Mechanism Exploration of Astaxanthin in the Treatment of Adriamycin-induced Cardiotoxicity Based on Network Pharmacology and Experimental Validation.

INTRODUCTION: Astaxanthin (AXT), a natural antioxidant recognized for its therapeutic potential in cancer and cardiovascular diseases, holds promise in mitigating adriamycin-induced cardiotoxicity (AIC). Nevertheless, the underlying mechanisms of AXT in AIC mitigation remain to be elucidated. Consequently, this study endeavors to elucidate the mechanism of AXT against AIC, employing an integrated approach. METHODS: Network pharmacology, molecular docking, and molecular dynamics simulations were harnessed to explore the molecular mechanism underlying AXT's action against AIC. Furthermore, the in-vitro AIC model was established with the H9c2 cell to generate transcriptome data for validation. RESULTS: A total of 533 putative AXT targets and 1478 AIC-related genes were initially screened by database retrieval and bioinformatics analysis. A total of 248 potential targets of AXT against AIC and several signaling pathways were identified by network pharmacology and enrichment analysis. Two core genes (CCL2 and NOS3) and the AGE-RAGE signaling pathway in diabetic complications were further highlighted by transcriptome validation based on the AIC in-vitro model. Additionally, molecular docking and dynamics analyses supported the robust binding affinity of AXT with the core targets. CONCLUSION: The study suggested that AXT might ameliorate AIC through the inhibition of CCL2 and NOS3 as well as AGE-RAGE signaling, which provide a theoretical basis for the development of a strategy against AIC.

A need to integrate pharmacological management for multimorbidity into dementia guidelines in Australia.

Introduction: Pharmacological management is a vital aspect of dementia care. Suboptimal medication prescribing and adverse drug reactions are major causes for ongoing concerns for the quality of care. This review aims to investigate the existence and comprehensiveness of Australian guidelines dedicated to supporting dementia care in the context of pharmacological management. Methods: Guideline registries and databases (EMBASE and CINAHL) were searched to identify Australian guidelines addressing pharmacological management in dementia care and to uncover barriers and considerations associated with guideline implementation. Results: Seven Australian guidelines were identified. Barriers to effective implementation were identified at individual, provider, and system levels. None of the identified guidelines provided comprehensive guidance on management of multimorbidity and polypharmacy. Discussion: Although Australian guidelines are available to guide pharmacological management in dementia, several barriers impede their effective implementation. There is an urgent need for updated guidelines that address the management of multimorbidity and polypharmacy in people living with dementia.

Iron Reduces the Trafficking of Fatty Acids from Human Immortalised Brain Microvascular Endothelial Cells Through Modulation of Fatty Acid Transport Protein 1 (FATP1/SLC27A1).

PURPOSE: Alzheimer's disease (AD) is associated with brain accumulation of amyloid-beta (Aß) and neurofibrillary tangle formation, in addition to reduced brain docosahexaenoic acid (DHA) and increased brain iron levels. DHA requires access across the blood-brain barrier (BBB) to enter the brain, and iron has been shown to affect the expression and function of a number of BBB transporters. Therefore, this study aimed to assess the effect of iron on the expression and function of fatty acid binding protein 5 (FABP5) and fatty acid transport protein 1 (FATP1), both which mediate brain endothelial cell trafficking of DHA. METHODS: The mRNA and protein levels of FABP5 and FATP1 in human cerebral microvascular endothelial (hCMEC/D3) cells was assessed by RT-qPCR and Western blot, respectively following ferric ammonium citrate (FAC) treatment (up to 750 µM, 72 h). The function of FABP5 and FATP1 was assessed via uptake and efflux of radiolabelled 3H-oleic acid and 14C-DHA. RESULTS: FAC (500 µM, 72 h) had no impact on the expression of FABP5 at the protein and mRNA level in hCMEC/D3 cells, which was associated with a lack of effect on the uptake of 14C-DHA. FAC led to a 19.7% reduction in FATP1 protein abundance in hCMEC/D3 cells with no impact on mRNA levels, and this was associated with up to a 32.6% reduction in efflux of 14C-DHA. CONCLUSIONS: These studies demonstrate a role of iron in down-regulating FATP1 protein abundance and function at the BBB, which may have implications on fatty acid access to the brain.

Exploring the link between comorbidities and Alzheimer's dementia in the Australian Imaging, Biomarker & Lifestyle (AIBL) study.

