Effects of Natural Products through Inhibiting Endoplasmic Reticulum Stress on Attenuation of Idiopathic Pulmonary Fibrosis.

With ever-increasing intensive studies of idiopathic pulmonary fibrosis (IPF), significant progresses have been made. Endoplasmic reticulum stress (ERS)/unfolded protein reaction (UPR) is associated with the development and progression of IPF, and targeting ERS/UPR may be beneficial in the treatment of IPF. Natural product is a tremendous source of new drug discovery, and accumulating studies have reported that many natural products show potential therapeutic effects for IPF via modulating one or more branches of the ERS signaling pathway. Therefore, this review focuses on critical roles of ERS in IPF development, and summarizes herbal preparations and bioactive compounds which protect against IPF through regulating ERS.

Association of sleep traits with benign prostatic hyperplasia in middle-aged and elderly men: A prospective analysis in UK Biobank.

AIMS: The association of sleep traits (insomnia, sleep duration, chronotype, daytime sleepiness, and snoring) with benign prostatic hyperplasia (BPH) is unclear. This research aimed to examine the effects of sleep traits on BPH risk. METHODS: A total of 170 241 men aged 38 to 73 years from UK Biobank were included. An overall healthy sleep score was created based on five sleep traits. A Cox regression model was utilized to compute adjusted hazard ratios (HRs) and population attributable fractions (PAFs) with 95% confidence intervals (CIs) for BPH risk in relation to sleep traits. RESULTS: During a median of 12.0 years follow-up, 13 026 incident BPH cases occurred. We observed that sleep duration (7-8 h/d; HR 0.95; 95% CI 0.92-0.99), no frequent insomnia (HR 0.71; 95% CI 0.69-0.74), and no frequent daytime sleepiness (HR 0.86; 95% CI 0.79-0.93) were significantly related to reduced BPH risk. Each one-point increment of the healthy sleep score was related to a decreased BPH risk, with an adjusted HR of 0.90 (95% CI 0.89-0.92). The multivariable-adjusted HR in men adopting five versus zero to one low-risk sleep traits was 0.68 (95% CI 0.61-0.75) for BPH risk. Estimates of the PAF indicated that 9.1% (95% CI 5.8-12.5%) of BPH cases would be prevented if all individuals had adopted all five low-risk sleep traits, assuming causality. CONCLUSIONS: Our study indicates an association between a healthy sleep pattern and a lower risk of BPH, emphasizing the importance of adhering to such patterns for potentially reducing BPH risk. Geriatr Gerontol Int 2024; 24: 675-682.

Rivaroxaban Plasma Concentration and Clinical Outcomes on Older Patients with Non-valvular Atrial Fibrillation and Pulmonary Infection.

INTRODUCTION: Infection may induce thrombotic and hemorrhagic events; however, it is currently unclear whether the inflammatory response affects the coagulation function and the clinical efficacy and safety of rivaroxaban in older patients with non-valvular atrial fibrillation (NVAF). OBJECTIVE: This project aimed to assess the effectiveness and safety of the non-vitamin K antagonist oral anticoagulant rivaroxaban in older patients with NVAF complicated by infection, and to provide a basis for possible drug dose adjustment. METHODS: A total of 152 NVAF patients aged ≥ 65 years admitted to the Fifth People's Hospital of Shanghai from June 2020 to May 2022 were included in this prospective, observational study. The changes in steady-state plasma concentration of rivaroxaban and FXa inhibition rate were compared between patients with and without infection, and the impact on the occurrence of infection, thrombotic events, and bleeding events was compared through 1-year follow-up. RESULTS: Our results showed that patients in the infection group had abnormal inflammation markers, as well as an increased occurrence of bleeding and thrombotic events during hospitalization and follow-up. The high incidence of bleeding events in patients was closely related to the occurrence of infection, lymphocyte reduction, and increased neutrophil-lymphocyte ratio. The increase in thrombotic events was related to a decrease in rivaroxaban plasma concentration. Bleeding events in patients taking anticoagulant drugs are not necessarily due to drug accumulation. CONCLUSIONS: Timely control of infection, assessment of bleeding and thrombotic risks, and selection of appropriate anticoagulation treatment strategies should be made in older NVAF patients who develop pulmonary infection. CLINICAL TRIALS REGISTRATION: Chinese Clinical Trial Registry Number ChiCTR2000033144.

