Formyl peptide enhances cancer immunotherapy by activating antitumoral neutrophils, and T cells.

Neutrophils are heterogeneous and plastic, with the ability to polarize from antitumour to protumour phenotype and modulate tumour microenvironment components. While some advances have been made, the neutrophil-targeting therapy remains underexplored. Activation of formyl peptide receptors (FPRs) by formylated peptides is needed for local control of infection through the recruitment of activated neutrophils while the potential contribution of antitumour activity remains underexplored. Here, we demonstrate that neutrophils can be harnessed to suppress tumour growth through the action of the formyl peptide (FP) on the formyl peptide receptor (FPR). Mechanistically, FP efficiently recruits neutrophils to produce reactive oxygen species production (ROS), resulting in the direct killing of tumours. Antitumour functions disappeared when neutrophils were depleted by anti-Ly6G antibodies. Interestingly, extensive T-cell activation was observed in mouse tumours treated with FP, showing the potential to alter the immune suppressed tumour microenvironment (TME) and further sensitize mice to anti-PD1 therapy. Transcriptomic and flow cytometry analyses revealed the mechanisms of FP-sensitized anti-PD1 therapy, mainly including stimulated neutrophils and an altered immune-suppressed tumour microenvironment. Collectively, these data establish FP as an effective combination partner for sensitizing anti-PD1 therapy by stimulating tumour-infiltrated neutrophils.

Effectiveness Differences of Ranibizumab and Aflibercept Action in the Treatment of Diabetic Retinopathy.

Objective: To compare the difference in the effectiveness of ranibizumab (LU) and aflibercept (AF) in the treatment of diabetic retinopathy (DR). Methods: Ninety-four patients with DR admitted to Sunshine Union Hospital from August 2020 to February 2022 were selected for the study and were divided into LU group (n = 47) and AF group (n = 47) according to the random number table method. Both groups underwent 25G vitrectomy in our hospital, with LU injected into the vitreous before surgery in the LU group and AF in the AF group. Vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in the pre-and post-injection atrial water were compared between the two groups, and the operative time, intraoperative bleeding, and the occurrence of medically induced fissures were recorded in both groups. In addition, the expression of best corrected visual acuity (BCVA), Central Macular Thickness (CMT), and inflammatory factors were compared before and after surgery. Finally, patients were counted for adverse reactions and prognosis of DR recurrence during treatment. Results: After injection, VEGF decreased and PEDF increased in both groups (P < .001). There were no differences in operative time (P = .604), intraoperative bleeding rate (P = .694), the incidence of medically induced fissure (P = .557), BCVA [P = .665 (T0), P > .999 (T1), P = .727 (T2)], and CMT [P = .688 (T0), P = .065 (T1), P = .148 (T2)] between the two groups, while IL-6, IL-8, and MMP-9 were lower in the AF group than in the LU group at 2 months after surgery (P < .001). Finally, there was no difference between both groups in terms of adverse effects and prognosis of DR recurrence rate (P = 1.000, .478). Conclusion: Both vitreous cavity injections of LU and AF can effectively reduce the expression of vascular-related factors in the atrial fluid of DR patients, but AF has a more significant inhibitory effect on the level of inflammatory factors in patients in the short term after treatment.

mRNA-based Vaccines Targeting the T-cell Epitope-rich Domain of Epstein Barr Virus Latent Proteins Elicit Robust Anti-Tumor Immunity in Mice.

Epstein-Barr virus (EBV) is associated with various malignancies and infects >90% of the global population. EBV latent proteins are expressed in numerous EBV-associated cancers and contribute to carcinogenesis, making them critical therapeutic targets for these cancers. Thus, this study aims to develop mRNA-based therapeutic vaccines that express the T-cell-epitope-rich domain of truncated latent proteins of EBV, including truncatedlatent membrane protein 2A (Trunc-LMP2A), truncated EBV nuclear antigen 1 (Trunc-EBNA1), and Trunc-EBNA3A. The vaccines effectively activate both cellular and humoral immunity in mice and show promising results in suppressing tumor progression and improving survival time in tumor-bearing mice. Furthermore, it is observed that the truncated forms of the antigens, Trunc-LMP2A, Trunc-EBNA1, and Trunc-EBNA3A, are more effective than full-length antigens in activating antigen-specific immune responses. In summary, the findings demonstrate the effectiveness of mRNA-based therapeutic vaccines targeting the T-cell-epitope-rich domain of EBV latent proteins and providing new treatment options for EBV-associated cancers.

