CSF-1 maintains pathogenic but not homeostatic myeloid cells in the central nervous system during autoimmune neuroinflammation.

The receptor for colony stimulating factor 1 (CSF-1R) is important for the survival and function of myeloid cells that mediate pathology during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). CSF-1 and IL-34, the ligands of CSF-1R, have similar bioactivities but distinct tissue and context-dependent expression patterns, suggesting that they have different roles. This could be the case in EAE, given that CSF-1 expression is up-regulated in the CNS, while IL-34 remains constitutively expressed. We found that targeting CSF-1 with neutralizing antibody halted ongoing EAE, with efficacy superior to CSF-1R inhibitor BLZ945, whereas IL-34 neutralization had no effect, suggesting that pathogenic myeloid cells were maintained by CSF-1. Both anti­CSF-1 and BLZ945 treatment greatly reduced the number of monocyte-derived cells and microglia in the CNS. However, anti­CSF-1 selectively depleted inflammatory microglia and monocytes in inflamed CNS areas, whereas BLZ945 depleted virtually all myeloid cells, including quiescent microglia, throughout the CNS. Anti­CSF-1 treatment reduced the size of demyelinated lesions and microglial activation in the gray matter. Lastly, we found that bone marrow­derived immune cells were the major mediators of CSF-1R­dependent pathology, while microglia played a lesser role. Our findings suggest that targeting CSF-1 could be effective in ameliorating MS pathology, while preserving the homeostatic functions of myeloid cells, thereby minimizing risks associated with ablation of CSF-1R­dependent cells.

A phase 3, open-label, single-arm study of vadadustat for anemia in chronic kidney disease for Japanese patients on hemodialysis not receiving erythropoiesis-stimulating agents.

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in Japan for the treatment of anemia in patients with chronic kidney disease (CKD). This phase 3, open-label, single-arm study evaluated the efficacy and safety of vadadustat in 24 Japanese patients with CKD-associated anemia on hemodialysis who were not receiving erythropoiesis-stimulating agents (ESAs). Patients received vadadustat for 24 weeks; the starting dose was 300 mg/day and doses were adjusted to achieve the target hemoglobin (Hb) range of 10.0-12.0 g/dL. The least squares mean of average Hb at Weeks 20 and 24 (95% confidence interval) was 10.75 g/dL (10.35, 11.14). The most common adverse event was shunt stenosis (25.0%). Adverse drug reactions (diarrhea and vomiting) occurred in two patients (8.3%) and the severity was mild. Vadadustat increased and maintained Hb levels within the target range and was generally well-tolerated in Japanese patients with anemia on hemodialysis not receiving ESAs.

Discovery of 5-{2-[5-Chloro-2-(5-ethoxyquinoline-8-sulfonamido)phenyl]ethynyl}-4-methoxypyridine-2-carboxylic Acid, a Highly Selective in Vivo Useable Chemical Probe to Dissect MCT4 Biology.

Due to increased lactate production during glucose metabolism, tumor cells heavily rely on efficient lactate transport to avoid intracellular lactate accumulation and acidification. Monocarboxylate transporter 4 (MCT4/SLC16A3) is a lactate transporter that plays a central role in tumor pH modulation. The discovery and optimization of a novel class of MCT4 inhibitors (hit 9a), identified by a cellular screening in MDA-MB-231, is described. Direct target interaction of the optimized compound 18n with the cytosolic domain of MCT4 was shown after solubilization of the GFP-tagged transporter by fluorescence cross-correlation spectroscopy and microscopic studies. In vitro treatment with 18n resulted in lactate efflux inhibition and reduction of cellular viability in MCT4 high expressing cells. Moreover, pharmacokinetic properties of 18n allowed assessment of lactate modulation and antitumor activity in a mouse tumor model. Thus, 18n represents a valuable tool for investigating selective MCT4 inhibition and its effect on tumor biology.

Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter). RESULTS: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively. CONCLUSIONS: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO2VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).

Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. METHODS: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52. RESULTS: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter. CONCLUSIONS: Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO2TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).

Synthesis of the Potent, Selective, and Efficacious ß-Secretase (BACE1) Inhibitor NB-360.

Starting from lead compound 4, the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF3 group delivered an excellent pharmacological profile with a pKa of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Aß levels in mice, rats, and dogs in acute and chronic treatment regimens.

Study Protocol for a Randomized Controlled Trial Evaluating the Effectof Chromium Picolinate Supplementation on Gene Expression of TumorNecrosis Factor-α and DNA Damage in Metabolic Syndrome Patients.