Multiple genetic mutations increase the risk of thrombosis associated with clopidogrel after percutaneous coronary intervention.

Background: The effect of multiple mutations in CYP2C19, PON1 and ABCB1 genes on the effectiveness and safety of dual antiplatelet therapy after percutaneous coronary intervention remains unclear. Methods: In total, 263 Chinese Han patients were enrolled in this study. Platelet aggregation rates and thrombosis risk were used to compare clopidogrel responses and outcomes in patients with different numbers of genetic mutations. Results: Our study demonstrated that 74% of the patients carried more than two genetic mutations. High platelet aggregation rates were associated with genetic mutations in patients receiving clopidogrel and aspirin after percutaneous coronary intervention. Genetic mutations were closely related to the recurrence of thrombotic events, but not bleeding. The number of genes that become dysfunctional in patients is directly correlated with the risk of recurrent thrombosis. Conclusion: Compared with CYP2C19 alone or the platelet aggregation rate, it is more helpful to predict clinical outcomes by considering the polymorphisms of all three genes.

The effects of different combinations of mutations in the genes CYP2C19, PON1 and ABCB1 on the effectiveness and safety of dual antiplatelet therapy in patients who undergo percutaneous coronary intervention (PCI) are unclear. In total, 263 Chinese Han patients receiving 75 mg clopidogrel and 100 mg aspirin daily for 12 months after PCI were enrolled in this study. ADP-induced platelet aggregation rates, thrombosis and bleeding risk were used to compare clopidogrel responses among the patients. Only 3.4% of patients had no mutations in CYP2C19, PON1 or ABCB1, and 74% of patients who chose to be genetically tested carried more than two mutations in these genes. High ADP-induced platelet aggregation rates in patients receiving clopidogrel and aspirin after PCI were associated with mutations in CYP2C19, PON1 and ABCB1. Patients with double or triple genetic mutations in CYP2C19, PON1 or ABCB1 had a higher risk of thrombosis within 18 months of follow-up. We conclude that multiple genetic polymorphisms influence platelet reactivity, bleeding and thrombosis risk during dual antiplatelet therapy after PCI.

Tanreqing injection protects against bleomycin-induced pulmonary fibrosis via inhibiting STING-mediated endoplasmic reticulum stress signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Idiopathic pulmonary fibrosis (IPF), characterized by excessive collagen deposition, is a progressive and typically fatal lung disease without effective therapeutic methods. Tanreqing injection (TRQ), a Traditional Chinese Patent Medicine, has been widely used to treat inflammatory respiratory diseases clinically. AIM OF THE STUDY: The present work aims to elucidate the therapeutic effects and the possible mechanism of TRQ against pulmonary fibrosis. METHODS: The pulmonary fibrosis murine model were constructed by the intratracheal injection of bleomycin (BLM). 7 days later, TRQ-L (2.6 ml/kg) and TRQ-H (5.2 ml/kg) were administered via intraperitoneal injection respectively for 21 days. The efficacy and underlying molecular mechanism of TRQ were investigated. RESULTS: Here, we showed that TRQ significantly inhibited BLM-induced lung edema and pulmonary function. TRQ markedly reduced BLM-promoted inflammatory cell infiltration in BALF and inflammatory cytokines release (TNF-α, IL-6, and IL-1ß) in serum and lung tissues. Meanwhile, TRQ also alleviated BLM-induced collagen synthesis and deposition. Simultaneously, TRQ attenuated BLM-induced pulmonary fibrosis through regulating the expression of fibrotic hallmarks, manifested by down-regulated α-SMA and up-regulated E-cadherin. Moreover, we found that TRQ significantly prevented STING, p-P65, BIP, p-PERK, p-eIF2α, and ATF4 expression in lung fibrosis mice. CONCLUSIONS: Taken together, our results indicated that TRQ positively affects inflammatory responses and lung fibrosis by regulating STING-mediated endoplasmic reticulum stress (ERS) signal pathway.