INTRODUCTION: Mounting evidence suggests that certain comorbidities may influence the clinical evolution of Alzheimer's dementia (AD). METHODS: We conducted logistic regression analyses on the medical history and cognitive health diagnoses of participants in the Australian Imaging, Biomarker & Lifestyle study (n = 2443) to investigate cross-sectional associations between various comorbidities and mild cognitive impairment (MCI)/AD. RESULTS: A mixture of associations were observed. Higher comorbidity of anxiety and other neurological disorders was associated with higher odds of AD, while arthritis, cancer, gastric complaints, high cholesterol, joint replacement, visual defect, kidney and liver disease were associated with lower odds of AD. DISCUSSION: This study underscores the links between specific comorbidities and MCI/AD. Further research is needed to elucidate the longitudinal comorbidity-MCI/AD associations and underlying mechanisms of these associations. Highlights: Comorbidities that significantly increased AD odds included anxiety and other neurological disorders.Arthritis, cancer, gastric complaints, high cholesterol, joint replacement, visual defect, kidney and liver disease were associated with lower odds of AD.Alcohol consumption had the most significant confounding effect in the study.Visual-AD association was modified by age, sex, and APOE ε4 allele status.Anxiety-AD and depression-AD associations were modified by sex.

Intra- and Peri-tumoral Radiomics Based on Dynamic Contrast Enhanced-MRI to Identify Lymph Node Metastasis and Prognosis in Intrahepatic Cholangiocarcinoma.

BACKGROUND: Lymph node metastasis (LNM) in patients with intrahepatic cholangiocarcinoma (iCCA) affects treatment strategies and prognosis. However, preoperative imaging is not reliable enough for identifying LNM. PURPOSE: To develop and validate a radiomics nomogram based on dynamic contrast enhanced (DCE)-MR images for identifying LNM and prognosis in iCCA. STUDY TYPE: Retrospective. SUBJECTS: Two hundred four patients with pathologically proven iCCA who underwent curative-intent resection and lymphadenectomy (training cohort: N = 107, internal test cohort: N = 46, and external test cohort: N = 51). FIELD STRENGTH/SEQUENCE: T1- and T2-weighted imaging, diffusion-weighted imaging and DCE imaging at 1.5 T or 3.0 T. ASSESSMENT: Radiomics features were extracted from intra- and peri-tumoral regions on preoperative DCE-MR images. Imaging features were evaluated by three radiologists, and significant variables in univariable and multivariable regression analysis were included in clinical model. The best-performing radiomics signature and clinical characteristics (intrahepatic duct dilatation, MRI-reported LNM) were combined to build a nomogram. Patients were divided into high-risk and low-risk groups based on their nomogram scores (cutoff = 0.341). Patients were followed up for 1-102 months (median 12) after surgery, the overall survival (OS) and recurrence-free survival (RFS) were calculated. STATISTICAL TESTS: Receiver operating characteristic (ROC) curve, calibration, decision curve, Delong test, Kaplan-Meier curves, log rank test. Two tailed P < 0.05 was considered statistically significant. RESULTS: The nomogram incorporating intra- and peri-tumoral radiomics features, intrahepatic duct dilatation and MRI-reported LNM obtained the best discrimination for LNM, with areas under the ROC curves of 0.946, 0.913, and 0.859 in the training, internal, and external test cohorts. In the entire cohort, high-risk patients had significantly lower RFS and OS than low-risk patients. High-risk of LNM was an independent factor of unfavorable OS and RFS. DATA CONCLUSION: The nomogram integrating intra- and peri-tumoral radiomics signatures has potential to identify LNM and prognosis in iCCA. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Network Pharmacology along with Molecular Docking to Explore the Mechanism of Danshen Injection against Anthracycline-induced Cardiotoxicity and Transcriptome Validation.

