Dantrolene alleviates mitochondrial dysfunction and neuroinflammation in traumatic brain injury by modulating the NF- ĸβ/Akt pathway
This study sought to evaluate whether Dantrolene can potentially provide neuroprotection in an in vivo model of TBI. Male wistar rats subjected to TBI were treated with DNT (10 mg/kg) 1 h and 12 h post surgery. Animals were assessed 24 h post-TBI to evaluate neurobehavioural deficits and cerebral edema. We evaluated the protein expressions of apoptotic, autophagic, and neuroinflammatory markers by immunoblotting, as well as Mitochondrial Membrane Potential (MMP) and Reactive Oxygen Species (ROS) via Flow Cytometry to ascertain the effects of DNT on TBI. We further analysed immunofluorescence staining with Glial Fibrillary ...
Source: Biochemical Pharmacology - April 30, 2024 Category: Drugs & Pharmacology Authors: Rohan Chakraborty Heena Tabassum Suhel Parvez Source Type: research
Macrophage-derived human resistin promotes perivascular adipose tissue dysfunction in experimental inflammatory arthritis
This study aimed to investigate the role of resistin in promoting PVAT dysfunction by increasing local macrophage and inflammatory cytokines content in antigen-induced arthritis (AIA). Resistin pharmacological effects were assessed by using C57Bl/6J wild-type (WT) mice, humanized resistin mice expressing human resistin in monocytes-macrophages (hRTN+/-/-), and resistin knockout mice (RTN-/-) with AIA and respective controls. We investigated AIA disease activity and functional, cellular, and molecular parameters of the PVAT. Resistin did not contribute to AIA disease activity and its concentrations were augmented in the PVA...
Source: Biochemical Pharmacology - April 30, 2024 Category: Drugs & Pharmacology Authors: Aline G Fedoce Fl ávio P Veras Marcos H Rosa Ayda H Schneider Isadora M Paiva Mirele R Machado Edismauro G Freitas-Filho Josiane F Silva Caio C Machado Jos é C Alves-Filho Fernando Q Cunha Leandra N Z Ramalho Paulo Louzada-Junior Anthony S Bonavia Rita Source Type: research
Targeting focal adhesion kinase (FAK) for cancer therapy: FAK inhibitors, FAK-based dual-target inhibitors and PROTAC degraders
Biochem Pharmacol. 2024 Apr 27:116246. doi: 10.1016/j.bcp.2024.116246. Online ahead of print.ABSTRACTFocal adhesion kinase (FAK), a non-receptor tyrosine kinase, plays an essential role in regulating cell proliferation, migration and invasion through both kinase-dependent enzymatic function and kinase-independent scaffolding function. The overexpression and activation of FAK is commonly observed in various cancers and some drug-resistant settings. Therefore, targeted disruption of FAK has been identified as an attractive strategy for cancer treatment. To date, numerous structurally diverse inhibitors targeting distinct dom...
Source: Biochemical Pharmacology - April 30, 2024 Category: Drugs & Pharmacology Authors: Ming Yang Hua Xiang Guoshun Luo Source Type: research
Dantrolene alleviates mitochondrial dysfunction and neuroinflammation in traumatic brain injury by modulating the NF- ĸβ/Akt pathway
This study sought to evaluate whether Dantrolene can potentially provide neuroprotection in an in vivo model of TBI. Male wistar rats subjected to TBI were treated with DNT (10 mg/kg) 1 h and 12 h post surgery. Animals were assessed 24 h post-TBI to evaluate neurobehavioural deficits and cerebral edema. We evaluated the protein expressions of apoptotic, autophagic, and neuroinflammatory markers by immunoblotting, as well as Mitochondrial Membrane Potential (MMP) and Reactive Oxygen Species (ROS) via Flow Cytometry to ascertain the effects of DNT on TBI. We further analysed immunofluorescence staining with Glial Fibrillary ...
Source: Biochemical Pharmacology - April 30, 2024 Category: Drugs & Pharmacology Authors: Rohan Chakraborty Heena Tabassum Suhel Parvez Source Type: research
Macrophage-derived human resistin promotes perivascular adipose tissue dysfunction in experimental inflammatory arthritis
This study aimed to investigate the role of resistin in promoting PVAT dysfunction by increasing local macrophage and inflammatory cytokines content in antigen-induced arthritis (AIA). Resistin pharmacological effects were assessed by using C57Bl/6J wild-type (WT) mice, humanized resistin mice expressing human resistin in monocytes-macrophages (hRTN+/-/-), and resistin knockout mice (RTN-/-) with AIA and respective controls. We investigated AIA disease activity and functional, cellular, and molecular parameters of the PVAT. Resistin did not contribute to AIA disease activity and its concentrations were augmented in the PVA...