Traditional Chinese medicine for prevention and treatment of hepatocellular carcinoma: A focus on epithelial-mesenchymal transition.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant cancers worldwide. Epithelial-mesenchymal transition (EMT), which endows epithelial cells with mesenchymal properties, plays an important role in the early stages of metastasis. Conventional cancer therapies have promising effects, but issues remain, such as high rates of metastasis and drug resistance. Thus, exploring and evaluating new therapies is an urgent need. Traditional Chinese medicines (TCMs) have been acknowledged for their multi-target and coordinated intervention effects against HCC. Accumulating evidence indicates that TCM can inhibit the malignancy of cells and the progression of EMT in HCC. However, studies on the effects of TCM on EMT in HCC are scarce. In this review, we summarized recent developments in anti-EMT TCMs and formulae, focusing on their underlying pharmacological mechanisms, to provide a foundation for further research on the exact mechanisms through which TCM affects EMT in HCC.

P-Rex1 Cooperates With TGFßR2 to Drive Lung Fibroblast Migration in Pulmonary Fibrosis.

Pulmonary fibrosis is a kind of interstitial lung disease with progressive pulmonary scar formation, leading to irreversible loss of lung functions. The TGF-ß1/Smad signaling pathway plays a key role in fibrogenic processes. It is associated with the increased synthesis of extracellular matrix, enhanced proliferation of fibroblasts, and transformation of alveolar epithelial cells into interstitial cells. We investigated P-Rex1, a PIP3-Gßγ-dependent guanine nucleotide exchange factor (GEF) for Rac, for its potential role in TGF-ß1-induced pulmonary fibrosis. A high expression level of P-Rex1 was identified in the lung tissue of patients with pulmonary fibrosis than that from healthy donors. Using the P-Rex1 knockdown and overexpression system, we established a novel player of P-Rex1 in mouse lung fibroblast migration. P-Rex1 contributed to fibrogenic processes in lung fibroblasts by targeting the TGF-ß type Ⅱ receptor (TGFßR2). The RNA-seq analysis for expression profiling confirmed the modulation of P-Rex1 in cell migration and the involvement of P-Rex1 in TGF-ß1 signaling. These results identified P-Rex1 as a signaling molecule involved in TGF-ß1-induced pulmonary fibrosis, suggesting that P-Rex1 may be a potential target for pulmonary fibrosis treatment.

Valproic acid reverses sorafenib resistance through inhibiting activated Notch/Akt signaling pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common lethal human malignancies worldwide. Sorafenib is the first-line drug approved by the United States Food and Drug Administration for HCC. However, the acquired resistance to sorafenib reduces its beneficial effects and limits clinical use. In this study, we established a sorafenib-resistant HCC cell line HepG2-SR by low-concentration gradient induction. Compared with the parental cell HepG2, the proliferation and anti-apoptosis were increased in drug-resistant cell HepG2-SR. Thorough comparisons of the molecular changes between parental HepG2 and sorafenib-resistant HepG2-SR cells indicated that the Notch signaling pathway and PI3K/Akt signaling pathway were associated with sorafenib resistance mechanisms. Notch1 and Akt were upregulated in sorafenib-resistant cells. However, we surprisingly found that valproic acid (VPA) combined with sorafenib could enhance the sensitivity of drug-resistant cells and reverse the increased levels of Notch1 and Akt in sorafenib-resistant HCC cells. Moreover, Akt inhibitor could suppress Notch1 expression, whereas the level of Akt phosphorylation decreased along with increasing dose of Notch inhibitor. Besides, we found that knockdown of Akt resulted in Notch1 reduction, whereas Notch1 reduction also led to a significant reduction in the phosphorylation of Akt. Collectively, our results indicated that Notch1 and Akt might play vital roles in sorafenib resistance in HCC cells and VPA might overcome the drug resistance to enhance the sensitivity of HCC cells to sorafenib through suppressing Notch/Akt signaling pathway. VPA combined with sorafenib may provide a potential targeting therapeutic regimen for clinically to solve the problem of sorafenib resistance.

Identification of P-Rex1 in the Regulation of Liver Cancer Cell Proliferation and Migration via HGF/c-Met/Akt Pathway.