INTRODUCTION: Although anthracyclines have demonstrated efficacy in cancer therapy, their utilization is constrained by cardiotoxicity. In contrast, Danshen injection (DSI), derived from Salvia miltiorrhiza, has a longstanding tradition of being employed to ameliorate cardiovascular ailments, including anthracycline- induced cardiotoxicity (AIC). Nonetheless, there is a notable dearth of comprehensive systematic investigation into the molecular mechanisms underlying DSI's effects on AIC. Consequently, this study was undertaken to explore the underlying mechanism by which DSI acted against AIC. METHODS: Employing network pharmacology approach, the current investigation undertook a comprehensive analysis of the impact of DSI on AIC, which was further validated by transcriptome sequencing with in vitro AIC model. Additionally, molecular docking was conducted to evaluate the binding of active ingredients to core targets. A total of 3,404 AIC-related targets and 12 active ingredients in DSI, including chrysophanol, luteolin, tanshinone IIA, isoimperatorin, among others, were collected by differentially expressed analysis and database search, respectively. RESULTS: The network pharmacology and enrichment analysis suggested 102 potential targets and 29 signaling pathways associated with the protective effect of DSI on AIC. Three core targets (CA12, NOS3, and POLH) and calcium signaling pathways were further validated by transcriptomic analysis of the in-vitro model. The high affinity of the active ingredients binding to corresponding targets was confirmed by molecular docking. CONCLUSION: The present study suggested that DSI might exert a cardioprotective effect on AIC via the inhibition of CA12, NOS3, and POLH, as well as the modulation of calcium signaling. Further experiments are warranted to verify the findings.

Polyunsaturated fatty acids-induced ferroptosis suppresses pancreatic cancer growth.

Despite recent advances in science and medical technology, pancreatic cancer remains associated with high mortality rates due to aggressive growth and no early clinical sign as well as the unique resistance to anti-cancer chemotherapy. Current numerous investigations have suggested that ferroptosis, which is a programed cell death driven by lipid oxidation, is an attractive therapeutic in different tumor types including pancreatic cancer. Here, we first demonstrated that linoleic acid (LA) and α-linolenic acid (αLA) induced cell death with necroptotic morphological change in MIA-Paca2 and Suit 2 cell lines. LA and αLA increased lipid peroxidation and phosphorylation of RIP3 and MLKL in pancreatic cancers, which were negated by ferroptosis inhibitor, ferrostatin-1, restoring back to BSA control levels. Similarly, intraperitoneal administration of LA and αLA suppresses the growth of subcutaneously transplanted Suit-2 cells and ameliorated the decreased survival rate of tumor bearing mice, while co-administration of ferrostatin-1 with LA and αLA negated the anti-cancer effect. We also demonstrated that LA and αLA partially showed ferroptotic effects on the gemcitabine-resistant-PK cells, although its effect was exerted late compared to treatment on normal-PK cells. In addition, the trial to validate the importance of double bonds in PUFAs in ferroptosis revealed that AA and EPA had a marked effect of ferroptosis on pancreatic cancer cells, but DHA showed mild suppression of cancer proliferation. Furthermore, treatment in other tumor cell lines revealed different sensitivity of PUFA-induced ferroptosis; e.g., EPA induced a ferroptotic effect on colorectal adenocarcinoma, but LA or αLA did not. Collectively, these data suggest that PUFAs can have a potential to exert an anti-cancer effect via ferroptosis in both normal and gemcitabine-resistant pancreatic cancer.

Exploring the association between cancer and cognitive impairment in the Australian Imaging Biomarkers and Lifestyle (AIBL) study.

An inverse association between cancer and Alzheimer's disease (AD) has been demonstrated; however, the association between cancer and mild cognitive impairment (MCI), and the association between cancer and cognitive decline are yet to be clarified. The AIBL dataset was used to address these knowledge gaps. The crude and adjusted odds ratios for MCI/AD and cognitive decline were compared between participants with/without cancer (referred to as C+ and C- participants). A 37% reduction in odds for AD was observed in C+ participants compared to C- participants after adjusting for all confounders. The overall risk for MCI and AD in C+ participants was reduced by 27% and 31%, respectively. The odds of cognitive decline from MCI to AD was reduced by 59% in C+ participants after adjusting for all confounders. The risk of cognitive decline from MCI to AD was halved in C+ participants. The estimated mean change in Clinical Dementia Rating-Sum of boxes (CDR-SOB) score per year was 0.23 units/year higher in C- participants than in C+ participants. Overall, an inverse association between cancer and MCI/AD was observed in AIBL, which is in line with previous reports. Importantly, an inverse association between cancer and cognitive decline has also been identified.

Flaxseed Gum/Arabic Gum/Tween 80-Based Oleogel as a Fat Substitute Applied in Emulsified Sausage: Physicochemical Properties, Sensory Attributes and Nutritional Quality.

