Metabolome-Wide Mendelian Randomization Assessing the Causal Role of Serum and Cerebrospinal Metabolites in Traumatic Brain Injury.

Previous studies have identified metabolites as biomarkers or potential therapeutic targets for traumatic brain injury (TBI). However, the causal association between them remains unknown. Therefore, we investigated the causal effect of serum metabolites and cerebrospinal fluid (CSF) metabolites on TBI susceptibility through Mendelian randomization (MR). Genetic variants related to metabolites and TBI were extracted from a corresponding genome-wide association study (GWAS). Causal effects were estimated through the inverse variance weighted approach, supplemented by a weighted median, weight mode, and the MR-Egger test. In addition, sensitivity analyses were further performed to evaluate the stability of the MR results, including the MR-Egger intercept, leave-one-out analysis, Cochrane's Q-test, and the MR-PRESSO global test. Metabolic pathway analysis was applied to uncover the underlying pathways of the significant metabolites in TBI. In blood metabolites, substances such as 4-acetaminophen sulfate and kynurenine showed positive links, whereas beta-hydroxyisovalerate and creatinine exhibited negative correlations. CSF metabolites such as N-formylanthranilic acid were positively related, while kynurenate showed negative associations. The metabolic pathway analysis highlighted the potential biological pathways involved in TBI. Of these 16 serum metabolites, 11 CSF metabolites and metabolic pathways may serve as useful circulating biomarkers in clinical screening and prevention, and may be candidate molecules for the exploration of mechanisms and drug targets.

Causal links between gut microbiomes, cytokines and risk of different subtypes of epilepsy: a Mendelian randomization study.

Objective: Recent research suggests a potential link between the gut microbiome (GM) and epilepsy. We undertook a Mendelian randomization (MR) study to determine the possible causal influence of GM on epilepsy and its various subtypes, and explore whether cytokines act as mediators. Methods: We utilized Genome-Wide Association Study (GWAS) summary statistics to examine the causal relationships between GM, cytokines, and four epilepsy subtypes. Furthermore, we assessed whether cytokines mediate the relationship between GM and epilepsy. Significant GMs were further investigated using transcriptomic MR analysis with genes mapped from the FUMA GWAS. Sensitivity analyses and reverse MR were conducted for validation, and false discovery rate (FDR) correction was applied for multiple comparisons. Results: We pinpointed causal relationships between 30 GMs and various epilepsy subtypes. Notably, the Family Veillonellaceae (OR:1.03, 95%CI:1.02-1.05, p = 0.0003) consistently showed a strong positive association with child absence epilepsy, and this causal association endured even after FDR correction (p-FDR < 0.05). Seven cytokines were significantly associated with epilepsy and its subtypes. A mediating role for cytokines has not been demonstrated. Sensitivity tests validated the primary MR analysis outcomes. Additionally, no reverse causality was detected between significant GMs and epilepsy. Of the mapped genes of notable GMs, genes like BLK, FDFT1, DOK2, FAM167A, ZSCAN9, RNGTT, RBM47, DNAJC21, SUMF1, TCF20, GLO1, TMTC1, VAV2, and RNF14 exhibited a profound correlation with the risk factors of epilepsy subtypes. Conclusion: Our research validates the causal role of GMs and cytokines in various epilepsy subtypes, and there has been no evidence that cytokines play a mediating role between GM and epilepsy. This could provide fresh perspectives for the prevention and treatment of epilepsy.

Comparative analysis of immunological changes following realgar and arsenic trioxide treatments in a murine model of myelodysplastic syndrome.