Relationship Between Platelets and the Clinical Efficacy of Umbilical Cord Mesenchymal Stem Cells for HBV-Related Acute-on-Chronic Liver Failure and Liver Cirrhosis: A Preliminary Clinical Study.

BACKGROUND: Previous studies have found that the production of platelets could enhance the therapeutic effects of stem cells. Nevertheless, there are still no articles reporting on the relationship between platelets and the clinical efficacy of umbilical cord mesenchymal stem cells (UCMSCs) for HBV-related acute-on-chronic liver failure (ACLF) and liver cirrhosis (LC). METHODS: In this retrospective observational study, patients who met the criteria were included. Patients were divided into subgroups according to the aims of this study. In the first part, the platelet count changes of ACLF and patients with LC after UCMSC therapy were compared and analyzed. Subgroup analysis based on UCMSC infusion times and patient age was also performed. In the second part, patients in the ACLF group and LC group were further divided into subgroups according to their platelet levels. Their clinical characteristics, demographics, and biochemical factors were compared. RESULTS: This study enrolled 64 patients with ACLF and 59 patients with LC. In both groups, platelet levels declined similarly. Compared with the short-course UCMSC treatment group (≤4 times), patients with ACLF and patients with LC with long-course UCMSC treatment (>4 times) showed an overall increasing trend. Younger patients with LC (<45 years) had significantly higher platelet levels than older patients with LC (≥45 years). However, this age difference was not present in the ACLF group. The median TBIL decrease and cumulative TBIL decrease were not significantly different between patients with high PLT and patients with low PLT after UCMSC transfusions. For patients with ACLF, the cumulative TBIL decrease and the median TBIL decrease were significantly greater than those of patients with LC at the same platelet level after UCMSC treatment. However, this difference was not observed at all time points. CONCLUSION: Trend of the platelet levels for HBV-related patients with ACLF and LC after UCMSC treatment did not parallel and varied according to treatment times and patients' age. Platelet levels did not affect the efficacy of MSCs for patients with ACLF or LC.

The role and mechanism of NDST1/NULP1 regulating right ventricular hypertrophy in hypoxic pulmonary hypertension.

Hypoxia leads to hypoxic pulmonary hypertension (HPH), causing right ventricular hypertrophy (RVH). RVH becomes a significant and nonnegligible public health issue in the world. In our study, we successfully established the HPH rat model and found that RVH happened in HPH, and then we observed an increased inflammation response in the heart tissue of HPH-induced RVH rats. Moreover, increased N-deacetylase-N-sulfotransferase-1 (NDST1) and decreased nuclear localized protein 1 (NULP1) were found in the heart tissue of HPH-induced RVH rats. An in vitro cell experiment showed that inhibition of NDST1 expression enhanced cell viability, reduced cell apoptosis, alleviated cardiomyocyte hypertrophy, decreased inflammation and increased phosphorylated AKT level, however, over-expression of NDST1 had opposite effects on these aspects. NULP1 reversed the effects of NDST1 on these regulations. Finally, we found that up-regulated NDST1 reduced NULP1 expression and down-regulated NDST1 increased NULP1 expression. Our study confirmed that inhibition of the NDST1/NULP1 pathway might contribute to the attenuation of HPH-induced RVH, and the mechanism may be related to the reduction of inflammation, cardiomyocyte apoptosis, and AKT phosphorylation.

Kallikrein-related peptidase-8 (KLK8) aggravated hypoxia-induced right ventricular hypertrophy by targeting P38 MAPK/P53 signaling pathway.

