PCSK9 dysregulates cholesterol homeostasis and triglyceride metabolism in olanzapine-induced hepatic steatosis via both receptor-dependent and receptor-independent pathways.

Schizophrenia, affecting approximately 1% of the global population, is often treated with olanzapine. Despite its efficacy, olanzapine's prolonged use has been associated with an increased risk of cardiovascular diseases and nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanism remains unclear. Proprotein convertase subtilisin kexin type 9 (PCSK9) plays a crucial role in lipid metabolism and is involved in NAFLD pathogenesis via an unknown mechanism. This study aims to investigate the role of PCSK9 in olanzapine-induced NAFLD. C57BL/6J mice and HepG2 and AML12 cell lines were treated with varying concentrations of olanzapine to examine the effects of olanzapine on PCSK9 and lipid metabolism. PCSK9 levels were manipulated using recombinant proteins, plasmids, and small interfering RNAs in vitro, and the effects on hepatic lipid accumulation and gene expression related to lipid metabolism were assessed. Olanzapine treatment significantly increased PCSK9 levels in both animal and cell line models, correlating with elevated lipid accumulation. PCSK9 manipulation demonstrated its central role in mediating hepatic steatosis through both receptor-dependent pathways (impacting NPC1L1) and receptor-independent pathways (affecting lipid synthesis, uptake, and cholesterol biosynthesis). Interestingly, upregulation of SREBP-1c, rather than SREBP-2, was identified as a key driver of PCSK9 increase in olanzapine-induced NAFLD. Our findings establish PCSK9 as a pivotal factor in olanzapine-induced NAFLD, influencing both receptor-related and metabolic pathways. This highlights PCSK9 inhibitors as potential therapeutic agents for managing NAFLD in schizophrenia patients treated with olanzapine.

SMYD3 activates the TCA cycle to promote M1-M2 conversion in macrophages.

BACKGROUND: SMYD3 refers to a histone lysine methyltransferase from the SMYD family, which acts as a gene transcriptional regulator chiefly through catalysis of the histone subunit 3 at lysine 4 trimethylation (H3K4me3). Great progress has been made that epigenetic modification plays a pivotal role in regulating macrophage polarization. However, the effects of the histone lysine methyltransferase SMYD3 on macrophage polarization and phenotypic switching are unclear. RESULTS: We found that LPS/IFN-γ-stimulated macrophages gradually transformed from M1 to M2 in the late stage, and SMYD3 played a key role in this process. As demonstrated by RNA-seq assessment, SMYD3 prominently activated a metabolic pathway known as TCA cycle inside macrophages during M1-M2 conversion. Besides, by modifying H3K4me3 histone, the target genes regulated by SMYD3 were identified via the ChIP-seq assessment, including citrate synthase (CS), succinate dehydrogenase complex subunit C (SDHC) and pyruvate carboxylase (PC). SMYD3 activated the transcriptional activities of the metabolic enzymes CS, SDHC and PC through H3K4me3 by causing the aggregation of citrate, an intramacrophage metabolite, and the depletion of succinate. And additionally, it facilitated the generation of ROS, as well as the expressions of genes associated with mitochondrial respiratory chain complexes. This increased ROS production ultimately induced mitophagy, triggering the M1 to M2 phenotype switch in the macrophages. CONCLUSIONS: Our study provides a detailed intrinsic mechanism in the macrophage phenotypic transition process, in short, SMYD3 promotes the M1-M2 conversion of macrophages by activating the TCA cycle through the simultaneous regulation of the transcriptional activities of the metabolic enzymes CS, SDHC and PC.

Tryptophan metabolism regulates inflammatory macrophage polarization as a predictive factor for breast cancer immunotherapy.