BACKGROUND: Myelodysplastic syndrome (MDS) is a prevalent hematological neoplastic disorder in clinics and its immunopathogenesis has garnered growing interest. Oral and intravenous arsenic agents have long been used to treat hematological malignancies. The main component of oral arsenic is realgar (arsenic disulfide), while arsenic trioxide is the main component of intravenous arsenic. METHODS: This study aimed to assess the effects of ATO and Realgar on the enhancement of peripheral blood, drug safety, and T cell immune status in the NUP98-HOXD13 (NHD13) mice model of MDS, specifically in the peripheral blood, spleen, and liver. RESULTS: The study findings indicate that realgar and arsenic trioxide (ATO) can improve peripheral hemogram in mice, whereas realgar promotes higher peripheral blood cell production than ATO. Furthermore, the clinical administration method and dose did not cause significant toxicity or side effects and thus can be considered safe. Coexistence and interconversion of hyperimmune function and immunosuppression in mice were also observed in this study. In addition, there were interactions between immune cells in the peripheral blood, spleen, and liver to regulate the immune balance of the body and activate immunity via T-cell activation. CONCLUSION: In summary, oral and intravenous arsenic agents are beneficial in improving peripheral hemogram and immunity in mice.

Enhancing Efficacy and Quality of Life in Patients with Herpes Zoster Infection in Hairy Cell Leukemia.

Hairy cell leukemia (HCL) is an infrequent and persistent B-cell inert lymphoid leukemia. In this study, we present the case of a 71-year-old female patient with a previous diagnosis of variant HCL who experienced a severe herpes zoster infection leading to an extensive skin eruption. The patient's initial diagnosis of HCL occurred 7 years ago, and she underwent treatment with cladribine, interferon, COP (cyclophosphamide, vincristine, and prednisone), benztropine tablets + clarithromycin dispersible, and ibrutinib. Immune disorders resulting from repeated prior chemotherapy and targeted therapy may potentially precipitate herpes zoster infection. Despite an initial two-week period of unresponsiveness to antivirals and nerve nutrition treatments, the introduction of topical Coptis liquid to the treatment regimen yielded significant efficacy. This case report underscores the potential of Chinese medicine as an adjunct to conventional antiviral therapy in the management of herpes zoster infection in immunocompromised patients. This treatment protocol has the potential to enhance efficacy, enhance quality of life, and serve as a more robust foundation for clinical diagnosis and improved treatments.

Adjunctive cariprazine as a novel effective strategy for treating major depressive disorder: A systematic review and meta-analysis.

BACKGROUND: Cariprazine has been approved by the Food and Drug Administration for treating bipolar depression and as an adjunctive treatment for Major Depressive Disorder (MDD). However, it remains unclear about its pharmacological efficacy in treating MDD. Therefore, a meta-analysis was conducted to investigate the adjunctive use of cariprazine in MDD. METHODS: Electronic databases were searched for eligible studies evaluating the efficacy and safety of cariprazine in patients with MDD up to November 15, 2023. The changes in Montgomery-Asberg Depression Rating Scale (MADRS) score and incidence of adverse events (AEs), which represents of efficacy and tolerability, are considered as the main outcomes. RESULTS: A total of 3066 patients with MDD included in all across 5 RCTs. With regard to MADRS score, cariprazine group showed better results than control group (SMD = -0.12, 95% CI -0.19 to -0.04, P = 0.002, 5 RCTs, n = 3066). Cariprazine, meanwhile, improved the MADRS response (RR = 1.19, 95% CI 1.08 to 1.31, P = 0.0004, 5 RCTs, n = 3066). For safety outcomes, statistical difference was observed in AEs (RR = 1.26, 95% CI 1.18 to 1.35, P < 0.00001, 5 RCTs, n = 3077). The suicide ideation and SAEs showed no statistical difference between two groups. CONCLUSION: Cariprazine demonstrated antidepressant effect as an augmentation therapy in treating MDD. Meanwhile, the tolerability of it was acceptable as an adjunctive treatment. However, studies with larger sample sizes are still needed to explore the optimal dosage.

Causal association of leisure sedentary behavior and cervical spondylosis, sciatica, intervertebral disk disorders, and low back pain: a Mendelian randomization study.