In the present study, flaxseed gum (FG), Arabic gum (GA) and Tween 80 were used to prepare oleogels through an emulsion-templated method, and the obtained oleogels were designed for the partial substitution of pork fat in emulsified sausage. An increment in FG concentrations enhanced the viscoelasticity of emulsions, which resulted in the improved stability of emulsion systems, with smaller droplet sizes. In addition, increased FG concentrations contributed to higher mechanical strength, denser network structure and lower oil loss of oleogels. As a fat substitute, the prepared oleogels improved the textural properties and nutritional quality of emulsified sausages. With the increase in the substitution level of oleogels, the hardness and chewiness of the emulsified sausage increased, and the cooking loss decreased. Meanwhile, the reformulation with oleogels decreased the saturated fat from 57.04 g/100 g lipid to 12.05 g/100 g lipid, while increasing the ratio of omega-6 to omega-3 essential fatty acids from 0.10 to 0.39. The obtained results demonstrated that the flaxseed gum/Arabic gum/Tween 80-based oleogels had huge potential to successfully replace pork fat in emulsified sausage products.

Fatty Acid-Binding Protein 4 is Essential for the Inflammatory and Metabolic Response of Microglia to Lipopolysaccharide.

Prolonged activation of microglia leads to excessive release of proinflammatory mediators, which are detrimental to brain health. Therefore, there are significant efforts to identify pathways mediating microglial activation. Recent studies have demonstrated that fatty acid-binding protein 4 (FABP4), a lipid binding protein, is a critical player in macrophage-mediated inflammation. Given that we have previously identified FABP4 in microglia, the aim of this study was to assess whether FABP4 activity contributed to inflammation, metabolism and immune function (i.e. immunometabolism) in immortalised mouse microglia (BV-2 cells) using the proinflammatory stimulus lipopolysaccharide (LPS) to induce general microglial activation. Microglial FABP4 expression was significantly increased following exposure to LPS, an outcome associated with a significant increase in microglial proliferation rate. LPS-stimulated BV-2 microglia demonstrated a significant increase in the production of reactive oxygen species (ROS) and tumour necrosis factor-alpha (TNF-α), phosphorylation of c-Jun N-terminal kinase (JNK), increased expression of Toll-like receptor 4 (TLR4), and reduced expression of uncoupling protein 2 (UCP2), all of which were reversed following FABP4 genetic silencing and chemical inhibition with BMS309403. The oxidation rate of 3H-oleic acid and microglial uptake of 3H-2-deoxy-D-glucose were modulated with LPS activation, processes which were restored with genetic and chemical inhibition of FABP4. This is the first study to report on the critical role of FABP4 in mediating the deleterious effects of LPS on microglial immunometabolism, suggesting that FABP4 may present as a novel therapeutic target to alleviate microglia-mediated neuroinflammation, a commonly reported factor in multiple neurodegenerative diseases.

Peripheral Administration of the Kv1.3-Blocking Peptide HsTX1[R14A] Improves Cognitive Performance in Senescence Accelerated SAMP8 Mice.

Increased expression of the voltage-gated potassium channel Kv1.3 in activated microglia, and the subsequent release of pro-inflammatory mediators, are closely associated with the progression of Alzheimer's disease (AD). Studies have shown that reducing neuroinflammation through the non-selective blockade of microglial Kv1.3 has the potential to improve cognitive function in mouse models of familial AD. We have previously demonstrated that a potent and highly-selective peptide blocker of Kv1.3, HsTX1[R14A], not only entered the brain parenchyma after peripheral administration in a lipopolysaccharide (LPS)-induced mouse model of inflammation, but also significantly reduced pro-inflammatory mediator release from activated microglia. In this study, we show that microglial expression of Kv1.3 is increased in senescence accelerated mice (SAMP8), an animal model of sporadic AD, and that subcutaneous dosing of HsTX1[R14A] (1 mg/kg) every other day for 8 weeks provided a robust improvement in cognitive deficits in SAMP8 mice. The effect of HsTX1[R14A] on the whole brain was assessed using transcriptomics, which revealed that the expression of genes associated with inflammation, neuron differentiation, synapse function, learning and memory were altered by HsTX1[R14A] treatment. Further study is required to investigate whether these changes are downstream effects of microglial Kv1.3 blockade or a result of alternative mechanisms, including any potential effect of Kv1.3 blockade on other brain cell types. Nonetheless, these results collectively demonstrate the cognitive benefits of Kv1.3 blockade with HsTX1[R14A] in a mouse model of sporadic AD, demonstrating its potential as a therapeutic candidate for this neurodegenerative disease.