BACKGROUND: Rho-GTPases and their activators, guanine nucleotide exchange factors (GEFs), are increasingly being recognized as essential mediators of oncogenic signaling. Although it is known that P-Rex1, a member of the Dbl family of GEFs for the Rac small GTPase, contributes to the migration of cancer cells, its exact role in liver cancer and the underlying mechanisms remain unclear. MATERIALS AND METHODS: Public datasets from the Gene Expression Omnibus database (GEO) and clinical liver cancer samples were analyzed to explore the expression of P-Rex1. P-Rex1 knockdown and overexpression cell lines were established using a recombinant lentiviral transfection system. BrdU and colony formation assays were performed to determine cell viability. Migratory capacity was analyzed using a transwell migration assay and an in vitro wound-healing assay. Nude mice bearing subcutaneous xenograft tumors were established to determine the effects of P-Rex1 on tumorigenesis in vivo. The role of P-Rex1 in hepatocarcinogenesis was determined through Western blot and co-immunoprecipitation. RESULTS: Induced expression of endogenous P-Rex1 was identified in liver cancer tumors when compared with adjacent nonmalignant tissues from clinical data. In response to HGF treatment, P-Rex1-knockdown cells displayed reduced proliferation and migration in vitro as well as reduced xenograft tumor growth in vivo. Overexpression of P-Rex1 promoted liver cancer cell proliferation and migration. P-Rex1 primarily acts as a downstream effector of GPCR signaling. This study demonstrated that downregulation of P-Rex1 led to a significant decrease in the phosphorylation of Akt and Erk1/2 by reducing the phosphorylation of the tyrosine kinase receptor c-Met. Furthermore, a physical association between P-Rex1 and c-Met was observed after HGF treatment, suggesting that P-Rex1 may be involved in the HGF/c-Met signaling pathway. CONCLUSION: These results support the role of P-Rex1 as a novel player in liver cancer, which suggest that targeting P-Rex1 may provide a potential strategy for liver cancer treatment.

Valproic acid overcomes sorafenib resistance by reducing the migration of Jagged2-mediated Notch1 signaling pathway in hepatocellular carcinoma cells.

Sorafenib resistance is a classic problem related to the treatment of advanced hepatocellular carcinoma (HCC). There is a recognized need to explore new drug resistance mechanisms and develop novel strategies to overcome the acquired resistance to sorafenib. Although one study has showed that the anti-epileptic drug valproic acid (VPA) could sensitize transforming growth factor-ß (TGF-ß)-induced sorafenib-resistant HCC cells, it is unclear whether VPA could reverse resistance to long-term clinical treatment with sorafenib. In this study, we successfully established sorafenib-resistant HCC cells by long-term sorafenib exposure. Compared with sensitive HCC cells, the proliferation, anti-apoptotic capability and migration of the sorafenib-resistant cells were enhanced. In addition, we found that VPA combined with sorafenib could overcome drug resistance by downregulating Jagged2-mediated Notch1 signaling pathway and epithelial-mesenchymal transition (EMT)-related proteins. Furthermore, the combination of VPA and sorafenib could obviously increase the sensitivity of drug-resistant cells in vitro and synergistically suppress tumor growth in vivo. These results provided a new insight that the use of VPA in combination with sorafenib was an effective method for clinically solving the problem of sorafenib resistance by modulating the Jagged2-mediated Notch1 signaling pathway and reversing the EMT phenotype.

Interaction between Traditional Chinese Medicine and Anticoagulant/Antiplatelet Drugs.

BACKGROUND: Traditional Chinese medicine (TCM) has been used for medical purposes since the ancient time and has gradually gained recognition worldwide. Nowadays, patients with thrombus presiding to anticoagulant/ antiplatelet drugs prefer taking TCM. However, an increasing number of studies on herb-drug interactions have been shown. Nevertheless, findings are frequently conflicting and vague. In this review, we discuss the herb-drug interactions between TCM and anticoagulant/antiplatelet drugs to provide guidance on concomitant ingestion with anticoagulant/antiplatelet drugs. METHODS: We undertook a structured search of medicine and drug databases for peer-reviewed literature using focused review questions. RESULTS: Danshen, Ginkgo, Ginger, H. Perforatum, SMY and Puerarin injection had directional regulation effects on the efficacy of anticoagulant drugs by altering the CYPs, pharmacokinetic indexs and hemorheological parameters. H. Perforatum inhibited the efficacy of Clopidogrel by enhancing the CYP3A4 activity and Ginkgo increased the efficacy of Ticlopidine. Additionally, Renshen, the formulae except SMY and injections except Puerarin injection could increase or decrease the efficacy of anticoagulant/antiplatelet drugs via regulating the CYPs, platelet aggregation, hemorheological parameters and others. CONCLUSION: Some cases have reported that TCMs may increase the bleeding risk or has no effect on coagulation when anticoagulant/antiplatelet drugs are concurrently used. However, pharmacokinetic studies have presented either consistent or slightly varying results. So it is difficult to ascertain whether the concurrent use of TCM may increase or reduce the pharmacologic effects of anticoagulant/antiplatelet drugs with adverse reactions. Therefore, herb-drug interactions of TCM and anticoagulant/antiplatelet drugs should be further explored and defined.