Background: Some studies suggest sedentary behavior is a risk factor for musculoskeletal disorders. This study aimed to investigate the potential causal association between leisure sedentary behavior (LSB) (including television (TV) viewing, computer use, and driving) and the incidence of sciatica, intervertebral disk degeneration (IVDD), low back pain (LBP), and cervical spondylosis (CS). Methods: We obtained the data of LSB, CS, IVDD, LBP, sciatica and proposed mediators from the gene-wide association studies (GWAS). The causal effects were examined by Inverse Variance Weighted (IVW) test, MR-Egger, weighted median, weighted mode and simple mode. And sensitivity analysis was performed using MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) and MR-Egger intercept test. Multivariable MR (MVMR) was conducted to investigate the independent factor of other LSB; while two-step MR analysis was used to explore the potential mediators including Body mass index (BMI), smoking initiation, type 2 diabetes mellitus (T2DM), major depressive disorder (MDD), schizophrenia, bipolar disorder between the causal association of LSB and these diseases based on previous studies. Results: Genetically associated TV viewing was positively associated with the risk of CS (OR = 1.61, 95%CI = 1.25 to 2.07, p = 0.002), IVDD (OR = 2.10, 95%CI = 1.77 to 2.48, p = 3.79 × 10-18), LBP (OR = 1.84, 95%CI = 1.53 to 2.21, p = 1.04 × 10-10) and sciatica (OR = 1.82, 95% CI = 1.45 to 2.27, p = 1.42 × 10-7). While computer use was associated with a reduced risk of IVDD (OR = 0.66, 95%CI = 0.55 to 0.79, p = 8.06 × 10-6), LBP (OR = 0.49, 95%CI = 0.40 to 0.59, p = 2.68 × 10-13) and sciatica (OR = 0.58, 95%CI = 0.46 to 0.75, p = 1.98 × 10-5). Sensitivity analysis validated the robustness of MR outcomes. MVMR analysis showed that the causal effect of TV viewing on IVDD (OR = 1.59, 95%CI = 1.13 to 2.25, p = 0.008), LBP (OR = 2.15, 95%CI = 1.50 to 3.08, p = 3.38 × 10-5), and sciatica (OR = 1.61, 95%CI = 1.03 to 2.52, p = 0.037) was independent of other LSB. Furthermore, two-step MR analysis indicated that BMI, smoking initiation, T2DM may mediate the causal effect of TV viewing on these diseases. Conclusion: This study provides empirical evidence supporting a positive causal association between TV viewing and sciatica, IVDD and LBP, which were potentially mediated by BMI, smoking initiation and T2DM.

Causal associations of Insomnia and postpartum depression: a two-sample mendelian randomization study.

BACKGROUND: Postpartum depression (PPD), a prevalent social-mental condition, impacts the mother and the newborn and several facets of their lives. It has been suggested that insomnia is related to both the occurrence and progression of PPD. However, because of lingering confounding and bias, it is impossible to determine the cause of this connection using observational analysis. In this study, we evaluate the causal importance of insomnia on postpartum depression using Mendelian randomization (MR). METHODS: Utilizing summary data from genome-wide association studies (GWAS), a two-sample MR study was conducted. A GWAS dataset of IEU study of the United Kingdom Biobank phenotypes comprising 462,341 people of European heritage yielded 38 single-nucleotide polymorphisms (SNPs) for insomnia. The PPD data were provided by the FinnGen project and comprised 7604 cases and 59,601 controls. Inverse variance weighting (IVW) was utilized for the primary MR analysis, with weighted median and MR-Egger as sensitivity analyses. RESULTS: As a result, we found that genetically predicted insomnia was positively associated with postpartum depression. The odds ratios (OR) of PPD were 1.849 (95% (confidence interval) CI 1.011-3.381; p = 0.046). CONCLUSION: For the first time, the causative role of sleeplessness for postpartum depression has been extensively evaluated in the current two-sample MR investigation. Our findings show that insomnia and PPD are related causally.

GRP78 inhibitor HA15 increases the effect of Bortezomib on eradicating multiple myeloma cells through triggering endoplasmic reticulum stress.