Prognostic value of LI-RADS category on MRI in patients with primary hepatic lymphoepithelioma-like carcinoma.

OBJECTIVES: To compare the clinical and MRI features of primary hepatic lymphoepithelioma-like carcinoma (LELC) categorized as LR-M or LR-4/5 using the Liver Imaging Reporting and Data System (LI-RADS) version 2018 and to determine the prognostic factors for recurrence-free survival (RFS). METHODS: In this retrospective study, 37 patients with surgically confirmed LELC were included. Two independent observers evaluated preoperative MRI features according to the LI-RADS version 2018. Clinical and imaging features were compared between two groups. RFS and the associated factors were evaluated using Cox proportional hazards regression analysis, Kaplan-Meier analysis, and log-rank test. RESULTS: In total, 37 patients (mean age, 58.5 ± 10.3 years) were evaluated. Sixteen (43.2%) LELCs were categorized as LR-M and twenty-one (56.8%) LELCs were categorized as LR-4/5. In the multivariate analysis, the LR-M category was an independent factor for RFS (HR 7.908, 95% CI 1.170-53.437; p = 0.033). RFS rates were significantly lower in patients with LR-M LELCs than in patients with LR-4/5 LELCs (5-year RFS rate, 43.8% vs.85.7%; p = 0.002). CONCLUSION: The LI-RADS category was significantly associated with postsurgical prognosis of LELC, with tumor categorized as LR-M having a worse RFS than those categorized as LR-4/5. KEY POINTS: • Lymphoepithelioma-like carcinoma patients categorized as LR-M have worse recurrence-free survival than those categorized as LR-4/5. • MRI-based LI-RADS categorization was an independent factor for postoperative prognosis of primary hepatic lymphoepithelioma-like carcinoma.

Prognostic role of aortic distensibility in patients with bicuspid aortic valve: a CMR study.

To evaluate the prognostic value of aortic distensibility measured by cardiovascular magnetic resonance (CMR) as predictors of prophylactic aortic valve or aortic surgery in patients with bicuspid aortic valve (BAV). 110 patients with BAV were included. Distensibility of middle ascending aorta (AscAo) and proximal descending aorta (DescAo) at baseline was determined using CMR. The association between aortic distensibility and primary endpoint of aortic valve and/or aortic surgery was investigated with Cox proportional hazard regression analyses. The receiver operating characteristics curves (ROC) of the area under receiver-operator (AUC) and DeLong test were used to evaluate and compare the performance of different models. During a median follow-up of 66.5 months [IQR 13-75 months], 42 patients experienced surgical treatments. After adjusting for traditional risk factors, aortic distensibility (P = 0.003) and severe valve dysfunction (P < 0.001) were found significantly associated with aortic valve and/or aortic surgery. The model 2 (aortic distensibility and severe valve dysfunction) is slightly better in predicting primary endpoint than the model 1 (aortic diameter and severe valve dysfunction) (AUC: 0.893 vs. 0.842, P = 0.106). In BAV patients, aortic distensibility and severe valve dysfunction are valuable predictors for final aortic valve and/or aortic surgery.

Oleic acid-bound FABP7 drives glioma cell proliferation through regulation of nuclear lipid droplet formation.

Fatty acid-binding protein 7 (FABP7), one of the fatty acid (FA) chaperones involved in the modulation of intracellular FA metabolism, is highly expressed in glioblastoma, and its expression is associated with decreased patients' prognosis. Previously, we demonstrated that FABP7 requires its binding partner to exert its function and that a mutation in the FA-binding site of FABP7 affects tumour biology. Here, we explored the role of FA ligand binding for FABP7 function in tumour proliferation and examined the mechanism of FABP7 and ligand interaction in tumour biology. We discovered that among several FA treatment, oleic acid (OA) boosted cell proliferation of FABP7-expressing cells. In turn, OA increased FABP7 nuclear localization, and the accumulation of FABP7-OA complex in the nucleus induced the formation of nuclear lipid droplet (nLD), as well as an increase in colocalization of nLD with promyelocytic leukaemia (PML) nuclear bodies. Furthermore, OA increased mRNA levels of proliferation-related genes in FABP7-expressing cells through histone acetylation. Interestingly, these OA-boosted functions were abrogated in FABP7-knockout cells and mutant FABP7-overexpressing cells. Thus, our findings suggest that FABP7-OA intracellular interaction may modulate nLD formation and the epigenetic status thereby enhancing transcription of proliferation-regulating genes, ultimately driving tumour cell proliferation.

