytokine-cytokine receptor interaction and MAPK signal's dominant cytokines were always highly expressed at various time points over the course of SAP.

Prenatal stress modulates HPA axis homeostasis of offspring through dentate TERT independently of glucocorticoids receptor.

In response to stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, and consequently glucocorticoids are released by the adrenal gland into the blood circulation. A large body of research has illustrated that excessive glucocorticoids in the hippocampus exerts negative feedback regulation of the HPA axis through glucocorticoid receptor (GR), which is critical for the homeostasis of the HPA axis. Maternal prenatal stress causes dysfunction of the HPA axis feedback mechanism in their offspring in adulthood. Here we report that telomerase reverse transcriptase (TERT) gene knockout causes hyperactivity of the HPA axis without hippocampal GR deficiency. We found that the level of TERT in the dentate gyrus (DG) of the hippocampus during the developmental stage determines the responses of the HPA axis to stressful events in adulthood through modulating the excitability of the dentate granular cells (DGCs) rather than the expression of GR. Our study also suggests that the prenatal high level of glucocorticoids exposure-induced hypomethylation at Chr13:73764526 in the first exon of mouse Tert gene accounted for TERT deficiency in the DG and HPA axis abnormality in the adult offspring. This study reveals a novel GR-independent mechanism underlying prenatal stress-associated HPA axis impairment, providing a new angle for understanding the mechanisms for maintaining HPA axis homeostasis.

Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN.

Major depressive disorder (MDD) is one of the most common mental disorders. We designed a fast-onset antidepressant that works by disrupting the interaction between the serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN). Chronic unpredictable mild stress (CMS) selectively increased the SERT-nNOS complex in the DRN in mice. Augmentation of SERT-nNOS interactions in the DRN caused a depression-like phenotype and accounted for the CMS-induced depressive behaviors. Disrupting the SERT-nNOS interaction produced a fast-onset antidepressant effect by enhancing serotonin signaling in forebrain circuits. We discovered a small-molecule compound, ZZL-7, that elicited an antidepressant effect 2 hours after treatment without undesirable side effects. This compound, or analogous reagents, may serve as a new, rapidly acting treatment for MDD.

The Prevalence and Risk Factors of Diabetic Retinopathy: Screening and Prophylaxis Project in 6 Provinces of China.

Purpose: To investigate the prevalence and associated factors of diabetic retinopathy (DR) and advanced DR in Chinese adults with diabetes mellitus (DM). Patients and Methods: A cross-sectional study was performed on 4831 diabetic patients from 24 hospitals from April 2018 to July 2020. Non-mydriatic fundus of patients were interpreted by an artificial intelligence (AI) system. Fundus photos that were unsuitable for AI interpretation were interpreted by two ophthalmologists trained by one expert ophthalmologist at Beijing Tongren Hospital. Medical history, height, weight, body mass index (BMI), glycosylated hemoglobin (HbA1c), blood pressure, and laboratory examinations were recorded. Results: A total of 4831 DM patients were included in this study. The prevalence of DR and advanced DR in the diabetic population was 31.8% and 6.6%, respectively. In multiple logistic regression analysis, male (odds ratio [OR], 1.39), duration of diabetes (OR, 1.05), HbA1c (OR, 1.11), farmer (OR, 1.39), insulin treatment (OR, 1.61), region (northern, OR, 1.78; rural, OR, 6.96), and presence of other diabetic complications (OR: 2.03) were associated with increased odds of DR. The factors associated with increased odds of advanced DR included poor glycemic control (HbA1c >7.0%) (OR, 2.58), insulin treatment (OR, 1.73), longer duration of diabetes (OR, 3.66), rural region (OR, 4.84), and presence of other diabetic complications (OR, 2.36), but overweight (BMI > 25 kg/m2) (OR, 0.61) was associated with reduced odds of advanced DR. Conclusion: This study shows that the prevalence of DR is very high in Chinese adults with DM, highlighting the necessity of early diabetic retinal screening.

[Retracted] miR­218­5p inhibits the stem cell properties and invasive ability of the A2B5+CD133­ subgroup of human glioma stem cells.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that Fig. 5 on p. 874 contained a series of DAPI panels within the figure that looked unexpectedly similar in appearance, with the similarities also evident in the second and 'Merge' data columns; moreover, of especial note, the similarities in the 'DAPI' panels for the Blank control experiments shown in Fig. 5C and D only affected a partial section of the data. In addition, the 'blank' and 'miR­control' panels in Fig. 6A also appeared to contain overlapping data. Independently of the issues that were raised by the interested reader, the authors themselves requested that their paper be retracted on account of having identified some problems with the presentation of various of the figures, and no longer being able to access their original data. The Editor of Oncology Reports has agreed that this paper should be retracted from the Journal, and apologizes to the readership for any inconvenience caused. [Oncology Reports 35: 869­877, 2016; DOI: 10.3892/or.2015.4418].