Metabolic syndrome (MS) is caused by environmental factors as well as genetic. Human studies of efficacy of chromium for glucose and lipid metabolism and insulin function is not still definitive. Furthermore, the effect of chromium supplementation on the expression of inflammatory genes in patients with MS has not been studied. We will assess effects of chromium picolinate supplementation on gene expression of tumor necrosis factor-α (TNF-α) and DNA damage in MS patients. In this triple-blind randomized placebo-controlled clinical trial, 48 MS patients will be randomly assigned into two groups to receive daily 400 µg chromium picolinate supplement or placebo for 12 weeks. The outcome measures include of change in fasting blood sugar, glycosylated hemoglobin A1C, inflammatory biomarkers, lipid profile, blood pressure, gene expression of TNF-α, and 8-hydroxy-deoxyguanosine concentration as DNA damage biomarker, will be quantified at baseline and end of intervention. This protocol was approved by Institutional Research Ethics Committee School of Public Health Shahid Sadoughi University of Medical Sciences (Approval ID: IR.SSU.SPH.REC.1399.141).

Chromium picolinate balances the metabolic and clinical markers in nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is a complicated disease and is considered as a severe global health problem affecting 30% of adults worldwide. The present study aimed to evaluate changes in oxidative stress, adipokines, liver enzyme, and body composition following treatment with chromium picolinate (CrPic) among patients with NAFLD. PARTICIPANTS AND METHODS: The current randomized, double-blind, placebo-controlled study was conducted on 46 NAFLD patients with the age range of 20-65 years. Patients were randomly classified into two groups, receiving either 400 µg CrPic tablets in two divided doses of 200 µg (23 patients) or placebo (23 patients) daily for 12 weeks. The participants' body composition and biochemical parameters were evaluated at the baseline and after 12 weeks. RESULTS: Serum levels of liver enzymes reduced significantly only in the CrPic group (P < 0.05 for all), but not between the groups after the intervention. Besides, there were significant differences between the study groups regarding body weight and body fat mass, total antioxidant capacity, superoxide dismutase, malondialdehyde, leptin, and adiponectin post-intervention (P = 0.017, P = 0.032, P = 0.003, P = 0.023, P = 0.012, P = 0.003, and P = 0.042, respectively). However, glutathione peroxidase and resistin levels did not differ significantly between groups (P = 0.127 and P = 0.688, respectively). DISCUSSION AND CONCLUSION: This study showed that consuming 400 µg/day of CrPic for 12 weeks in patients with NAFLD causes a significant change in leptin, adiponectin, oxidative stress (expect glutathione peroxidase), and body weight, compared to baseline. Nevertheless, it does not affect liver enzymes. Therefore, the CrPic supplementation may improve adipokines, some anthropometric indices, and oxidative stress in patients with NAFLD.

Global Phase 3 programme of vadadustat for treatment of anaemia of chronic kidney disease: rationale, study design and baseline characteristics of dialysis-dependent patients in the INNO2VATE trials.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are currently the mainstay of treatment for anaemia of chronic kidney disease (CKD). Vadadustat is an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that stimulates endogenous erythropoietin formation. The INNO2VATE programme comprises two studies designed to evaluate the safety and efficacy of vadadustat versus the ESA darbepoetin alfa in ameliorating anaemia in patients with dialysis-dependent CKD (DD-CKD). Here we describe the trial design along with patient demographics and baseline characteristics. METHODS: Two Phase 3, open-label, sponsor-blind, active-controlled trials enrolled adults with anaemia of CKD who recently initiated dialysis and had limited ESA exposure (incident DD-CKD trial) or were receiving maintenance dialysis with ESA treatment (prevalent DD-CKD trial). Study periods include correction/conversion (Weeks 0-23), maintenance (Weeks 24-52), long-term treatment (Weeks 53 to end of treatment) and safety follow-up. The primary safety endpoint is the time to the first major adverse cardiovascular event and the primary efficacy endpoint is the change in haemoglobin (baseline to Weeks 24-36). RESULTS: A total of 369 and 3554 patients were randomized in the incident DD-CKD and prevalent DD-CKD trials, respectively. Demographics and baseline characteristics were similar among patients in both trials and comparable to those typically observed in DD-CKD. CONCLUSIONS: The two INNO2VATE trials will provide important information on the safety and efficacy of a novel approach for anaemia management in a diverse DD-CKD population. Demographics and baseline characteristics of enrolled patients suggest that study results will be representative for a large proportion of the DD-CKD population.

Vadadustat for anemia in chronic kidney disease patients on peritoneal dialysis: A phase 3 open-label study in Japan.