Metabolic reprogramming plays a pivotal role in regulating macrophage polarization and function. However, the impact of macrophage tryptophan metabolism on polarization within the breast cancer microenvironment remains elusive. In this study, we used single-cell transcriptome analysis and found that macrophages had the highest tryptophan metabolic activity in breast cancer, melanoma, and head and neck squamous cell carcinoma (HNSC). Further analysis revealed that the tryptophan metabolic activity of macrophages was positively correlated with the M1 macrophage scores in breast cancer. Pancancer analysis found positive correlations between tryptophan metabolism and the M1 macrophage score in almost all tumor types. Spatial transcriptome analysis revealed higher tryptophan metabolism in regions with higher M1 macrophage score in breast cancer tissues. Immune infiltration analysis revealed that the high tryptophan metabolism group exhibited a higher immune score, an increased proportion of CD8+ T cells, augmented cytolytic activity mediated by CD8+ T cells, and elevated expression of immune checkpoint molecules. Spatial immunophenotype cohort analysis exhibited that breast cancer patients expected to respond to immunotherapy had stronger tryptophan metabolism, with a 73.8 % area under the ROC curve. Single-cell transcriptome analysis of the immunotherapy cohort found that patients responding to immunotherapy had higher macrophage tryptophan metabolism prior to treatment initiation. Finally, in vitro experiments demonstrated elevated expression of tryptophan metabolic enzymes in M1 macrophages. Moreover, tryptophan facilitated the expression of M1 polarization markers, whereas inhibitors of tryptophan metabolic enzymes, such as NLG919, LM10, and Ro 61-8048, inhibited the expression of M1 polarization markers. In conclusion, this study identified a dual role for macrophage tryptophan metabolism in breast cancer; on the one hand, it promotes macrophage M1 polarization, while on the other hand, it serves as a promising predictor for the effectiveness of immunotherapy in breast cancer.

Efficacy and Safety of Radiotherapy Combined with Pyrotinib in the Treatment of HER2-Positive Breast Cancer with Brain Metastases.

Purpose: To explore the efficacy and safety of pyrotinib combined with different radiotherapy modes in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients with brain metastasis (BM). Patients and Methods: This study is a retrospective analysis of patients diagnosed with BM who underwent treatment with pyrotinib between November 2018 and April 2023. A total of 66 patients were administered radiotherapy in conjunction with pyrotinib (Group A), while 26 patients received pyrotinib as a standalone treatment (Group B). Within Group A, 18 patients underwent conventional fractionated radiotherapy (2Gy/F), while 48 patients received hyperfractionated radiotherapy (HFRT) (≥3Gy/F). The primary endpoints were intracranial progression-free survival (IC-PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR) and clinical benefit rate (CBR). Results: The ORR of Group A was 54.5% (36/66), while the ORR of Group B was 34.6% (9/26) (P= 0.047). The CBR of Group A was 89.4% (59/66) and that of Group B was 69.2% (18/26) (P= 0.041). The IC-PFS between Group A and Group B were 12 months and 8 months, respectively (P< 0.001), and the OS were 20 months and 16 months, respectively (P= 0.065). In Group A, the IC-PFS and OS between the conventional fractionation radiotherapy group and the HFRT group were 10 months and 12 months, respectively (P= 0.001) and 16 months and 24 months, respectively (P< 0.001). No serious adverse reactions were observed in Group A and Group B. Conclusion: For HER2-positive BC patients with BM, it is recommended to adopt the treatment mode of HFRT combined with pyrotinib, which can improve the local control and survival of patients.

Expanding the applications of immune checkpoint inhibitors in advanced lung cancer beyond disease progression.