[Corrigendum] Downregulation of RNF138 inhibits cellular proliferation, migration, invasion and EMT in glioma cells via suppression of the Erk signaling pathway.

Following the publication of the above paper, during a routine examination of the raw data the authors noticed errors in Fig. 5 in the published version of the article. Essentially, in Fig. 5A on p. 3291, the western blot data for MMP2 (for the U87 cell line) did not match with the original data: An image from Fig. 7A (the western blotting data for Bcl2 in the U87 cell line had been erroneously selected during the process of assembling the figure); however, the authors were able to locate the original western blot data for MMP2 pertaining to Fig. 5A, and the corrected version of Fig. 5 is shown below. Note that these errors did not affect the overall conclusions reported in the study. All the authors agree to the publication of this corrigendum, and are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish it; furthermore, they apologize for any inconvenience caused to the readership of the Journal. [Oncology Reports 40: 3285­3296, 2018; DOI: 10.3892/or.2018.6744].

Novel clusters of newly-diagnosed type 2 diabetes and their association with diabetic retinopathy: a 3-year follow-up study.

BACKGROUND: Cluster analysis may assist in stratifying heterogeneous clinical presentations of type 2 diabetes (T2D). However, the association of cluster-based subgroups with diabetes-related outcomes such as diabetic retinopathy remains unclear. This study was aimed to address this issue with novel clusters of T2D derived from four simple parameters. METHOD: We developed a k-means clustering model in participants with newly diagnosed T2D (N = 1910) from the SENSIBLE and SENSIBLE-Addition studies, based on body mass index (BMI), waist circumference (WC), mean arterial pressure (MAP), and hemoglobin A1c (HbA1c). Diabetic retinopathy was ascertained with the protocol from the Early Treatment of Diabetic Retinopathy Study. Participants (N = 515) without diabetic retinopathy at baseline were followed-up for 3 years. Logistic regression analyses were performed to obtain the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Three clusters were identified, with cluster 0, 1 and 2 accounting for 48.2, 8.9 and 42.9%, respectively. Participants with T2D were featured by the lowest BMI, WC, MAP, and HbA1c in cluster 0, poor glycemic condition in cluster 1, and the highest BMI, WC, and MAP in cluster 2. Compared with cluster 0, cluster 1 was associated with increased odds of diabetic retinopathy in both the cross-sectional study (OR 6.25, 95% CI: 3.19-12.23) and the cohort study (OR 9.16, 95% CI: 2.08-40.34), while cluster 2 was not. Moreover, most participants remained their clusters unchanged during follow-up. CONCLUSIONS: Our cluster-based analysis showed that participants with poor glycemic condition rather than high blood pressure and obesity had higher risk of diabetic retinopathy.

Evaluation of quality change in Salviae miltiorrhizae radix et rhizoma during drying by LF-NMR and HPLC.

Salviae miltiorrhizae radix et rhizoma (Danshen, in Chinese) is one of the traditional Chinese medicines commonly used in clinical practice. In this study, low field nuclear magnetic resonance (LF-NMR) was used to detect changes in the moisture content during the drying of Danshen. Three water states (bound, immobilized, and free) in Danshen were investigated by multi-exponential fitting of the NMR data. Mass changes during drying were analyzed using high-performance liquid chromatography and partial least squares discriminant analysis. The results revealed that two components, salvianolic acid B and tanshinone, were the main chemical substances that produced the differences. Correlations were found among chemical substances, color, and moisture. LF-NMR can quickly assess the moisture content during drying. It also provides a practical tool for the production and processing of medicines or slices.

Comparing Symptomatic and Asymptomatic Carotid Artery Atherosclerosis in Patients With Bilateral Carotid Vulnerable Plaques Using Magnetic Resonance Imaging.