Right ventricular (RV) hypertrophy and further heart failure are major co-morbidities, resulting in the premature death of patients with hypoxic pulmonary hypertension (HPH). The regulatory effects of kallikrein-related peptidase (KLK) family members on cardiac function have been extensively studied. However, to the best of the authors' knowledge, the regulatory effects of KLK8 on RV hypertrophy caused by HPH have yet to be reported. The aim of the present study was to assess KLK8 expression in the RV tissue of HPH-modeled rats, and to further explore the effects and underlying mechanism of KLK8 in regulating the hypertrophy of hypoxia-induced H9c2 cardiomyocytes. In HPH model rats, increases in the right ventricle hypertrophy index, the right ventricular systolic pressure, cardiac output, as well as pulmonary artery wall thickness were observed. Western blot analysis revealed that KLK8 expression and MAPK/p53 signaling activity were enhanced in the RVs of rats in an RV HPH rat model. In hypoxia-induced H9c2 cardiomyocytes, KLK8 overexpression promoted cardiomyocyte hypertrophy, whereas KLK8 silencing showed the opposite results. KLK8 overexpression increased the expression levels of ventricular hypertrophy markers, including atrial natriuretic peptide, brain natriuretic peptide and myosin heavy chain 7, which were blocked upon addition of the p38 MAPK inhibitor, SB202190. Conversely, KLK8 silencing caused a decrease in the expression levels of the ventricular hypertrophy markers, which were further reduced via inhibition of the p38 MAPK/p53 signaling pathway. Taken together, the results of the present study have shown that KLK8 may subtly regulate RV hypertrophy, and therefore KLK8 may be a promising therapeutic target for treating HPH-induced RV hypertrophy.

Upregulation of long non-coding RNA myocardial infarction-associated transcription is correlated with coronary artery stenosis and elevated inflammation in patients with coronary atherosclerotic heart disease.

Coronary atherosclerotic heart disease (CAD) is a chronic disease caused by multiple risk factors. Aberrant expression of long non-coding RNAs (lncRNAs) has been regarded as an independent risk factor of CAD. This study evaluated lncRNA myocardial infarction-associated transcription (MIAT) expression in CAD patients and its clinical significance. Totally, 155 CAD patients and 76 non-CAD controls were enrolled. MIAT expression was detected using reverse transcription quantitative polymerase chain reaction. The clinical diagnostic significance of MIAT was evaluated by plotting the receiver operating characteristic (ROC) curve. The levels of inflammatory cytokines were detected using enzyme-linked immunosorbent assay. microRNA (miR)-29b-3p expression and pregnancy-associated plasma protein A (PAPPA) level were detected. MIAT expression in CAD patients (4.23 [1.22-6.50]) was higher than that in non-CAD controls (1.64 [0.05-2.93]) (p < 0.01) and had an independent correlation with CAD. The area under ROC curve of predicting CAD was calculated as 0.790, the specificity as 71.40%, and the sensitivity as 70.00%. MIAT expression was positively correlated with the C-reactive protein level (r = 0.769, p < 0.0001) and pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and IL-8 levels, while negatively correlated with the anti-inflammatory cytokine IL-10. MIAT was positively correlated with Gensini score and had an independent correlation with it. LncRNA MIAT sponged miR-29b-3p and miR-29b-3p targeted PAPPA. In conclusion, lncRNA MIAT was upregulated in the peripheral blood of CAD patients and elicited clinical diagnostic significance. MIAT participated in the development of CAD via miR-29b-3p/PAPPA axis. This study provides insights into a potential target for the diagnosis and treatment of CAD.

The impact of recipient age on the effects of umbilical cord mesenchymal stem cells on HBV-related acute-on-chronic liver failure and liver cirrhosis.