Background: Immunotherapy, particularly the utilization of immune checkpoint inhibitors (ICIs), assumes a pivotal role in the comprehensive management of advanced lung cancer. There has been substantial deliberation regarding the appropriateness of extending ICIs treatment beyond the point of disease progression. This study delves into the potential benefits of sustained utilization of ICIs subsequent to disease progression in patients. Methods: A retrospective analysis was conducted on a cohort of 248 patients diagnosed with advanced lung cancer who received treatment with ICIs. The study population comprised 99 patients in the treatment beyond progression (TBP) group and 42 patients in the non-treatment beyond progression (NTBP) group. Parameters including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) were assessed. The Cox proportional hazard regression model was employed to analyze prognostic factors related to immunotherapy. Results: Patients undergoing primary treatment with PD-1/PD-L1 inhibitors exhibited a median progression-free survival (mPFS) of 5.3 months. In the context of disease progression, a comparison between the TBP and NTBP groups was performed with respect to mPFS. The results demonstrated that the TBP group manifested an mPFS of 8.6 months, contrasting with the NTBP group's mPFS of 4.0 months (p=0.028). The mean overall survival (mOS) in the TBP group exhibited a statistically significant increase in comparison to the NTBP group (14.1 months vs. 6.0 months, p=0.028). Evaluation of the objective response rate (ORR) between the TBP and NTBP groups revealed a substantial distinction. The TBP group displayed an ORR of 12.1%, while the NTBP group exhibited a lower ORR of 2.4%. The statistical analysis yielded a p-value of 0.068, signifying a notable trend towards significance. The disease control rate (DCR) was also assessed and exhibited a noteworthy variance between the two groups, with a higher DCR of 92.9% in contrast to 71.4% in the control group (p = 0.001). Conclusion: Subsequent to ICIs treatment, a subset of patients may derive continued benefits from anticancer therapy, notwithstanding the progression of their advanced lung cancer.

Circadian pattern subtyping unveiling distinct immune landscapes in breast cancer patients for better immunotherapy.

BACKGROUND: While epidemiological studies have established a firm link between circadian disruption and tumorigenesis, the role and mechanism are not fully understood, complicating the design of therapeutic targets related to circadian rhythms (CR). Here, we aimed to explore the intertumoral heterogeneity of CR and elucidate its impact on the tumor microenvironment (TME), drug sensitivity, and immunotherapy. METHODS: Based on unsupervised clustering of 28 CR genes, two distinct CR subtypes (cluster-A and cluster-B) were identified in the TCGA cohort. We further constructed a circadian rhythm signature (CRS) based on the CR genes primarily responsible for clustering to quantify CR activity and to distinguish CR subtypes of individual patients from external datasets. CR subtypes were evaluated by TME characteristics, functional annotation, clinical features, and therapeutic response. RESULTS: The cluster-B (low-CRS) group was characterized by highly enriched immune-related pathways, high immune cell infiltration, and high anti-tumor immunity, while the cluster-A (high-CRS) group was associated with immunosuppression, synaptic transmission pathways, EMT activation, poor prognosis, and drug resistance. Immunohistochemistry (IHC) results demonstrated that high CD8+ T cell infiltration was associated with low-CR-protein expression. Importantly, patients with low CRS were more likely to benefit from immune checkpoint blockade (ICB) treatment, possibly due to their higher tumor mutation burden (TMB), increased immune checkpoint expression, and higher proportion of "hot" immunophenotype. CONCLUSION: In a nutshell, the cross talk in CR could reflect the TME immunoreactivity in breast cancer. Besides providing the first comprehensive pathway-level analysis of CR in breast cancer, this work highlights the potential clinical utility of CR for immunotherapy.

Lactate from glycolysis regulates inflammatory macrophage polarization in breast cancer.

Globally, breast cancer is one of the leading causes of cancer death in women. Metabolic reprogramming and immune escape are two important mechanisms supporting the progression of breast cancer. Lactate in tumors mainly comes from glycolysis and glutaminolysis. Using multiomics data analysis, we found that lactate is mainly derived from glycolysis in breast cancer. Single-cell transcriptome analysis found that breast cancer cells with higher malignancy, especially those in the cell cycle, have higher expression levels of glycolytic metabolic enzymes. Combined with clinical data analysis, it was found that the expression of the lactate transporter SLC16A3 is correlated with breast cancer molecular subtypes and immune infiltration. Among 22 immune cells, macrophages are the most abundant immune cells in breast cancer tissues, and the proportion of M1 macrophages is lower in the high SLC16A3 expression group. Finally, in vitro experiments confirmed that lactate could inhibit the expression of M1 macrophage markers at both RNA and protein levels. In conclusion, we found that lactate produced by glycolysis regulates the polarization of inflammatory macrophages in breast cancer.