Tropisetron attenuates lipopolysaccharide induced neuroinflammation by inhibiting NF-κB and SP/NK1R signaling pathway.

Tropisetron, an antagonist of serotonin type 3 receptors (5-HT3Rs), has been investigated in colonic inflammatory process. Since substance P/neurokinin 1 receptor (SP/NK1R) signaling pathway plays a key role in several sensory neuronal inflammatory. We evaluated the anti-inflammatory activity of tropisetron in mice cerebral cortex, and discovered that it was a potential inhibitor in LPS-mediated neuron inflammation through SP/NK1R signaling pathway. We found that tropisetron significantly reduced the increased number of iba-1 positive microglia, down-regulated the gene transcription and protein expression of IL-1ß,IL-6 and TNF-α in LPS stimulated cerebral cortex. To characterize the inhibitory mechanism of tropisetron at the SP response in inflammation, we further examined the effect of tropisetron on NF-κB and SP/NK1R signaling pathway in the process of mice cerebral cortex inflammation. We found that tropisetron inhibited the gene transcription and protein expression of NF-κB, SP, NK1R via inhibiting 5-HT3R activity. These findings might provide new insights into the anti-inflammatory activities of 5-HT3R inhibitor tropisetron, which would be the interaction of serotonin receptor signaling and SP/NK1R pathway. These might highlight their potential to design novel therapeutic strategies to manage inflammatory diseases.

Precision Medicine: Update on Diagnosis and Therapeutic Strategies of Hepatocellular Carcinoma.

Recent advances in multiple omics technologies and the advent of massively parallel sequencing provide technical supports for the implementation of precision medicine. The precision medicine emphasizes that heterogeneous diseases can be well classified into more precise subtypes by the powerful detection methods and integration of clinical features, so that the clinicians should develop more accurate diagnosis and therapeutic strategies for the disease subtype population in an effort to maximize the efficacy and minimize the unnecessary side effects. Oncology is at the forefront of precision medicine, as malignant tumors have significant heterogeneity and are among the leading causes of death nationally and worldwide. The incidence and mortality of Hepatocellular Carcinoma (HCC), a kind of extraordinarily heterogeneous malignancy, have been increasing worldwide, making it a major public health concern. Such heterogeneity affects key signaling pathways, driving phenotypic variation, influences tumor evolution, and poses severe challenges to HCC treatment. The application of precision medicine will have certain impact on HCC diagnosis and treatment strategies. Herein, we summarize the updates and challenges in high-risk population screening, prevention, diagnosis, staging and therapy of HCC under the concept of precision medicine.

Metabolomic approach to understand the acute and chronic hepatotoxicity of Veratrum nigrum extract in mice based on ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.

Veratrum nigrum L. (VN) is a poisonous traditional Chinese medicine herb present since thousands of years in China. Clinical studies have shown that VN has the ability to cause hepatotoxicity, which severely limits its clinical use. The mechanism of its hepatotoxicity has not been fully elucidated. The purpose of this study was to develop and characterize a model of acute and chronic hepatotoxicity induced by Veratrum nigrum L. extract (VNE) to understand the mechanism of liver tissue metabolomics approach using on ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOFMS). Mice were administered with VNE in the acute and chronic phases. Histopathologic inspections and biochemistry analysis disclosed severe liver damage after exposure to VNE. A partial least-squares discriminant analysis (PLS-DA) of the metabolomic profiles of rat liver tissues highlighted a number of metabolic disturbances induced by VNE, focusing on purine and pyrimidine metabolism, tryptophan metabolism, phospholipid metabolism, sphingolipid metabolism and fatty acid metabolism. These findings could well explain VNE-induced acute and chronic hepatotoxicity and reveal several potential biomarkers associated with this toxicity. This indicates that UHPLC-Q-TOFMS-based metabolomics approach demonstrated its feasibility and allowed a better understanding of VNE-induced liver toxicity dynamically.