BACKGROUND: The results of a previous study verified that umbilical cord mesenchymal stem cells (UCMSCs) have good therapeutic effects for the treatment of HBV-related acute-on-chronic liver failure (ACLF) and liver cirrhosis (LC). Nevertheless, it is still unknown whether the effects of UCMSCs are affected by recipient age. METHODS: Patients treated with UCMSCs who met the criteria of HBV-related ACLF and liver cirrhosis were identified in this retrospective observational study. Patients were divided into subgroups according to the World Health Organization (WHO) age criteria (< 45 vs. ≥ 45 years). Group A included young ACLF patients (< 45 y), and group B included older ACLF patients (≥ 45 y). Young LC patients (< 45 y) were assigned to group C, and group D included older LC patients (≥ 45 y). Patients' clinical characteristics, demographics, biochemical factors, and model for end-stage liver disease (MELD) scores were compared for 24 weeks. RESULTS: Sixty-four ACLF patients and 59 LC patients were enrolled in this study. Compared with patients in groups B and C, patients in group A did not show significant superiority in terms of the levels of ALT, AST, TBIL, AFP, and PTA and MELD scores. However, the median decrease and cumulative decrease in the TBIL and ALT levels of patients in group C were larger than those of patients in group D after four weeks of UCMSC transfusions. For older patients (≥ 45 y), the cumulative decrease and the median decrease in the TBIL of ACLF patients were significantly greater than those of LC patients after UCMSC treatment. However, the median decrease in ALT levels of ACLF patients was significantly greater than that of LC patients during UCMSC treatment, and the cumulative decrease in ALT levels of ACLF patients was significantly greater than that of LC patients at all time points. CONCLUSION: The therapeutic effects of UCMSCs for HBV-related acute-on-chronic liver failure and liver cirrhosis varied partly by patient age. Assessing patient age is necessary prior to UCMSC clinical use.

Design and Discovery of Natural Cyclopeptide Skeleton Based Programmed Death Ligand 1 Inhibitor as Immune Modulator for Cancer Therapy.

Blockade of immune checkpoint PD-1/PD-L1 facilitates the rescue of immune escapes of tumor cells. Though various monoclonal antibodies have been approved for clinical therapy, the development of small molecular inhibitors lags behind antibodies partially owing to the challenges of protein-protein interaction (PPI) blocker design. In this work, we adopted the skeleton of natural cyclopeptidic antibiotics gramicidin S as the start point for PD-1/PD-L1 inhibitor exploring and discovered a series of novel cyclopeptides that could interfere with the PPI of PD-1/PD-L1 based on several rounds of structural design and optimization. The representative active cyclopeptide 66 can bind two PD-L1 and efficiently block the PD-1/PD-L1 interaction, recruit the immune cells to the tumor cells, enhance their killing against tumor cells by promoting the release of granzyme B and perforin, and display significant CD8+ T cell-dependent tumor suppression activity in vivo.

Enhanced therapeutic effects of umbilical cord mesenchymal stem cells after prolonged treatment for HBV-related liver failure and liver cirrhosis.

BACKGROUND: Umbilical cord mesenchymal stem cells (UCMSCs) have been demonstrated to have good therapeutic effects in the treatment of HBV-related liver diseases. However, the therapeutic effect of UCMSCs on HBV-related liver failure and liver cirrhosis and the variations in the efficacy of UCMSCs after different treatment courses remain poorly understood. Therefore, this study was designed to answer these two questions. METHODS: This was an observational study that retrospectively considered a 3-year period during which 513 patients who received stem cell infusion and met the criteria of hepatic failure and liver cirrhosis were identified from the databases of the Third Affiliated Hospital of Sun Yat-sen University. The eligible patients were categorized into the liver failure group and liver cirrhosis group. The two groups were divided into different subgroups according to the duration of stem cell therapy. In the liver failure group, group A received more than 4 weeks and group B received less than 4 weeks of stem cell therapy. In the liver cirrhosis group, patients who received more than 4 weeks of stem cell therapy belonged to group C, and the patients in group D received less than 4 weeks of stem cell therapy. The patients were followed up for 24 weeks. The demographics, clinical characteristics, biochemical factors, and model for end-stage liver disease (MELD) scores were recorded and compared among different groups. RESULTS: A total of 64 patients met the criteria for liver failure, and 59 patients met the criteria for liver cirrhosis. After UCMSC treatment, the levels of alanine aminotransferase (ALT), glutamic-oxaloacetic transaminase (AST), and total bilirubin (TBIL) at all postbaseline time points were significantly lower than those at baseline in the liver failure group and liver cirrhosis group; the prothrombin activity (PTA) and MELD scores gradually improved in only the liver failure group. Four weeks after UCMSC treatment, patients who received prolonged treatment with UCMSCs had a larger decrease in TBIL levels than patients who terminated treatment with UCMSCs. After more than 4 weeks of UCMSC treatment, there were no statistically significant differences in the changes in ALT, AST, TBIL, and PTA values and MELD scores between patients with liver failure who received prolonged treatment with UCMSCs and patients with liver cirrhosis who received prolonged treatment with UCMSCs at any time point. However, the median decrease and cumulative decrease in the TBIL level of patients with liver failure with a standard 4-week treatment course were larger than those of patients with liver cirrhosis with a standard 4-week treatment course. CONCLUSION: Peripheral infusion of UCMSCs showed good therapeutic effects for HBV-related liver failure and liver cirrhosis. Prolonging the treatment course can increase the curative effect of UCMSCs for end-stage liver disease, especially for patients with cirrhosis.