Bortezomib (BTZ), a selective proteasome inhibitor, exhibits a significant efficacy in the therapy of multiple myeloma (MM) partly through triggering endoplasmic reticulum (ER) stress-dependent apoptosis. However, sensitivity to BTZ varies greatly among patients. ER stress functions as a double-edged sword in regulating cell survival depending on cell context and ER stress extent. The major aim of this study was to investigate whether GRP78 inhibitor, HA15, increased the therapeutic effect of BTZ on MM to through further increasing ER stress and shifting the balance towards cell apoptosis. The biological role of BTZ and HA15 was assessed using Cell counting kit- (CCK-) 8, colony formation, and Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labelling (TUNEL) assay. We found that BTZ combined with HA15 remarkably decreased MM cell viability more effective than BTZ monotherapy, though low dose of HA15 did not exhibit a significant cytotoxicity to MM cells. BTZ combined with HA15 also repressed colony formation ability of MM cell and accelerated MM cell apoptosis compared with BTZ monotherapy. Mechanistically, HA15 synergized with BTZ to trigger ER stress, as evidence by significantly increased expression of ER stress markers (GRP78, ATF4, CHOP, and XBP1). Importantly, unfolded protein response (UPR) inhibitor significantly damaged the effect of BTZ combined with HA15 on accelerating MM cell death. In vivo, combination treatment with BTZ and HA15 inhibited tumor growth more effective than BTZ alone, whereas these effects were blocked by UPR inhibitor. Taken together, these results demonstrate that ER stress is a critical pathway in regulating MM cell survival, and that combination treatment with BTZ and HA15 may be an effective strategy to treat MM patients that fail to respond to BTZ monotherapy.

Determination of Cuproptosis-related Subtypes, Development of a Prognostic Model, and Characterization of Tumor Microenvironment Infiltration in Acute Myeloid Leukemia.

BACKGROUND/AIM: Acute myeloid leukemia (AML) is a severe malignancy of the bone marrow marked by an abnormal accumulation of bone marrow precursors. Cuproptosis is a recently identified type of copper-dependent regulatory cell apoptosis that relies on mitochondrial respiration. However, its participation in the development of AML remains unclear. This study analyzed the association between cuproptosis-related genes and the prognosis of AML patients. MATERIALS AND METHODS: Cases of AML were acquired from TCGA, GEO, and TARGET and the molecular subgroups characterized by genes associated with cuproptosis, besides the associated cell infiltration of the tumor microenvironment (TME) were investigated. The cuproptosis score was developed using the minor absolute shrinkage and selection operator (LASSO) tool to evaluate the cuproptosis features of a single tumor sample. RESULTS: Two distinct molecular subgroups related to cuproptosis were discovered in AML with different prognoses. The cellular infiltration assay of TME showed immunological heterogeneity between the two subtypes. The cuproptosis score predicted tumor subgroups, immunity, and prognosis. A small cuproptosis value was marked by a good prognosis, whereas the anti-PD-1/PD-L1 immunotherapy group suggested the same cuproptosis group was related to an elevated immunotherapy potency. CONCLUSION: The cuproptosis score is a biomarker important for determining the molecular subgroups, prognosis, TME cell infiltration features, and immunotherapeutic efficacy of individuals with leukemia.

Exploring underlying mechanism of artesunate in treatment of acute myeloid leukemia using network pharmacology and molecular docking

Background Acute myeloid leukemia (AML) is a highly heterogeneous hematological cancer. The current diagnosis and therapy model of AML has gradually shifted to personalization and accuracy. Artesunate, a member of the artemisinin family, has anti-tumor impacts on AML. This research uses network pharmacology and molecular docking to anticipate artesunate potential mechanisms of action in the therapy of AML. Methods Screening the action targets of artesunate through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), PubChem, and Swiss Target Prediction databases; The databases of Online Mendelian Inheritance in Man (OMIM), Disgenet, GeneCards, and Drugbank were utilized to identify target genes of AML, and an effective target of artesunate for AML treatment was obtained through cross-analysis. Protein–protein interaction (PPI) networks are built on the Cytoscape platform. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on the relevant targets using R software. Finally, using molecular docking technology and Pymol, we performed verification of the effects of active components and essential targets. Results Artesunate 30 effective targets for treating AML include CASP3, EGFR, MAPK1, and STAT3, four targeted genes that may have a crucial function in disease management. The virus infection-related pathway (HeptatisB (HBV), Human papillomavirus (HPV), Epstein-Barr virus (EBV) infection and etc.), FoxO, viral carcinogenesis, and proteoglycans in cancer signaling pathways have all been hypothesized to be involved in the action mechanism of GO, which is enriched in 2044 biological processes, 125 molecular functions, 209 cellular components, and 106 KEGG pathways (AU)

Redox-Responsive Dendrimer Nanogels Enable Ultrasound-Enhanced Chemoimmunotherapy of Pancreatic Cancer via Endoplasmic Reticulum Stress Amplification and Macrophage Polarization.