Combination of sorafenib and Valproic acid synergistically induces cell apoptosis and inhibits hepatocellular carcinoma growth via down-regulating Notch3 and pAkt.

Sorafenib is currently the only approved first-line targeted drug against advanced hepatocellular carcinoma (HCC). However, unsatisfactory efficacy and resistance of sorafenib raises the urgent need to develop more effective therapeutic strategies for HCC. Here, we evaluated the effects of combination of histone deacetylase inhibitor Valproic acid (VPA) and sorafenib in HCC both in vitro and in vivo. Co-treatment of sorafenib and VPA synergistically inhibited HCC cell viability, induced cell apoptosis, along with the up-regulation of p21, Bax, cleaved caspase9, cleaved caspase3, cleaved PARP and down-regulation of Bcl-xL, suggesting this combination activated intrinsic apoptotic pathway. Our further experiment results showed that sorafenib plus VPA decreased tumor burden more effectively than sorafenib or VPA mono-therapy in nude mice subcutaneous xenograft model. Histological and serological analysis demonstrated well tolerance of this combination in vivo. On a molecular level, our results presented a possible crosstalk between Notch3 and Akt signaling. Sorafenib increased the expression of Notch3 in a dosage dependent manner, along with the phosphorylation of Akt in HCC cells. In comparison, this induction of Notch3 and pAkt could be decreased by VPA, implying that Notch3 and pAkt are of significance in the treatment of HCC, which may account for the synergism of sorafenib and VPA. In conclusion, the combination of sorafenib and VPA offers a potential targeting therapeutic regimen for HCC in the future.

Laboratory monitoring of rivaroxaban and assessment of its bleeding risk.

BACKGROUND: The aims of this study were to investigate the effects of rivaroxaban on routine coagulation assays using our local, widely available, reagents and to study the relationship between sensitive coagulation assays and bleeding risk caused by rivaroxaban. METHODS: Prothrombin time (PT), activated partial thromboplastin time (APTT) and anti-factor Xa (FXa) chromogenic assays (Biophen DiXaI) and inhibition of FXa activity were performed in normal pooled plasma (NPP) spiked with rivaroxaban and plasma samples from patients treated with rivaroxaban. RESULTS: In vitro, the linear correlation coefficient of measured concentrations of rivaroxaban, by Biophen DiXaI, and spiked concentrations of rivaroxaban was 0.99. PT and APTT showed good linear correlation with rivaroxaban concentrations, while other assays showed poor correlation. In vivo, PT showed a moderate linear correlation with rivaroxaban concentrations while APTT had a weak correlation with rivaroxaban concentrations. In vitro and in vivo, the rivaroxaban concentrations, measured by Biophen DiXaI, always showed good correlation with the inhibition of FXa activity, and PT values showed moderate correlation with the inhibition of FXa activity. CONCLUSIONS: Biophen DiXaI can be considered as a quantitative method to monitor the anticoagulation activity of rivaroxaban, and could be used to evaluate bleeding risk caused by rivaroxaban. The PT reagent (Thrombosis S) could be considered as a rough method to monitor the anticoagulation activity of rivaroxaban and evaluate bleeding risk caused by rivaroxaban.

Notch Signaling Activation in Cervical Cancer Cells Induces Cell Growth Arrest with the Involvement of the Nuclear Receptor NR4A2.

Cervical cancer is a second leading cancer death in women world-wide, with most cases in less developed countries. Notch signaling is highly conserved with its involvement in many cancers. In the present study, we established stable cervical cell lines with Notch activation and inactivation and found that Notch activation played a suppressive role in cervical cancer cells. Meanwhile, the transient overexpression of the active intracellular domain of all four Notch receptors (ICN1, 2, 3, and 4) also induced the suppression of cervical cancer Hela cell growth. ICN1 also induced cell cycle arrest at phase G1. Notch1 signaling activation affected the expression of serial genes, especially the genes associated with cAMP signaling, with an increase of genes like THBS1, VCL, p63, c-Myc and SCG2, a decrease of genes like NR4A2, PCK2 and BCL-2. Particularly, The nuclear receptor NR4A2 was observed to induce cell proliferation via MTT assay and reduce cell apoptosis via FACS assay. Furthermore, NR4A2's activation could reverse ICN1-induced suppression of cell growth while erasing ICN1-induced increase of tumor suppressor p63. These findings support that Notch signaling mediates cervical cancer cell growth suppression with the involvement of nuclear receptor NR4A2. Notably, Notch/NR4A2/p63 signaling cascade possibly is a new signling pathway undisclosed.