The SMYD3-MTHFD1L-formate metabolic regulatory axis mediates mitophagy to inhibit M1 polarization in macrophages.

BACKGROUND: SMYD3 (protein 3 containing SET and MYND structural domains) belongs to the SMYD methylesterase family and is a histone lysine methyltransferase that promotes gene transcription mainly by catalysing the trimethylation of lysine at position 4 of histone subunit 3 (H3K4me3). Studies have shown that SMYD3 plays a key role in tumour cell proliferation and differentiation; however, its role in macrophage polarization is unclear. METHODS: We screened the M1- and M2-polarized macrophage differential histone modifying enzyme using bioinformatics analysis. The SMYD3 overexpression plasmid was transfected into M1 macrophages, and the SMYD3-regulated target gene was analysed by RNA-seq and ChIP-Seq. The effect of knocking down MTHFD1L on M1 polarization and the change of the intracellular metabolite formic acid content were investigated. M1 macrophages were stimulated with different concentrations of formic acid (2, 10 and 40 mM) to detect the expression of M1-related genes, ROS production, and changes in the expression of the mitophagy-related proteins LC3, PINK1 and p-Parkin. RESULTS: Here, we used bioinformatics to analyse SMYD3, a histone methyltransferase associated with M1 polarization; overexpression of SMYD3 significantly suppressed the LPS/IFN-γ-induced M1 phenotype in macrophages. RNA-seq analysis demonstrated that SMYD3 significantly activated the one-carbon folate metabolic pathway in M1 macrophages. In addition, we used ChIP-seq analysis to identify methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) as the target gene of the transcriptional activation by SMYD3 through H3K4me3 histone modification. Activation of MTHFD1L causes the accumulation of the intracellular metabolite formate. Exogenous stimulation with different concentrations of formate increased the expression of key genes involved in the mitochondrial respiratory chain complex, ROS production, and the expression of autophagy-related proteins LC3, PINK1, and p-Parkin and suppressed the expression of M1-related genes. CONCLUSIONS: Our study demonstrates that SMYD3 regulates the activity of the mitochondrial metabolic enzyme MTHFD1L through H3K4me3 histone methylation modification, promotes formate synthesis and induces mitophagy, which inhibits M1 polarization in macrophages.

Case Report: A Mysterious Giant Thrombus in the Right Atrium in a Patient With Dilated Cardiomyopathy.

An isolated right atrial thrombus is a life-threatening entity that is extremely rare in patients with dilated cardiomyopathy (DCM), which is characterized by a reduced left ventricular function and consequent left ventricular thrombosis. Here, we present the case of a mysterious isolated giant right atrial thrombus in a male patient with DCM. The presence of deep vein thrombosis prompted us to investigate for other underlying diseases for his right atrial thrombus. Interestingly, the elevation of two tumor markers indicated the likelihood of cancer-associated thrombosis. Further, the computed tomography demonstrated a spiculated mass in the lower right lung that was confirmed by an endobronchial biopsy as lung squamous cell carcinoma. Consequently, the giant thrombus in the right atrium should be attributed principally to lung squamous cell carcinoma on the background of DCM. After 3 weeks of enoxaparin, the echocardiogram indicated partial resolution of the thrombus. However, the patient suffered sudden death due to pulmonary embolism.

Metformin Ameliorates Hepatic Steatosis induced by olanzapine through inhibiting LXRα/PCSK9 pathway.