KIF15 facilitates gastric cancer via enhancing proliferation, inhibiting apoptosis, and predict poor prognosis.

BACKGROUND: Kinesin superfamily proteins (KIFs) can transport membranous organelles and protein complexes in an ATP-dependent manner. Kinesin family member 15 (KIF15) is overexpressed in various cancers. However, the function of KIF15 in gastric cancer (GC) is still unclear. METHODS: GC patients' data from The Cancer Genome Atlas (TCGA) were analyzed by bioinformatics methods. The expression of KIF15 was examined in GC and paracarcinoma tissues from 41 patients to verify the analysis results. The relationship between KIF15 expression and clinical characteristics were also observed by bioinformatics methods. Kaplan-Meier survival analysis of 122 GC patients in our hospital was performed to explore the relationship between KIF15 expression levels and GC patients' prognosis. KIF15 was downregulated in GC cell lines AGS and SGC-7901 by transfecting a lentivirus-mediated shRNA plasmid targeting KIF15. In vitro, GC cell proliferation and apoptosis were detected by MTT assay, colony formation assay, and Annexin V-APC staining. In vivo, xenograft experiments were used to verify the in vitro results. Furthermore, Human Apoptosis Antibody Array kit was used to screen possible targets of KIF15 in GC cell lines. RESULTS: The bioinformatics results showed that KIF15 expression levels were higher in GC tissues than in normal tissues. IHC showed same results. High expression of KIF15 was statistical correlated with high age and early histologic stage. Kaplan-Meier curves indicated that high KIF15 expression predict poor prognosis in patients with GC. MTT assay and colony formation assay showed that KIF15 promote GC cell proliferation. Annexin V-APC staining found that KIF15 can inhibit GC cell apoptosis. Xenograft experiments reveal that downregulating KIF15 can inhibit GC tumor growth and promote GC apoptosis. Through detection of 43 anti-apoptotic proteins by the Human Apoptosis Antibody Array kit, it was confirmed that knocking down KIF15 can reduce seven anti-apoptotic proteins expression. CONCLUSIONS: Taken together, our study revealed a critical role for KIF15 to inhibit GC cell apoptosis and promote GC cell proliferation. KIF15 may decrease anti-apoptotic proteins expression by regulating apoptosis pathways. High expression of KIF15 predicts a poor prognosis in patients with GC. KIF15 might be a novel prognostic biomarker and a therapeutic target for GC.

Degradation of intracellular TGF-ß1 by PROTACs efficiently reverses M2 macrophage induced malignant pathological events.

The first proteolysis targeting chimeras for the intracellular elimination of transforming growth factor-ß1 (TGF-ß1), which contributes to various diseases, are described. The appropriately designed DT-6 could efficiently degrade intracellular TGF-ß1, and inhibit M2 macrophage induced epithelial to mesenchymal transition and invasive migration of cancer cells.

Effects of over-load iron on nutrient digestibility, haemato-biochemistry, rumen fermentation and bacterial communities in sheep.