Valproic acid induces NET cell growth arrest and enhances tumor suppression of the receptor-targeted peptide-drug conjugate via activating somatostatin receptor type II.

BACKGROUND: Human pancreatic carcinoids, a type of neuroendocrine tumors, are asymptomatic and difficult to diagnose, with the effects of traditional anti-cancer therapies being limited. The histone deacetylase (HDAC) inhibitor valproic acid (VPA) was evaluated for its effects alone and in combination with receptor-targeting peptide-drug conjugate via increasing drug internalization. MATERIALS AND METHODS: The in vitro and in vivo assays were used to evaluate the effects of VPA and somatostatin receptor-targeting camptothecin-somatostatin conjugate (CPT-SST). RESULTS: VPA induced proliferation suppression, cell apoptosis and cell cycle arrest. VPA acts as a HDAC inhibitor to induce a decrease of HDAC4 and an increase of acetylated histone 4 (AcH4). Meanwhile, most importantly, besides activating Notch signaling, VPA was observed to stimulate the expression of somatostatin receptor type 2 (SSTR2) that has been applied for receptor-targeting therapies. This characteristic was used for a combination therapy of VPA and CPT-SST. The combination displayed much more potent anti-tumor effects on carcinoid tumor growth by increasing SSTR2 density and drug internalization in target tumor cells. CONCLUSION: The combination of VPA and a SSTR2-targeting agent provides us a promising approach in treatment of carcinoid tumors.

The Histone Deacetylase Inhibitor Vaproic Acid Induces Cell Growth Arrest in Hepatocellular Carcinoma Cells via Suppressing Notch Signaling.

Hepatocellular carcinoma (HCC) is a type of malignant cancer. Notch signaling is aberrantly expressed in HCC tissues with more evidence showing that this signaling plays a critical role in HCCs. In the present study, we investigate the effects of the anti-convulsant drug valproic acid (VPA) in HCC cells and its involvement in modulating Notch signaling. We found that VPA, acting as a histone deacetylase (HDAC) inhibitor, induced a decrease in HDAC4 and an increase in acetylated histone 4 (AcH4) and suppressed HCC cell growth. VPA also induced down-regulation of Notch signaling via suppressing the expression of Notch1 and its target gene HES1, with an increase of tumor suppressor p21 and p63. Furthermore, Notch1 activation via overexpressing Notch1 active form ICN1 induced HCC cell proliferation and anti-apoptosis, indicating Notch signaling played an oncogenic role in HCC cells. Meanwhile, VPA could reverse Notch1-induced increase of cell proliferation. Interestingly, VPA was also observed to stimulate the expression of G protein-coupled somatostatin receptor type 2 (SSTR2) that has been used in receptor-targeting therapies. This discovery supports a combination therapy of VPA with the SSTR2-targeting agents. Our in vitro assay did show that the combination of VPA and the peptide-drug conjugate camptothecin-somatostatin (CPT-SST) displayed more potent anti-proliferative effects on HCC cells than did each alone. VPA may be a potential drug candidate in the development of anti-HCC drugs via targeting Notch signaling, especially in combination with receptor-targeting cytotoxic agents.

Lamotrigine attenuates cerebral ischemia-induced cognitive impairment and decreases ß-amyloid and phosphorylated tau in the hippocampus in rats.

Lamotrigine (LTG) has shown benefits in animal models of cerebral ischemia, but the mechanism involved was not fully studied. This study was carried out to examine the effects of LTG on cognitive dysfunction, ß-amyloid1-42 accumulation, and tau protein hyperphosphorylation in the hippocampus of ischemic rats. Transient ischemic stroke was induced by middle cerebral artery occlusion. The Morris water maze test was used to evaluate the cognitive function of rats. We found that LTG significantly attenuated ischemia-induced cognitive deficits and decreased neuronal injury in the hippocampal CA1 zone. Moreover, LTG reduced ß-amyloid1-42 and phosphorylated tau (AT8) in the hippocampus after ischemia. These results suggested that the cognition-protective effects of LTG after cerebral ischemia might involve inhibition of toxic ß-amyloid accumulation and tau hyperphosphorylation in the hippocampus.