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in patients with chronic kidney disease (CKD). This phase 3, open-label, 24-week single-arm study evaluated the efficacy and safety of vadadustat in 42 Japanese CKD patients with anemia undergoing peritoneal dialysis. Patients received oral vadadustat for 24 weeks, initiated at 300 mg/day and doses were adjusted to achieve the target hemoglobin (Hb) range of 11.0-13.0 g/dL. Least squares mean of average Hb at weeks 20 and 24 was 11.35 g/dL, which was within the target range. The most frequent adverse events were catheter site infections (23.8%), which were not related to vadadustat treatment. Vadadustat was generally well tolerated and effective in controlling Hb levels within the target range, indicating the usefulness of vadadustat for treating anemia in Japanese CKD patients undergoing peritoneal dialysis.

Vadadustat: First Approval.

Vadadustat (VAFSEO®) is a prolyl hydroxylase inhibitor being developed by Akebia Therapeutics, Inc. (Akebia) for the treatment of anaemia associated with chronic kidney disease (CKD). Akebia is collaborating with Mitsubishi Tanabe Pharma Corporation on the development and commercialization of vadadustat in Japan and with Otsuka Pharmaceutical Co. Ltd on the development and commercialization of vadadustat in the USA, the EU and certain other territories. The drug is approved in Japan for use in adult patients with anaemia associated with CKD and regulatory submissions are planned in the USA and the EU. This article summarizes the milestones in the development of vadadustat leading to this first approval.

Discovery of Clinical Candidate (5-(3-(4-Chlorophenoxy)prop-1-yn-1-yl)-3-hydroxypicolinoyl)glycine, an Orally Bioavailable Prolyl Hydroxylase Inhibitor for the Treatment of Anemia.

The design and discovery of a new series of (5-alkynyl-3-hydroxypicolinoyl)glycine inhibitors of prolyl hydroxylase (PHD) are described. These compounds showed potent in vitro inhibitory activity toward PHD2 in a fluorescence polarization-based assay. Remarkably, oral administration of 17, with an IC50 of 64.2 nM toward PHD2, was found to stabilize HIF-α, elevate erythropoietin (EPO), and alleviate anemia in a cisplatin-induced anemia mouse model with an oral dose of 25 mg/kg. Rat and dog studies showed that 17 has good pharmacokinetic properties, with oral bioavailabilities of 55.7 and 54.0%, respectively, and shows excellent safety profiles even at a high dose of 200 mg/kg in these animals. Based on these results, 17 is currently being evaluated in a phase I clinical trial for anemia.

Efficacy and tolerability of a nutraceutical combination of red yeast rice, guggulipid, and chromium picolinate evaluated in a randomized, placebo-controlled, double-blind study.

Hypercholesterolemia is the major risk factor in the development of coronary heart disease. Coronary heart disease is a leading cause of morbidity and mortality in many countries worldwide. An increasing attention is now paid to nutraceuticals development for prevention and cure of dyslipidemia, especially for patients who do not wish to use chemical statins. The cholesterol lowering effect and the tolerability of NutraforChol®, a nutraceutical product containing red yeast rice extract, guggulipid extract and chromium picolinate, was evaluated on subjects who had total cholesterol level 200-239 mg/dL and LDL cholesterol level 100-159 mg/dL. In this study, a randomized, placebo-controlled, double-blind study which consisted of 4 weeks run-in period and 8 weeks treatment period was performed. Based on the study results, NutraforChol® effectively decreased total cholesterol (-15.9 %) and LDL level (-19.9 %) after two weeks consumption. The total cholesterol and LDL reduction were maintained during 8 weeks study period. At study termination (week 8), there was a significant difference between total cholesterol level of NutraforChol® treated group (173.5 ± 21.7 mg/dL) and placebo-treated group (204.5 ± 22.8 mg/dL) (p < 0.05). In addition, there was a significant difference between LDL level at week 8 in NutraforChol® group (115.5 ± 22.2 mg/dL) and placebo-treated group (145.1 ± 23.7 mg/dL) (p < 0.05). The tolerability of NutraforChol® was also evaluated. There were no significant changes (p > 0.05) on renal and liver function parameters between baseline and study termination. Thus, NutraforChol® may be considered as a complementary or alternative safe nutraceuticals for the treatment of mild dyslipidemic subjects.

Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience.