There is a risk of iron overload in grazing livestock. However, the effects on nutrient absorption and rumen function induced by excessive iron have not been well understood. Therefore, the purpose of present study was to investigate the impact of over-load iron on growth performance, nutrient digestibility, blood biochemistry, rumen fermentation and bacterial communities in sheep. Twenty-four German Mutton Merino cross-bred sheep with weight (42.66 ± 2.34 kg BW) were randomly divided into 4 groups, each with 6 replicates and 1 sheep per replicate. The basal diet consisted of 60% Leymus chinensis hay and 40% concentrate. The sheep in 4 groups were fed the basal diets supplemented with 50 (Control), 500 (T1), 1,000 (T2) and 1,500 (T3) mg Fe/kg as ferrous sulphate monohydrate (FeSO4 ·H2 O) respectively. And the actual contents of iron in the diet were determined to be 457.68 (control), 816.42 (T1), 1,256.78 (T2) and 1,725.63 (T3) mg/kg respectively. The experiment lasted 62 days including a 7-day metabolism trial. During the whole experiment, the digestibility of dry matter, organic matter, neutral detergent fibre and acid detergent fibre showed a quadratic increase with increasing over-load iron levels (p < .05), and maximum responses were found with 500 mg/kg supplementation. However, the response of total VFA concentration showed a quadratic decrease, as did the concentrations of propionate, butyrate and valerate (p < .05). Serum total iron-binding capacity on day 30 showed a quadratic decrease with the increase in high-dose iron, while the serum iron content increased linearly at day 60 (p < .05). Excessive iron resulted in the change in bacterial communities. An increase in over-load iron linearly decreased the abundance of bacteria in the phylum Bacteroidetes (p < .05), but linearly increased the Firmicutes (p = .037) and Proteobacteria (p = .018). In addition, there was a quadratic effect (p = .003) on the Fibrobacteres, which was higher in the 500 and 1,000 mg/kg Fe-supplemented groups. At the genus level, there were quadratic effects on the abundances of Selenomonas_1 (p = .023) and Ruminococcaceae_UCG-014 (p = .016). Furthermore, feeding of iron linearly increased the relative abundances of Succiniclasticum and Succinivibrionaceae_UCG-002 (p < .05). These results indicate that increasing ferrous sulphate monohydrate in diets had no negative impact on the growth performance, but it changed nutrient digestibility, blood iron parameters, rumen fermentation and bacterial communities in sheep.

Furowanin A Exhibits Antiproliferative and Pro-Apoptotic Activities by Targeting Sphingosine Kinase 1 in Osteosarcoma.

Osteosarcoma (OS) is one of the most common malignant bone tumors among children and young adults. Furowanin A (Fur A), one of the active ingredients of Millettia pachycarpa Benth, has been found to exert pro-apoptotic activity in human leukemia cells. This study is designed to evaluate the efficacy of Fur A against OS. The effect of Fur A on cell viability was assessed by Cell Counting Kit-8 (CCK-8) assay. Western blotting and quantitative real-time PCR (qRT-PCR) were performed to determine the protein and mRNA level of sphingosine kinase 1 (SphK1), respectively. To validate the role of SphK1 in the pro-apoptotic activity of Fur A, overexpressing SphK1 vector and siRNA targeting SphK1 were utilized to transfect OS cells. Moreover, an OS xenograft murine model was used to analyze the therapeutic efficacy of Fur A in vivo. Fur A treatment led to a dose-dependent decrease in the number of viable cells. It also exhibited antiproliferative activity and significantly promoted apoptotic cell death in OS cell lines. Our results showed that the anticancer activity of Fur A was associated with downregulation of SphK1 and inactivation of its downstream signaling. The mediatory role of SphK1 was validated when the pro-apoptotic activity of Fur A was significantly blocked by SphK1 overexpression, while SphK1 knockdown sensitized the OS cells to Fur A. We concluded that Fur A can exhibit anti-growth and pro-apoptotic activities in vitro and in vivo in OS by downregulating SphK1. Our study highlights the possibility of utilizing Fur A as a chemotherapeutic agent in the treatment of OS. Anat Rec, 302:1941-1949, 2019. © 2019 American Association for Anatomy.

Synthesis and evaluation of anticancer activity of BOC26P, an ortho-aryl chalcone sodium phosphate as water-soluble prodrugs in vitro and in vivo.