Developing a multifunctional nanoplatform to achieve efficient theranostics of tumors through multi-pronged strategies remains to be challenging. Here, the design of the intelligent redox-responsive generation 3 (G3) poly(amidoamine) dendrimer nanogels (NGs) loaded with gold nanoparticles (Au NPs) and chemotherapeutic drug toyocamycin (Au/Toy@G3 NGs) for ultrasound-enhanced cancer theranostics is showcased. The constructed hybrid NGs with a size of 193 nm possess good colloidal stability under physiological conditions, and can be dissociated to release Au NPs and Toy in the reductive glutathione-rich tumor microenvironment (TME). The released Toy can promote the apoptosis of cancer cells through endoplasmic reticulum stress amplification and cause immunogenic cell death to maturate dendritic cells. The loaded Au NPs can induce the conversion of tumor-associated macrophages from M2-type to antitumor M1-type to remodulate the immunosuppressive TME. Combined with antibody-mediated immune checkpoint blockade, effective chemoimmunotherapy of a pancreatic tumor mouse model can be realized, and the chemoimmunotherapy effect can be further ultrasound enhanced due to the sonoporation-improved tumor permeability of NGs. The developed Au/Toy@G3 NGs also enable Au-mediated computed tomography imaging of tumors. The constructed responsive dendrimeric NGs tackle tumors through a multi-pronged chemoimmunotherapy strategy targeting both cancer cells and immune cells, which hold a promising potential for clinical translations.

Ultrasound-enhanced theranostics of orthotopic breast cancer through a multifunctional core-shell tecto dendrimer-based nanomedicine platform.

Design of multifunctional nanoplatforms combined with ultrasound-targeted microbubble destruction (UTMD) technology for enhanced tumor accumulation is feasible to solve the bottleneck of theranostics. Herein, we present the development of zwitterion-modified gadolinium (Gd)-chelated core-shell tecto dendrimers (CSTDs) as a nanomedicine platform (PCSTD-Gd) for enhanced magnetic resonance (MR) imaging-guided chemo-gene therapy of orthotopic breast cancer with the assistance of UTMD. In our design, CSTDs synthesized via supramolecular recognition of ß-cyclodextrin and adamantane were covalently linked with tetraazacyclododecane tetraacetic acid-Gd(III) chelators, modified with 1,3-propane sultone to achieve good protein-resistance property, and used for co-delivery of an microRNA 21 inhibitor (miR 21i) and an anticancer drug doxorubicin (DOX). The overall design is quite advantageous and cooperative. The CSTDs with a greater size than single-generation core dendrimers have amplified the enhanced permeability and retention effect for better passive tumor targeting, with a larger r1 relaxivity for sensitive MR imaging and serum-enhanced gene delivery efficiency due to the better compaction ability as well as the protein resistance ability, and with larger interior space for improved drug loading. Through the unique design and the assistance of UTMD, the obtained PCSTD-Gd/DOX/miR 21i polyplexes enable enhanced MR imaging-guided combined chemo-gene therapy of an orthotopic breast cancer model in vivo.

Exploring underlying mechanism of artesunate in treatment of acute myeloid leukemia using network pharmacology and molecular docking.