Studies have confirmed that olanzapine, the mainstay treatment for schizophrenia, triggers metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). However, the etiology of olanzapine-induced NAFLD is poorly understood. Proprotein convertase subtilisin kexin type 9 (PCSK9) is involved in NAFLD pathogenesis, and metformin can significantly decrease circulating PCSK9. The purpose of this study was to investigate the role of PCSK9 and explore the therapeutic effect of metformin for olanzapine-associated NAFLD. Olanzapine significantly upregulated PCSK9 and promoted lipid accumulation in mouse livers and HepG2 and AML12 cells. Metformin ameliorated these pathological alterations. PCSK9 upstream regulator liver X receptor α (LXRα) was significantly upregulated in olanzapine-induced NAFLD. LXRα antagonist treatment and LXRα overexpression resulted in a decrease and increase of PCSK9, respectively. Hepatic lipogenesis-associated genes FAS and SCD1 were significantly upregulated in olanzapine-induced NAFLD mice and HepG2 cells overexpressing PCSK9, and genes related to lipid ß-oxidation (SCAD and PPARα) were downregulated, while metformin reversed these changes. In addition, we found that LXRα overexpression compromised the effect of metformin on PCSK9 levels and intracellular lipid droplet formation. Taken together, our findings suggest that olanzapine enhances hepatic PCSK9 expression by upregulating LXRα, thereby increasing FAS and SCD1 expression as well as decreasing SCAD and PPARα, and promoting lipid accumulation, and, subsequently, NAFLD, which is ameliorated by metformin.

H2O2 gel bleaching induces cytotoxicity and pain conduction in dental pulp stem cells via intracellular reactive oxygen species on enamel/dentin disc.

BACKGROUND: Bleaching is widely accepted for improving the appearance of discolored teeth; however, patient compliance is affected by bleaching-related complications, especially bleaching sensitivity. This study aimed to investigate the role of reactive oxygen species (ROS) in cytotoxicity and pain conduction activated by experimental tooth bleaching. METHODS: Dental pulp stem cells with or without N-acetyl-L-cysteine (NAC), an ROS scavenger, were cultured on the dentin side of the enamel/dentin disc. Subsequently, 15% (90 min) and 40% (30 min) bleaching gels were painted on the enamel surface. Cell viability, intracellular ROS, Ca2+, adenosine triphosphate (ATP), and extracellular ATP levels were evaluated using the Cell Counting Kit-8 assay, 2',7'-dichlorodihydrofluorescein diacetate, CellROX, fura-3AM fluorescence assay, and ATP measurement kit. The rat incisor model was used to evaluate in vivo effects after 0, 1, 3, 7, and 30 days of bleaching. Changes in gene and protein expression of interleukin 6 (IL-6), tumor necrosis factor-alpha (TNFα), transient receptor potential ankyrin 1 (TRPA1), and Pannexin1 (PANX1) in dental pulp stem cells and pulp tissue were detected through RT-PCR, western blotting, and immunofluorescence. RESULTS: The bleaching gel suppressed dental pulp stem cell viability and extracellular ATP levels and increased intracellular ROS, Ca2+, and intracellular ATP levels. The mRNA and protein expression of IL-6, TNFα, TRPA1, and PANX1 were up-regulated in vitro and in vivo. Furthermore, the 40% gel had a stronger effect than the 15% gel, and NAC ameliorated the gel effects. CONCLUSIONS: Our findings suggest that bleaching gels induce cytotoxicity and pain conduction in dental pulp stem cells via intracellular ROS, which may provide a potential therapeutic target for alleviating tooth bleaching nociception.

TRPA1 triggers hyperalgesia and inflammation after tooth bleaching.