We compared plaque characteristics between symptomatic and asymptomatic sides in patients with bilateral carotid vulnerable plaques using magnetic resonance imaging (MRI). Participants (n = 67; mean age: 65.8 ± 7.7 years, 61 males) with bilateral carotid vulnerable plaques were included. Vulnerable plaques were characterized by intraplaque hemorrhage (IPH), large lipid-rich necrotic core (LRNC), or fibrous cap rupture (FCR) on MRI. Symptomatic vulnerable plaques showed greater plaque burden, LRNC volume (median: 221.4 vs 134.8 mm3, P = .003), IPH volume (median: 32.2 vs 22.5 mm3, P = .030), maximum percentage (Max%) LRNC (median: 51.3% vs 41.8%, P = .002), Max%IPH (median: 13.4% vs 9.5%, P = .022), cumulative slices of LRNC (median: 10 vs 8, P = .005), and more juxtaluminal IPH and/or thrombus (29.9% vs 6.0%, P = .001) and FCR (37.3% vs 16.4%, P = .007) than asymptomatic ones. After adjusting for plaque burden, differences in juxtaluminal IPH and/or thrombus (odds ratio [OR]: 5.49, 95% CI: 1.61-18.75, P = .007) and FCR (OR: 2.90, 95% CI: 1.16-7.24, P = .022) between bilateral sides remained statistically significant. For patients with bilateral carotid vulnerable plaques, symptomatic plaques had greater burden, more juxtaluminal IPH and/or thrombus, and FCR compared with asymptomatic ones. The differences in juxtaluminal IPH and/or thrombus and FCR between bilateral sides were independent of plaque burden.

Agomelatine: An Astounding Sui-generis Antidepressant?

Major depressive disorder (MDD) is one of the foremost causes of disability and premature death worldwide. Although the available antidepressants are effective and well tolerated, they also have many limitations. Therapeutic advances in developing a new drug's ultimate relation between MDD and chronobiology, which targets the circadian rhythm, led to a renewed focus on psychiatric disorders. In order to provide a critical analysis about antidepressant properties of agomelatine, a detailed PubMed (Medline), Scopus (Embase), Web of Science (Web of Knowledge), Cochrane Library, Google Scholar, and PsycInfo search was performed using the following keywords: melatonin analog, agomelatine, safety, efficacy, adverse effects, pharmacokinetics, pharmacodynamics, circadian rhythm, sleep disorders, neuroplasticity, MDD, bipolar disorder, anhedonia, anxiety, generalized anxiety disorder (GAD), and mood disorders. Agomelatine is a unique melatonin analog with antidepressant properties and a large therapeutic index that improves clinical safety. Published articles revealed that agomelatine is a melatonin receptors (MT1 and MT2) agonist and 5HT2C receptor antagonist. The effects receptors' on melatonin receptors enable the resynchronization of irregular circadian rhythms with beneficial effects on sleep architectures. In this way, agomelatine is accredited for its unique mode of action, which helps to exert antidepressant effects and resynchronize the sleep-wake cycle. To sum up, an agomelatine has not only antidepressant properties but also has anxiolytic effects.

Analysis of Chemical Constituents of Traditional Chinese Medicine Jianqu before and after Fermentation Based on LC-MS/MS.

OBJECTIVE: To detect the chemical constituents in Jianqu samples under different fermentated states by using UPLC-QTOF-MS/MS technology, to conduct preliminary analyses, and to establish an HPLC method for the simultaneous determination of hesperidin and naringenin in Jianqu, and the variation of the two components during fermentation were compared. METHODS: Waters ACQUITYTM UPLC HSST3 column (2.1 mm × 100 mm, 1.8 µm) was used; the mobile phase was 0.1% formic acid aqueous solution (A)-0.1% formic acid acetonitrile (B); The flow rate was 0.4 mL·min-1 with gradient elution; the column temperature was 45 °C; injection volume was 5 µL. The mass spectra of the samples were collected by negative ion mode under the electrospray ion source, and the data were screened and matched by UNIFI software. Hypersil gold C18 column (100 mm × 2.1 mm, 1.9 µm) was used; the mobile phase was acetonitrile (A)-0.1% acetic acid (B);; the flow rate with gradient elution was 0.3 mL·min-1; the column temperature was 30 °C; the injection volume was 2 µL. The content changes of hesperetin and naringenin in Jianqu at different fermentation time were detected. RESULTS: A total of 54 compounds were identified, including flavonoids, amino acids, organic acids, terpenoids, coumarins, lignans, and other compounds. Under the selected HPLC conditions, the linear relationship between hesperidin and naringenin was discovered (r2 = 0.9996). The content of hesperidin and naringenin changed significantly in the whole fermentation process. The highest concentration of content was observed at 36 h of fermentation and then decreased to varying degrees. CONCLUSION: This experiment can effectively identify various chemical components in Jianqu during different fermentation periods, and determine the content of the characteristic components, so as to provide a scientific basis for further study of Jianqu fermentation processing technology as well as a sound pharmacodynamic material basis.