BACKGROUND: Acute myeloid leukemia (AML) is a highly heterogeneous hematological cancer. The current diagnosis and therapy model of AML has gradually shifted to personalization and accuracy. Artesunate, a member of the artemisinin family, has anti-tumor impacts on AML. This research uses network pharmacology and molecular docking to anticipate artesunate potential mechanisms of action in the therapy of AML. METHODS: Screening the action targets of artesunate through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), PubChem, and Swiss Target Prediction databases; The databases of Online Mendelian Inheritance in Man (OMIM), Disgenet, GeneCards, and Drugbank were utilized to identify target genes of AML, and an effective target of artesunate for AML treatment was obtained through cross-analysis. Protein-protein interaction (PPI) networks are built on the Cytoscape platform. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on the relevant targets using R software. Finally, using molecular docking technology and Pymol, we performed verification of the effects of active components and essential targets. RESULTS: Artesunate 30 effective targets for treating AML include CASP3, EGFR, MAPK1, and STAT3, four targeted genes that may have a crucial function in disease management. The virus infection-related pathway (HeptatisB (HBV), Human papillomavirus (HPV), Epstein-Barr virus (EBV) infection and etc.), FoxO, viral carcinogenesis, and proteoglycans in cancer signaling pathways have all been hypothesized to be involved in the action mechanism of GO, which is enriched in 2044 biological processes, 125 molecular functions, 209 cellular components, and 106 KEGG pathways. Molecular docking findings revealed that artesunate was critically important in the therapy of AML due to its high affinity for the four primary disease targets. Molecular docking with a low binding energy yields helpful information for developing medicines against AML. CONCLUSIONS: Consequently, artesunate may play a role in multi-targeted, multi-signaling pathways in treating AML, suggesting that artesunate may have therapeutic potential for AML.

Efficacy and tolerability of zuranolone in patients with depression: a meta-analysis of randomized controlled trials.

Background: As a novel antidepressant drug, zuranolone has been initially applied in treating depression. This study investigated the efficacy and safety of its administration in patients with depression. Methods: The Embase, PubMed, and Cochrane library databases were searched for available studies up to 1 Nov 2023. The primary outcome was the change on day 15 depression severity scores compared to baseline. Secondary outcomes included remission and response rates on day 15. Safety outcomes included incidence of treatment-emergent adverse events (TEAEs) and individual AEs. Trial sequential analysis (TSA) was used to evaluate the ideal samplesize. Results: Six studies with 1884 patients were included. Zuranolone offered significantly greater changes in day 15 depression severity scores (mean difference = 2.43, 95% confidence interval [CI]: 1.36 to 3.49, p < 0.00001) compared to placebo; this was also observed at other time points. Differences in response (relative risk [RR] = 1.33, 95% CI: 1.15 to 1.54, p < 0.0001) and remission (RR = 1.46, 95% CI: 1.15 to 1.85, p = 0.002) rates were also statistically significant. For safety outcomes, zuranolone group showed more incidence of TEAE than the placebo group (RR: 1.15, 95% CI: 1.06 to 1.25, p = 0.0005, I 2 = 0%). As for individual AEs, significant differences were observed in dizziness (RR = 2.17, 95% CI: 1.22 to 3.86, p = 0.008) and somnolence (RR = 2.43, 95% CI: 1.35 to 4.37, p = 0.003. No significant difference was observed in other AEs. The result of TSA indicated that the cumulative curve crossed the conventional (Z = 1.96) boundary but not reach TSA boundary (RIS = 1910). Conclusion: Our findings suggest that zuranolone has a rapid short-term antidepressant effect during administration. Although more TEAEs were observed in zuranolone, most of them were slight and temporary. However, studies with larger sample sizes and longer follow-up are needed. Systematic Review Registration: https://inplasy.com/inplasy-2023-5-0104/, identifier INPLASY202350104.

Ultrasound-Induced Microbubble Cavitation Combined with miR-34a-Loaded Nanoparticles for the Treatment of Castration-Resistant Prostate Cancer.