Hyperalgesia has become a major problem restricting the clinical application of tooth bleaching. We hypothesized that transient receptor potential ankyrin 1 (TRPA1), a pain conduction tunnel, plays a role in tooth hyperalgesia and inflammation after bleaching. Dental pulp stem cells were seeded on the dentin side of the disc, which was cut from the premolar buccal tissue, with 15% (90 min) or 40% (3 × 15 min) bleaching gel applied on the enamel side, and treated with or without a TRPA1 inhibitor. The bleaching gel stimulated intracellular reactive oxygen species, Ca2+, ATP, and extracellular ATP in a dose-dependent manner, and increased the mRNA and protein levels of hyperalgesia (TRPA1 and PANX1) and inflammation (TNFα and IL6) factors. This increment was adversely affected by TRPA1 inhibitor. In animal study, the protein levels of TRPA1 (P = 0.0006), PANX1 (P < 0.0001), and proliferation factors [PCNA (P < 0.0001) and Caspase 3 (P = 0.0066)] increased significantly after treated rat incisors with 15% and 40% bleaching gels as detected by immunohistochemistry. These results show that TRPA1 plays a critical role in sensitivity and inflammation after tooth bleaching, providing a solid foundation for further research on reducing the complications of tooth bleaching.

Olanzapine leads to nonalcoholic fatty liver disease through the apolipoprotein A5 pathway.

The antipsychotic drug olanzapine was reported to induce nonalcoholic fatty liver disease (NAFLD), whereas the underlying mechanism remains incompletely understood. This study investigated whether apolipoprotein A5 (apoA5) and sortilin, two interactive factors involved in NAFLD pathogenesis, are implicated in olanzapine-induced NAFLD. In our study, at week 8, olanzapine treatment successfully induced hepatic steatosis in female C57 BL/6 J mice, which was independent of body weight gain. Likewise, olanzapine effectively mediated hepatocyte steatosis in HepG2 cells characterized by substantially elevated intracellular lipid droplets. Increased plasma triglyceride concentration and decreased plasma apoA5 levels were observed in mice treated with 8-week olanzapine. Surprisingly, olanzapine markedly enhanced hepatic apoA5 protein levels in mice, without a significant effect on rodent hepatic ApoA5 mRNA. Our in vitro study showed that olanzapine reduced apoA5 protein levels in the medium and enhanced apoA5 protein levels in hepatocytes, whereas this drug exerted no effect on hepatocyte APOA5 mRNA. By transfecting APOA5 siRNA into HepG2 cells, it was demonstrated that APOA5 knockdown effectively reversed olanzapine-induced hepatocyte steatosis in vitro. In addition, olanzapine drastically increased sortilin mRNA and protein levels in vivo and in vitro. Interestingly, SORT1 knockdown reduced intracellular apoA5 protein levels and increased medium apoA5 protein levels in vitro, without affecting intracellular APOA5 mRNA levels. Furthermore, SORT1 knockdown greatly ameliorated hepatocyte steatosis in vitro. This study provides the first evidence that sortilin inhibits the hepatic apoA5 secretion that is attributable to olanzapine-induced NAFLD, which provides new insight into effective strategies against NAFLD for patients with schizophrenia administered olanzapine.

Oroxylin A inhibits Kaposi's sarcoma-associated herpes virus (KSHV) vIL-6-mediated lymphatic reprogramming of vascular endothelial cells through modulating PPARγ/Prox1 axis.