Modulating interfacial structure and lipid digestion of natural Camellia oil body by roasting and boiling processes.

Oil body (OB) is the lipid-storage organelle in oilseed, and its stability is crucial for oilseed processing. Herein, effects of roasting and boiling on the structure, stability, and in vitro lipid digestion of Camellia OB were studied. The interfacial structure and physical stability of the extracted OB were investigated by electrophoresis, confocal-Raman spectroscopy, zeta-potential, and surface hydrophobicity, etc. Boiling caused protein loss on the OB surfaces, forming a stable phospholipid interface, which resulted in coalescence of the droplets (d > 100 µm) and negative ζ-potential (-3 âˆ¼ -8 mV) values at a pH of 2.0. However, roasting partially denatured the proteins in the seeds, which were adsorbed on the OB surfaces. The random coil structure of interfacial protein increased to ∼20 % after thermal treatment. Besides, heating decreased the surface hydrophobicity of OB and improved lipid digestion. After boiling 60 min, the extent of lipolysis increased from 41.7 % (raw) to 57.4 %.

A Fluorescent Peptide Toxin for Selective Visualization of the Voltage-Gated Potassium Channel KV1.3.

Upregulation of the voltage-gated potassium channel KV1.3 is implicated in a range of autoimmune and neuroinflammatory diseases, including rheumatoid arthritis, psoriasis, multiple sclerosis, and type I diabetes. Understanding the expression, localization, and trafficking of KV1.3 in normal and disease states is key to developing targeted immunomodulatory therapies. HsTX1[R14A], an analogue of a 34-residue peptide toxin from the scorpion Heterometrus spinifer, binds KV1.3 with high affinity (IC50 of 45 pM) and selectivity (2000-fold for KV1.3 over KV1.1). We have synthesized a fluorescent analogue of HsTX1[R14A] by N-terminal conjugation of a Cy5 tag. Electrophysiology assays show that Cy5-HsTX1[R14A] retains activity against KV1.3 (IC50 ∼ 0.9 nM) and selectivity over a range of other potassium channels (KV1.2, KV1.4, KV1.5, KV1.6, KCa1.1 and KCa3.1), as well as selectivity against heteromeric channels assembled from KV1.3/KV1.5 tandem dimers. Live imaging of CHO cells expressing green fluorescent protein-tagged KV1.3 shows co-localization of Cy5-HsTX1[R14A] and KV1.3 fluorescence signals at the cell membrane. Moreover, flow cytometry demonstrated that Cy5-HsTX1[R14A] can detect KV1.3-expressing CHO cells. Stimulation of mouse microglia by lipopolysaccharide, which enhances membrane expression of KV1.3, was associated with increased staining by Cy5-HsTX1[R14A], demonstrating that it can be used to identify KV1.3 in disease-relevant models of inflammation. Furthermore, the biodistribution of Cy5-HsTX1[R14A] could be monitored using ex vivo fluorescence imaging of organs in mice dosed subcutaneously with the peptide. These results illustrate the utility of Cy5-HsTX1[R14A] as a tool for visualizing KV1.3, with broad applicability in fundamental investigations of KV1.3 biology, and the validation of novel disease indications where KV1.3 inhibition may be of therapeutic value.

Altered blood-brain barrier and blood-spinal cord barrier dynamics in amyotrophic lateral sclerosis: Impact on medication efficacy and safety.

The access of drugs into the central nervous system (CNS) is regulated by the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). A large body of evidence supports perturbation of these barriers in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Modifications to the BBB and BSCB are also reported in amyotrophic lateral sclerosis (ALS), albeit these modifications have received less attention relative to those in other neurodegenerative diseases. Such alterations to the BBB and BSCB have the potential to impact on CNS exposure of drugs in ALS, modulating the effectiveness of drugs intended to reach the brain and the toxicity of drugs that are not intended to reach the brain. Given the clinical importance of these phenomena, this review will summarise reported modifications to the BBB and BSCB in ALS, discuss their impact on CNS drug exposure, and suggest further research directions so as to optimise medicine use in people with ALS.

Blockade of Microglial Kv1.3 Potassium Channels by the Peptide HsTX1[R14A] Attenuates Lipopolysaccharide-mediated Neuroinflammation.