Major limitations of chalcones as clinical anticancer agents are water insolubility and poor bioavailability, which may be improved by a classic phosphate prodrug strategy that targets non-specific alkaline phosphatase (ALP) for releasing the parent drug in vivo. In this study, we found that BOC26P, a phosphate prodrug of chalcone OC26, exhibits excellent water solubility and improved plasma concentration in vivo by either i.v. or p.o. compared with the parent drug. In pace with decreased inhibitory activity of BOC26P against microtubule polymerization in vitro and in cells, the antiproliferative activity of BOC26P is attenuated in A549 and HLF cells. However, the antitumor effect of BOC26P increases in an A549 xenograft model as compared to the equimolar concentration of OC26, suggesting that complex tumor microenvironment would be another important influence factor to regulate the antitumor activity of BOC26Pin vivo. In conclusion, these observations showed that the traditional phosphate prodrug strategy would be a promising and easy method to increase water solubility and anticancer activity of chalcones for the clinical developments of anticancer agents.

Identification of 4-arylidene curcumin analogues as novel proteasome inhibitors for potential anticancer agents targeting 19S regulatory particle associated deubiquitinase.

The proteasomal 19S regulatory particle (RP) associated deubiquitinases (DUBs) have attracted much attention owing to their potential as a therapeutic target for cancer therapy. Identification of new entities against 19S RP associated DUBs and illustration of the underlying mechanisms is crucial for discovery of novel proteasome blockers. In this study, a series of 4-arylidene curcumin analogues were identified as potent proteasome inhibitor by preferentially blocking deubiquitinase function of proteasomal 19S RP with moderate 20S CP inhibition. The most active compound 33 exhibited a major inhibitory effect on 19S RP-associated ubiquitin-specific proteases 14, along with a minor effect on ubiquitin C-terminal hydrolase 5, which resulted in dysfunction of proteasome, and subsequently accumulated ubiquitinated proteins (such as IκB) in several cancer cells. Remarkably, though both 19S RP and 20S CP inhibition induced significantly endoplasmic reticulum stress and triggered caspase-12/9 pathway activation to promote cancer cell apoptosis, the 19S RP inhibition by 33 avoided slow onset time, Bcl-2 overexpression, and PERK-phosphorylation, which contribute to the deficiencies of clinical drug Bortezomib. These systematic studies provided insights in the development of novel proteasome inhibitors for cancer treatment.

Cholesteryl Ester Transfer Protein Intimately Involved in Dyslipidemia-Related Susceptibility to Cognitive Deficits in Type 2 Diabetic Patients.

BACKGROUND: Cholesteryl ester transfer protein (CETP) is involved in diabetic dyslipidemia. OBJECTIVE: We aim to test the hypothesis that CETP might be of importance in mediating dyslipidemia-related susceptibility to cognitive deficits in diabetic patients. METHODS: We recruited 190 type 2 diabetic patients and divided them into two groups according to the Montreal Cognitive Assessment (MoCA) score. The association between CETP and cognitive decline was analyzed with logistic regression and stratification. RESULTS: There were 110 diabetic patients with mild cognition impairment (MCI) and 80 healthy cognition subjects as controls. Dyslipidemia is more common among diabetic patients with MCI; they had a significant increase of serum CETP concentrations, which was negatively correlated with MoCA (r = -0.638; p < 0.001). Negative correlations were also found between the serum CETP concentration with the Auditory Verbal Learning Test (r = -0.266; p = 0.008), indicating memory deficit. Logistic regression analysis revealed that CETP concentration was an independent factor of diabetic MCI (p < 0.001). Further stratification study showed that high serum levels of CETP was an independent risk factor of MCI in diabetic patients with a low density lipoproteins level ≥2.59 mmol/L, or high density lipoproteins level ≤1.0 mmol/L for men and ≤1.3 mmol/L for women, or TG level ≥1.7 mmol/L, after adjusting for age, sex, education, and glucose control (all ps < 0.05). CONCLUSIONS: CETP was intimately involved in dyslipidemia-related susceptibility to cognitive decline, especially memory function in type 2 diabetic patients.

Intensified low-density lipoprotein-cholesterol target of statin therapy and cancer risk: a meta-analysis.