BACKGROUND AND PURPOSE: Kaposi's sarcoma-associated herpes virus (KSHV) vIL-6 is sufficient to induce lymphatic reprogramming of vascular endothelial cells, which is a key event in Kaposi's sarcoma (KS) development. This study was aimed to investigate the effect of Chinese herb oroxylin A on lymphatic reprogramming and neovascularization by KSHV vIL-6 in vitro and in vivo. METHODS: The lymphatic-phenotype endothelial cell line was generated by lentiviral KSHV vIL-6 infection. Cell viability and apoptosis were determined by MTT assay or flow cytometry with annexin V/propidium iodide staining. Migration, invasion, and neovascularization of the vIL-6-expressing lymphatic-phenotype endothelial cells were determined by wound healing assay, transwell chamber assay, microtubule formation assay, and chick chorioallantoic membrane assay, respectively. Quantitative polymerase chain reaction and Western blot analysis were used to test the expression of Prox1, VEGFR3, podoplanin, LYVE-1, and PPARγ in cells. Co-localization of Prox1 and PPARγ was determined by immunofluorescence. Ubiquitination of Prox1 was detected by in vivo ubiquitination assay. RESULTS: The lymphatic-phenotype endothelial cell line expressing KSHV vIL-6 was successfully generated. Oroxylin A induced cellular invasion abrogation, apoptosis induction, and neovascularization inhibition of the vIL-6-expressing endothelial cells. Mechanically, oroxylin A elevated PPARγ expression, which in turn interacted with and facilitated Prox1 to undergo ubiquitinational degradation, and subsequently leads to VEGFR3, LYVE-1, and podoplanin reduction. CONCLUSION: Through modulating PPARγ/Prox1 axis, oroxylin A inhibits lymphatic reprogramming and neovascularization of KSHV vIL-6. Thus, oroxylin A may serve as a candidate for the treatment of KS as well as other aggressive angiomas.

PGRMC1-dependent autophagy by hyperoside induces apoptosis and sensitizes ovarian cancer cells to cisplatin treatment.

Cisplatin treatment some times leads to chemoresistance, which is now acknowledged partially due to the inductive expression of progesterone receptor membrane component (PGRMC)1 in ovarian cancer cells. PGRMC1 enhances autophagy, activates cytochrome p450, and inveigles signaling pathways to promote cell survival and reduce the effect of drug treatments. In this study, we give first line evidence that hyperoside inhibits cell viability, triggers autophagy and apoptosis in ovarian cancer cell lines. Mechanistically, PGRMC1-dependent autophagy was utilized by hyperoside to induce apoptotic cell death. Hyperoside induced the conversion of LC3B-I to LC3B-II and the formation of autophagosomes in ovarian cancer cells. Notably, PGRMC1 colocolized with LC3B­II, and PGRMC1 overexpression enhanced hyperoside-induced autophagy and apoptosis, while PGRMC1 knockdown abrogated the action. Additionally, AKT signaling and Bcl-2 family were also involved in the hyperoside-induced autophagy and apoptosis. Importantly, in cisplatin-resistant ovarian cancer cells where PGRMC1 was overexpressed, hyperoside sensitized the cells to cisplatin treatment. Together these findings indicate hyperoside functions as a complementary therapy for ovarian cancer patients receiving platinum-based therapy.

[Application of regional arterial infusion chemotherapy in short-term neoadjuvant chemotherapy for advanced gastric cancer].

OBJECTIVE: To explore the feasibility of short-term neoadjuvant chemotherapy (NACT) in patients with advanced gastric cancer (AGC), and to compare clinical efficacy of short-term neoadjuvant chemotherapy with different ways. METHODS: Clinical data of 310 AGC patients treated with one course of NACT using EOF regimen(epirubicin, oxaliplatin and fluorouracil plus calcium folinate) in our hospital from January 2008 to December 2011 were retrospectively analyzes. Efficacy was compared between regional arterial infusion chemotherapy and intravenously chemotherapy. RESULTS: All the 310 AGC patients completed one course of NACT and none was interrupted by adverse events. Postoperative pathological remission rate was 33.9% (105/310) and 5 patients (1.6%) had complete pathological remission. The pathologic response rate in the regional arterial infusion chemotherapy group was higher than that in the intravenously chemotherapy group(42.4% vs. 23.6%, P = 0.001). Multivariate analysis revealed that chemotherapy method(HR=1.827, 95% CI:1.006-3.316, P = 0.048) was associated with significantly higher pathologic response. CONCLUSIONS: Pathological response rate is quite low following short-term NACT. Regional arterial infusion chemotherapy with short-term NACT can improve the pathological response rate of advanced gastric cancer.