The expression of voltage-gated potassium Kv1.3 channels is increased in activated microglia, with non-selective blockade reported to attenuate microglial-mediated neuroinflammation. In this study, we evaluated the impact of a potent and selective peptidic blocker of Kv1.3 channels, HsTX1[R14A], on microglial-mediated neuroinflammation in vitro and in vivo. Treatment with both 0.1 and 1 µg/mL lipopolysaccharide (LPS) significantly (p < 0.05) increased Kv1.3 abundance on the surface of BV-2 microglia in association with increased levels of mRNA for tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The increased transcription of TNF-α and IL-6 was significantly attenuated (by 24.9 and 20.2%, respectively) by HsTX1[R14A] (100 nM). The concomitant increase in TNF-α and IL-6 release from BV-2 microglia was significantly attenuated by HsTX1[R14A] by 10.7 and 12.6%, respectively. In LPS-treated primary mouse microglia, the levels of TNF-α and nitric oxide were also attenuated by HsTX1[R14A] (26.1 and 20.4%, respectively). In an LPS-induced mouse model of neuroinflammation, both an immediate and delayed subcutaneous dose of HsTX1[R14A] (2 mg/kg) significantly reduced plasma and brain levels of the pro-inflammatory mediators TNF-α, IL-1ß and IL-6, with no impact on the anti-inflammatory IL-10. These results demonstrate that HsTX1[R14A] is a promising therapeutic candidate for the treatment of diseases with a neuroinflammatory component.

Structure, assembly and application of novel peanut oil body protein extracts nanoparticles.

Oil bodies (OBs), which are found mainly in the seeds or nuts of oleaginous plants, are spherical droplets with a triacylglycerol core covered by phospholipid-protein layer. Oil body protein extracts (OBPEs), mainly oleosins, contribute to the unique physicochemical stability of OBs. The application of OBPEs in aqueous environment has been greatly limited by their highly hydrophobic structures. In this study, OBPEs were successfully extracted from peanut seeds and their profiles were characterized by LC-MS/MS. OBPEs nanoparticles were successfully assembled in aqueous environment for the first time using the antisolvent precipitation method. The mean diameter of OBPEs nanoparticles was 215.6 ± 1.8 nm with a polydispersity index of 0.238 ± 0.005. The morphology of these colloidal particles was found to be roughly spherical shape as confirmed by transmission electron microscopy (TEM). Oil-in-water (O/W) Pickering emulsions with good stability against coalescence could be formed at protein concentration as low as 0.1 mg/mL. Cryo-scanning electron microscopy (cryo-SEM) confirmed that spherical nanoparticles were packed at the oil-water interface. This research will greatly expand the applications of OBPEs in structuring the interfaces and developing novel formulations in the food and pharmaceutical fields.

Ligand Bound Fatty Acid Binding Protein 7 (FABP7) Drives Melanoma Cell Proliferation Via Modulation of Wnt/ß-Catenin Signaling.

PURPOSE: Fatty acid-binding protein 7 (FABP7) involved in intracellular lipid dynamics, is highly expressed in melanomas and associated with decreased patient survival. Several studies put FABP7 at the center of melanoma cell proliferation. However, the underlying mechanisms are not well deciphered. This study examines the effects of FABP7 on Wnt/ß-catenin signaling that enhances proliferation in melanoma cells. METHODS: Skmel23 cells with FABP7 silencing and Mel2 cells overexpressed with wild-type FABP7 (FABP7wt) and mutated FABP7 (FABP7mut) were used. Cell proliferation and migration were analyzed by proliferation and wound-healing assay, respectively. Transcriptional activation of the Wnt/ß-catenin signaling was measured by luciferase reporter assay. The effects of a specific FABP7 inhibitor, MF6, on proliferation, migration, and modulation of the Wnt/ß-catenin signaling were examined. RESULTS: FABP7 siRNA knockdown in Skmel23 decreased proliferation and migration, cyclin D1 expression, as well as Wnt/ß-catenin activity. Similarly, FABP7wt overexpression in Mel2 cells increased these effects, but FABP7mut abrogated these effects. Pharmacological inhibition of FABP7 function with MF6 suppressed FABP7-regulated proliferation of melanoma cells. CONCLUSION: These results suggest the importance of the interaction between FABP7 and its ligands in melanoma proliferation modulation, and the beneficial implications of therapeutic targeting of FABP7 for melanoma treatment.