BACKGROUND: This study aimed to investigate the relationship between an intensified low-density lipoprotein-cholesterol (LDL-c) target of statin therapy and cancer risk. METHODS: Data from PUBMED, EMBASE, and the Cochrane Central Register of Controlled Trials as of September 2014 were searched for randomized controlled trials on statins. An intensified LDL-c target of <2.59 mmol/L (100 mg/dL) or a relative LDL-c reduction by at least 30% of the baseline was the primary criterion for all the trials that were included in this meta-analysis. The I(2) statistic was used to measure heterogeneity among the trials, and risk estimates were calculated for cancer incidence in this random-effect meta-analysis. RESULTS: Nine eligible studies were identified with 59,571 participants, of whom 5379 developed cancer during the follow-up period (2691 were given statins and 2688 were given control treatment). The intensified LDL-c target of statin therapy did not affect cancer incidence (odds ratio, 1.00; 95% confidence interval, 0.94 - 1.06; I(2) = 1.6%, p = 0.42), which included some common cancers. Subgroup analysis showed that neither the chemical properties nor the variety of the statins accounted for the residual variation in risk. CONCLUSIONS: The intensified LDL-c target of statin therapy had no effect on the overall incidence of cancer, including some common cancers. Therefore, intensified statin therapy does not need to be changed among adult clinical patients.

A Novel Adeno-Associated Virus-Based Genetic Vaccine Encoding the Hepatitis C Virus NS3/4 Protein Exhibits Immunogenic Properties in Mice Superior to Those of an NS3-Protein-Based Vaccine.

More than 170 million individuals worldwide are infected with hepatitis C virus (HCV), and up to an estimated 30% of chronically infected individuals will go on to develop progressive liver disease. Despite the recent advances in antiviral treatment of HCV infection, it remains a major public health problem. Thus, development of an effective vaccine is urgently required. In this study, we constructed novel adeno-associated virus (AAV) vectors expressing the full-length NS3 or NS3/4 protein of HCV genotype 1b. The expression of the NS3 or NS3/4 protein in HepG2 cells was confirmed by western blotting. C57BL/6 mice were intramuscularly immunised with a single injection of AAV vectors, and the resultant immune response was investigated. The AAV2/rh32.33.NS3/4 vaccine induced stronger humoral and cellular responses than did the AAV2/rh32.33.NS3 vaccine. Our results demonstrate that AAV-based vaccines exhibit considerable potential for the development of an effective anti-HCV vaccine.

An investigation into the therapeutic effects of statins with metformin on polycystic ovary syndrome: a meta-analysis of randomised controlled trials.

OBJECTIVES: To investigate the therapeutic effects of statins with metformin on polycystic ovary syndrome (PCOS). SETTINGS: Endocrinology department. PARTICIPANTS: MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials were searched until October 2014. Studies comparing statins and placebo, as well as the combination of statins and metformin and metformin alone, were included in the analysis. INTERVENTIONS: Data were independently extracted by two researchers; any convergence was resolved by a third reviewer. PRIMARY AND SECONDARY OUTCOME MEASURES: The following properties were extracted from the qualified trials to identify the effects of statins: clinical variables, metabolic characteristics, hormone outcomes, sign of inflammation, glucose parameters and insulin outcomes. RESULTS: Data from four trials comparing statin and metformin with metformin alone were analysed. The combination of statins and metformin decreases the levels of C reactive protein (standardised mean difference (SMD) -0.91; 95% CI -1.81 to -0.02; p=0.046), triglyceride (SMD -1.37; 95% CI -2.46 to -0.28; p=0.014), total cholesterol (SMD -1.28; 95% CI -1.59 to -0.97; p=0.000) and low-density lipoprotein (LDL) cholesterol (SMD -0.74; 95% CI -1.03 to -0.44; p=0.000). However, the combined therapy fails to reduce fasting insulin (SMD -0.92; 95% CI -2.07 to 0.24; p=0.120), homeostasis model assessment of insulin resistance (SMD -1.15; 95% CI -3.36 to 1.06; p=0.309) and total testosterone (SMD -1.12; 95% CI -2.29 to 0.05; p=0.061). Analysis of the five trials comparing statin with placebo shows that statin monotherapy reduces LDL-cholesterol, triglyceride and total cholesterol. CONCLUSIONS: Combined statin and metformin therapy can improve lipid and inflammation parameters, but cannot effectively improve insulin sensitivity and reduce hyperandrogenism in women with PCOS. A large-scale randomised controlled study must be conducted to ascertain the long-term effects of the therapy.