Prolyl hydroxylase domain oxygen sensors are dioxygenases that regulate the activity of hypoxia-inducible factor (HIF), which controls renal and hepatic erythropoietin production and coordinates erythropoiesis with iron metabolism. Small molecule inhibitors of prolyl hydroxylase domain dioxygenases (HIF-PHI [prolyl hydroxylase inhibitor]) stimulate the production of endogenous erythropoietin and improve iron metabolism resulting in efficacious anemia management in patients with CKD. Three oral HIF-PHIs-daprodustat, roxadustat, and vadadustat-have now advanced to global phase III clinical development culminating in the recent licensing of roxadustat for oral anemia therapy in China. Here, we survey current clinical experience with HIF-PHIs, discuss potential therapeutic advantages, and deliberate over safety concerns regarding long-term administration in patients with renal anemia.

Early Aß reduction prevents progression of cerebral amyloid angiopathy.

OBJECTIVE: Clinical trials targeting ß-amyloid peptides (Aß) for Alzheimer disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or Aß being the wrong target. Targeting Aß to prevent cerebral amyloid angiopathy (CAA) has not been rigorously followed, although the causal role of Aß for CAA and related hemorrhages is undisputed. CAA occurs with normal aging and to various degrees in AD, where its impact and treatment is confounded by the presence of parenchymal Aß deposition. METHODS: APPDutch mice develop CAA in the absence of parenchymal amyloid, mimicking hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D). Mice were treated with a ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. We used 3-dimensional ultramicroscopy and immunoassays for visualizing CAA and assessing Aß in cerebrospinal fluid (CSF) and brain. RESULTS: CAA onset in mice was at 22 to 24 months, first in frontal leptomeningeal and superficial cortical vessels followed by vessels penetrating the cortical layers. CSF Aß increased with aging followed by a decrease of both Aß40 and Aß42 upon CAA onset, supporting the idea that combined reduction of CSF Aß40 and Aß42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continuing for 4 months revealed a 90% Aß reduction in CSF and largely prevented CAA progression and associated pathologies. INTERPRETATION: This is the first study showing that Aß reduction at early disease time points largely prevents CAA in the absence of parenchymal amyloid. Our observation provides a preclinical basis for Aß-reducing treatments in patients at risk of CAA and in presymptomatic HCHWA-D. ANN NEUROL 2019;86:561-571.

Safety and Efficacy of NC120 for Improving Lipid Profile: A Double Blind Randomized Controlled Trial.

BACKGROUND: the use of statin to lower blood cholesterol is often associated with bothersome adverse effects such as myopathy and liver dysfunction. NC120 is herbal lipid lowering drug containing red yeast rice (RYR) extract, guggulipid, and chromium picolinate, and expected to have better safety profile. The aim of this study was to evaluate the efficacy and safety profiles of NC120 in lowering blood lipid. METHODS: this was a double blind randomized clinical trial comparing NC120 with placebo in subjects with hypercholesterolemia. Two capsules of NC120 or placebo were administered twice a day for 28 days. Blood total-cholesterol, LDL-cholesterol, and triglyceride were measured on day-0, day-7, and day-28. Unpaired t-test was used to compare study parameter between groups, and one-way ANOVA was used to compare within group. RESULTS: 25 subjects received NC120 and 24 subjects received placebo. Significant decrease of total cholesterol and LDL-cholesterol were observed since day-7 in NC120 group, while the changes in placebo group were not significant at all time of observation. No significant decrease of triglyceride was observed in NC120 group and in placebo group. Side effects were minor and comparable between the two groups. CONCLUSION: NC120 is effective in reducing total cholesterol and LDL-cholesterol, but not triglyceride. This drug shows a good safety profile, and thus can be considered for patients who can not tolerate statin drugs.

Depletion of tumor-associated macrophages enhances the anti-tumor effect of docetaxel in a murine epithelial ovarian cancer.

Docetaxel (DTXL), a new member of the taxoid family, has been used for cancer treatment. However, increasing cases of DTXL resistance have been reported. Tumor-associated macrophages (TAMs) have been implicated in tumor invasion and chemo-resistance. Eliminating TAMs by inhibiting colony stimulating factor-1 receptor (CSF-1R) has emerged as a promising strategy for cancer treatment. BLZ945 is a CSF-1R inhibitor and has anti-tumor function. In present study, anti-tumor effects of combination treatment of BLZ945 and DTXL were investigated. We established a mouse ovarian cancer model and investigated the effect of BLZ945, DTXL single treatment or combination treatment on TAMs infiltration, tumor growth, CD8+ T cell infiltration and cancer metastasis. DTXL treatment increased the infiltration while BLZ945 induced cell apoptosis in macrophages. DTXL/BLZ945 combination treatment significantly inhibited tumor growth, reduced the abundance of TAMs, increased CD8+ T cell infiltration and prevented lung metastasis. Depletion of Tumor-Associated Macrophages (TAMs) by BLZ945 enhanced the anti-tumor effect of DTXL in a murine epithelial ovarian cancer.

