Increased dietary intake of niacin is correlated with reduced risk of Alzheimer's Disease and age-associated cognitive decline. The goal of this study is to collect data on the penetration of commercially available, FDA approved, extended-release niacin into the spinal fluid. One dose of 500 mg nicotinic acid will be used (in addition to placebo) to build a dose response curve for this compound in human cerebrospinal fluid. This objective will demonstrate target engagement of HCAR2 in the central nervous system, after oral treatment with niacin. The primary endpoints are to show increased nicotinic acid levels in blood and cerebrospinal fluid. A secondary endpoint is to collect safety and tolerability data of niacin in this particular population.

Start Date01 Oct 2024

Sponsor / Collaborator

Indiana University

[+1]

NCT06406140 / Enrolling by invitationPhase 2/3IIT

Potential Effect of Niacin on Lipoprotein (a) Concentration and Hyperphosphatemia in End-Stage Renal Disease Patients Undergoing Hemodialysis

The goal of this clinical trial is to learn if Niacin has an effect on lipoprotein (a) concentration and hyperphosphatemia, which represent strong risk factors for cardiovascular diseases, in End-stage renal disease (ESRD) patients undergoing hemodialysis. It will also learn about the safety of Niacin. The main questions it aims to answer are:
* Does Niacin lower lipoprotein (a) concentration?
* Does Niacin treat hyperphosphatemia in End-stage renal disease (ESRD) patients undergoing hemodialysis? Researchers will compare Niacin to a control group (taking no drug) to see if drug Niacin works to treat hyperphosphatemia and lower lipoprotein (a) concentration.
Participants will:
* Take drug Niacin or no drug every day for 3 months
* Visit the clinic once every 2 weeks for checkups and tests
All Patients will be subjected to the following:
1. Informed consent.
2. Demographics and history taking: Using Patient Data sheet.
3. Laboratory evaluation including:
Kidney function tests: blood urea,serum creatinine, albumin ,uric acid. Complete blood count (CBC). Lipid profile:Lipoprotein (a),total cholesterol,triglyceride,high density lipoprotein (HDL), low density lipoprotein (LDL).
Phosphorous, calcium, sodium, parathyroid hormone (PTH), alkaline phosphatase (ALP).
C-reactive protein (CRP).

Start Date15 Mar 2024

Sponsor / Collaborator

Al-Azhar University

JPRN-jRCT1041230130 / RecruitingEarly Phase 1IIT

Study of metabolite changes by niacin-related supplements on healthy subjects - Niacin metabolism

Start Date11 Jan 2024

Sponsor / Collaborator-

100 Clinical Results associated with NIACR1 x HCAR3

100 Translational Medicine associated with NIACR1 x HCAR3

0 Patents (Medical) associated with NIACR1 x HCAR3

Literatures (Medical) associated with NIACR1 x HCAR3

01 Nov 2024·Cell Reports

Structural basis for ligand recognition of the human hydroxycarboxylic acid receptor HCAR3

Article

Author: Qian, Chungen ; Pan, Xin ; Zhu, Lizhe ; Li, Xinyu ; Chen, Geng ; Liu, Aijun ; Zhang, Binghao ; Ning, Peiruo ; Zhang, Zhiyi ; Wang, Qinggong ; Gong, Kaizheng ; Xiang, Xufu ; Du, Yang ; Li, Jiancheng ; Ye, Fang

Hydroxycarboxylic acid receptor 3 (HCAR3), a class A G-protein-coupled receptor, is an important cellular energy metabolism sensor with a key role in the regulation of lipolysis in humans. HCAR3 is deeply involved in many physiological processes and serves as a valuable target for the treatment of metabolic diseases, tumors, and immune diseases. Here, we report four cryoelectron microscopy (cryo-EM) structures of human HCAR3-Gi1 complexes with or without agonists: the endogenous ligand 3-hydroxyoctanoic acid, the drug niacin, the highly subtype-specific agonist compound 5c (4-(n-propyl)amino-3-nitrobenzoic acid), and the apo form. Together with mutagenesis and functional analyses, we revealed the recognition mechanisms of HCAR3 for different agonists. In addition, the key residues that determine the ligand selectivity between HCAR2 and HCAR3 were also illuminated. Overall, these findings provide a structural basis for the ligand recognition, activation, and selectivity and G-protein coupling mechanisms of HCAR3, which contribute to the design of HCAR3-targeting drugs with high efficacy and selectivity.

01 Feb 2024·Psychiatry and Clinical Neurosciences

Altered HCAR3 expression may underlying the blunted niacin responses of the psychiatric disorders and the risk of schizophrenia

Article

Author: Gao, Yan ; He, Lin ; Ji, Feng ; Wan, Chunling ; Jiang, Jie ; Guan, Lili ; Li, Shuhui ; Sun, Liya ; Tian, Yusheng ; Hu, Xiaowen ; Li, Zhiqiang ; Wang, Dandan ; Li, Zhuyun ; Zhang, Juan

AimBlunted niacin response (BNR) was an endophenotype of schizophrenia, but the underlying mechanism remains unclarified. The objective of this study was to verify whether genes associated with BNR pathway constitute the genetic basis and the pathological mechanism of BNR phenotypic psychiatric patients.MethodsTwo independent sample sets consisting of 971 subjects were enrolled in this study. A total of 62 variants were genotyped in the discovery set, then the related variants were verified in the verification set. The published PGC GWAS data were used to validate the associations between the variants and psychiatry disorders. RT‐PCR analysis, eQTL data, and Dual‐Luciferase Reporter experiment were used to investigate the potential molecular mechanisms of the variants underlying BNR.ResultsThe results showed that two SNPs, rs56959712 in HCAR2 and rs2454721 in HCAR3 were significantly associated with niacin response. The risk allele T of rs2454721 could affect the niacin responses of psychiatric patients through elevated HCAR3 gene expression. These two genes, especially HCAR3, were significantly associated with the risk of schizophrenia, as identified in this study and verified using the published GWAS data.ConclusionHCAR3 is a novel schizophrenia susceptibility gene which is significantly associated with blunted niacin response in schizophrenia. In‐depth investigation of HCAR3 is of great significance for uncovering the pathogenesis and propose new therapeutic targets for psychiatric disorders, especially for the BNR subgroup patients.

01 Aug 2022·Journal of Molecular Modeling

Computational insights on molecular interactions of acifran with GPR109A and GPR109B

Article

Author: Adepu, Kiran Kumar ; Anishkin, Andriy ; Chintapalli, Sree V ; Kachhap, Sangita ; Bhandari, Dipendra

Acifran is a well-known agonist of G-protein-coupled receptor protein, namely GPR109A. Acifran is primarily used in the treatment of dyslipidemia, myocardial infractions, and atherosclerosis in humans due to its lower vascular and metabolic side effects. However, experimental and computational studies on interaction sites of acifran with GPR proteins (GPR109A and GPR109B) are lacking. Our computational studies using docking and molecular dynamics simulation revealed that acifran binds distinctly to both GPR109A and GPR109B, but with lower affinity to the latter. The weak binding of acifran-GPR109B is mainly due to the presence of residues S91 and N94 in ECL1 and I178 amino acid in ECL2 region of GPR109B, whereas R111 and R251 residues in TMH3 and TMH6 are crucial for GPR109A-acifran complex stability. Additionally, molecular mechanics/Poisson-Boltzmann solvent accessible surface area (MM/PBSA) analysis revealed that both GPR109A- and GPR109B-acifran complexes are energetically stable with lower calculated binding free energy values for the latter. Energy-minimized structures of GPR109A-acifran and GPR109B-acifran complex.

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