Currently chemotherapy drugs are usually used as first-line treatments for castration-resistant prostate cancer (CRPC), but they are ineffective and accompanied by serious side effects. MicroRNA-34a (miR-34a) simultaneously targets multiple genes related to the cell apoptosis in CRPC cells without obvious side effects. It has shown great potential in the treatment of CRPC. Previous studies focused on miR-34a increasing the sensitivity of chemotherapy drugs to chemoresistant prostate cancer cells. There are few researches on miR-34a alone in the treatment of CRPC. But the macromolecular miR-34a is difficult to enter the cell and is easily degraded by nuclease. Therefore, we constructed methoxy polyethylene glycol-polylacticco-glycolic acid-polylysine (mPEG-PLGA-PLL) nanoparticles to encapsulate miR-34a (miR-34a/NP). The results showed that miR-34a/NP protects miR-34a from degradation by nucleases and can be phagocytized by PC-3 CRPC cells. Ultrasound induces microbubble cavitation (UIMC) improves cell membrane permeability and capillary gaps, and further promotes miR-34a/NP to enter cells PC-3 and prostate cancer xenografts. The miR-34a/NP that enters the cell and tumor tissue releases miR-34a, which suppressed CRPC cells PC-3 proliferation, promoted its apoptosis, and inhibited the growth of CRPC xenografts. Our research verified that miR-34a/NP, especially combined with UIMC, has a significant anti-tumor effect on CRPC.

Multi-scale structural changes in lintnerized starches from three coloured potatoes.

Three kinds of potato starch were treated with 2.2 N HCl at 35 °C for 40 days, and their susceptibility to acid hydrolysis and the resulting structural changes were evaluated. Red potato starch was more susceptible to acid hydrolysis and presented highest rate of hydrolysis. Lintnerized starches had relatively low average molecular weights and z-average radius of gyration. HPAEC analyses showed three lintners presented different molecular size distributions. Lintnerized yellow potato starch had few chains of DP ≤ 12 (2.58 mol%) and more chains of DP ≥ 37 (8.16 mol%). Furthermore, the similarities of the branch-chain length distributions before and after debranching indicated the lintners consisted primarily of linear molecules. After lintnerization, most starch granules were degraded, and the birefringence disappeared from some granules. X-ray diffraction patterns revealed that the relative crystallinity significantly increased after lintnerization. DSC analyses showed that lintners displayed broader thermal-transitions.

The potential of lactulose and melibiose, two novel trehalase-indigestible and autophagy-inducing disaccharides, for polyQ-mediated neurodegenerative disease treatment.

The unique property of trehalose encourages its pharmaceutical application in aggregation-mediated neurodegenerative disorders, including Alzheimer's, Parkinson's, and many polyglutamine (polyQ)-mediated diseases. However, trehalose is digested into glucose by trehalase and which reduced its efficacy in the disease target tissues. Therefore, searching trehalase-indigestible analogs of trehalose is a potential strategy to enhance therapeutic effect. In this study, two trehalase-indigestible trehalose analogs, lactulose and melibiose, were selected through compound topology and functional group analyses. Hydrogen-bonding network analyses suggest that the elimination of the hydrogen bond between the linker ether and aspartate 321 (D321) of human trehalase is the key for lactulose and melibiose to avoid the hydrolyzation. Using polyQ-mediated spinocerebellar ataxia type 17 (SCA17) cell and slice cultures, we found the aggregation was significantly prohibited by trehalose, lactulose, and melibiose, which may through up-regulating of autophagy. These findings suggest the therapeutic applications of trehalase-indigestible trehalose analogs in aggregation-associated neurodegenerative diseases.

Indole and synthetic derivative activate chaperone expression to reduce polyQ aggregation in SCA17 neuronal cell and slice culture models.

In spinocerebellar ataxia type 17 (SCA17), the expansion of a translated CAG repeat in the TATA box binding protein (TBP) gene results in a long polyglutamine (polyQ) tract in the TBP protein, leading to intracellular accumulation of aggregated TBP and cell death. The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events. In this study, we used Tet-On SH-SY5Y cells with inducible SCA17 TBP/Q79-green fluorescent protein (GFP) expression to test indole and synthetic derivative NC001-8 for neuroprotection. We found that indole and NC001-8 up-regulated chaperone expression to reduce polyQ aggregation in neuronal differentiated TBP/Q79 cells. The effects on promoting neurite outgrowth and on reduction of aggregation on Purkinje cells were also confirmed with cerebellar primary and slice cultures of SCA17 transgenic mice. Our results demonstrate how indole and derivative NC001-8 reduce polyQ aggregation to support their therapeutic potentials in SCA17 treatment.