The ß-secretase (BACE) inhibitor NB-360 in preclinical models: From amyloid-ß reduction to downstream disease-relevant effects.

Inhibition of ß-secretase 1 (BACE-1; also known as ß-site amyloid precursor protein-cleaving enzyme-1) is a current approach to fight the amyloid-ß (Aß) deposition in the brains of patients with Alzheimer's disease, and a number of BACE-1 inhibitors are being tested in clinical trials. The BACE-1 inhibitor NB-360, although not a clinical compound, turned out to be a valuable pharmacological tool to investigate the effects of BACE-1 inhibition on the deposition of different Aß species in amyloid precursor protein (APP) transgenic mice. Furthermore, chronic animal studies with NB-360 revealed relationships between BACE-1 inhibition, Aß deposition, and Aß-related downstream effects on neuroinflammation, neuronal function, and markers of neurodegeneration. NB-360 effects on the processing of physiological BACE-1 substrates as well as on nonenzymatic BACE-1 functions have been investigated, complementing studies in BACE-1 knockout mice. Because NB-360 is also an inhibitor for BACE-2, nonclinical studies in adult animals revealed physiological effects of BACE-2 inhibition. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

Organic Chromium Form Alleviates the Detrimental Effects of Heat Stress on Nutrient Digestibility and Nutrient Transporters in Laying Hens.

In the present study, we investigated the effects of chromium-picolinate (CrPic) and chromium-histidinate (CrHis) on nutrient digestibility and nutrient transporters in laying hens exposed to heat stress (HS). Hens (n = 1800; 16 weeks old) were kept in cages in temperature-controlled rooms at either 22 ± 2 °C for 24 h/day (thermoneutral (TN)) or 34 ± 2 °C for 8 h/day, from 08:00 to 17:00, followed by 22 °C for 16 h (HS) for 12 weeks. Hens reared under both environmental conditions were fed one of three diets: a basal diet and the basal diet supplemented with either 1.600 mg of CrPic (12.43% Cr) or 0.788 mg of CrHis (25.22% Cr) per kg of diet, delivering 200 µg elemental Cr per kg of diet. HS impaired the nutrient digestibility and nutrient transports in laying hens (P < 0.001). However, both Cr sources increased digestibility of dry matter (DM; P < 0.001), organic matter (OM; P < 0.05), crude protein (CP; P < 0.001), and crude fat (CF; P < 0.001). Both Cr sources partially alleviated detrimental effects of HS on fatty acid-binding and transport protein1 (FABP1, FATP1), glucose (SGLT1, GLUT1, GLUT10), protein (PepT1, PepT2), and amino acid transporters (ASCT1, bo,+AT1, CAT1, EAAT1, LAT1) of the ileum (P < 0.0001). The efficacy of Cr as CrHis was more notable than Cr as CrPic, which could be attributed to higher bioavailability. Finally, the detrimental effects of HS on nutrient digestibility and nutrient transporters were alleviated by CrPic and CrHis. These findings may justify the use of CrPic and CrHis in poultry.

Microglial modulation through colony-stimulating factor-1 receptor inhibition attenuates demyelination.

Multiple sclerosis (MS) is one of the most common causes of progressive disability affecting young people with very few therapeutic options available for its progressive forms. Its pathophysiology involves demyelination and neurodegeneration apparently driven by microglial activation, which is physiologically dependent on colony-stimulating factor-1 receptor (CSF-1R) signaling. In the present work, we used microglial modulation through oral administration of brain-penetrant CSF-1R inhibitor BLZ945 in acute and chronic cuprizone (CPZ)-induced demyelination to evaluate preventive and therapeutic effects on de/remyelination and neurodegeneration. Our results show that BLZ945 induced a significant reduction in the number of microglia. Preventive BLZ945 treatment attenuated demyelination in the acute CPZ model, mainly in cortex and external capsule. In contrast, BLZ945 treatment in the acute CPZ model failed to protect myelin or foster remyelination in myelin-rich areas, which may respond to a loss in microglial phagocytic capacity and the consequent impairment in oligodendroglial differentiation. Preventive and therapeutic BLZ945 treatment promoted remyelination and neuroprotection in the chronic model. These results could be potentially transferred to the treatment of progressive forms of MS.