Source: Biochemical Pharmacology - April 30, 2024 Category: Drugs & Pharmacology Authors: Aline G Fedoce Fl ávio P Veras Marcos H Rosa Ayda H Schneider Isadora M Paiva Mirele R Machado Edismauro G Freitas-Filho Josiane F Silva Caio C Machado Jos é C Alves-Filho Fernando Q Cunha Leandra N Z Ramalho Paulo Louzada-Junior Anthony S Bonavia Rita Source Type: research
Targeting focal adhesion kinase (FAK) for cancer therapy: FAK inhibitors, FAK-based dual-target inhibitors and PROTAC degraders
Biochem Pharmacol. 2024 Apr 27:116246. doi: 10.1016/j.bcp.2024.116246. Online ahead of print.ABSTRACTFocal adhesion kinase (FAK), a non-receptor tyrosine kinase, plays an essential role in regulating cell proliferation, migration and invasion through both kinase-dependent enzymatic function and kinase-independent scaffolding function. The overexpression and activation of FAK is commonly observed in various cancers and some drug-resistant settings. Therefore, targeted disruption of FAK has been identified as an attractive strategy for cancer treatment. To date, numerous structurally diverse inhibitors targeting distinct dom...
Source: Biochemical Pharmacology - April 30, 2024 Category: Drugs & Pharmacology Authors: Ming Yang Hua Xiang Guoshun Luo Source Type: research
Developing insulin-like peptide 5-based antagonists for the G protein-coupled receptor, RXFP4
Biochem Pharmacol. 2024 Apr 26:116239. doi: 10.1016/j.bcp.2024.116239. Online ahead of print.ABSTRACTHuman insulin-like peptide 5 (INSL5) is a gut hormone produced by colonic L-cells, and its biological functions are mediated by Relaxin Family Peptide Receptor 4 (RXFP4). Our preliminary data indicated that RXFP4 agonists are potential drug leads for the treatment of constipation. More recently, we designed and developed a novel RXFP4 antagonist, A13-nR that was shown to block agonist-induced activity in cells and animal models. We showed that A13-nR was able to block agonist-induced increases in colon motility in mice of b...
Source: Biochemical Pharmacology - April 28, 2024 Category: Drugs & Pharmacology Authors: Hongkang Wu Thomas N G Handley Bradley L Hoare Herodion A Hartono Daniel J Scott David K Chalmers Ross A D Bathgate Mohammed Akhter Hossain Source Type: research
ONC212 enhances YM155 cytotoxicity by triggering SLC35F2 expression and NOXA-dependent MCL1 degradation in acute myeloid leukemia cells
In this study, we investigated the apoptotic mechanism of ONC212 in acute myeloid leukemia (AML) cells. ONC212 induces apoptosis, MCL1 downregulation, and mitochondrial depolarization in AML U937 cells. Ectopic MCL1 expression alleviates mitochondria-mediated apoptosis in ONC212-treated U937 cells. ONC212 triggers AKT phosphorylation, inducing NOX4-dependent ROS production and promoting HuR transcription. HuR-mediated ATF4 mRNA stabilization stimulates NOXA and SLC35F2 expression; ONC212-induced upregulation of NOXA leads to MCL1 degradation. The synergistic effect of ONC212 on YM155 cytotoxicity was dependent on increased...
Source: Biochemical Pharmacology - April 28, 2024 Category: Drugs & Pharmacology Authors: Jing-Ting Chiou Long-Sen Chang Source Type: research
Sesamin ameliorates nonalcoholic hepatic steatosis by inhibiting CD36-mediated hepatocyte lipid accumulation in vitro and in vivo
In this study, we observed the anti-hepatic steatosis effects of Ses in palmitate/oleate (PA/OA)-incubated primary mouse hepatocytes, AML12 hepatocytes, and HepG2 cells, as well as in high-fat, high-cholesterol diet-induced NASH mice. RNA sequencing analysis revealed that cluster of differentiation 36 (CD36), a free fatty acid (FA) transport protein, was involved in the Ses-mediated inhibition of hepatic fat accumulation. Moreover, the overexpression of CD36 significantly increased hepatic steatosis in both Ses-treated PA/OA-incubated HepG2 cells and NASH mice. Furthermore, Ses treatment suppressed insulin-induced de novo ...
Source: Biochemical Pharmacology - April 28, 2024 Category: Drugs & Pharmacology Authors: Ya-Ping Bai Teng Zhang Zheng-Yan Hu Yan Zhang De-Guo Wang Meng-Yun Zhou Ying Zhang Fang Zhang Xiang Kong Source Type: research
Overexpression of soluble epoxide hydrolase reduces post-ischemic recovery of cardiac contractile function
Biochem Pharmacol. 2024 Apr 26:116237. doi: 10.1016/j.bcp.2024.116237. Online ahead of print.ABSTRACTCytochromes P450 can metabolize endogenous fatty acids, such as arachidonic acid, to bioactive lipids such as epoxyeicosatrienoic acids (EETs) that have beneficial effects. EETs protect hearts against ischemic damage, heart failure or fibrosis; however, their effects are limited by hydrolysis to less active dihydroxy oxylipins by soluble epoxide hydrolase (sEH), encoded by the epoxide hydrolase 2 gene (EPHX2, EC 3.3.2.10). Pharmacological inhibition or genetic disruption of sEH/EPHX2 have been widely studied for their impac...
Source: Biochemical Pharmacology - April 28, 2024 Category: Drugs & Pharmacology Authors: Matthew L Edin Artiom Gruzdev J Alyce Bradbury Joan P Graves Ginger W Muse David R Goulding Fred B Lih Laura M DeGraff Darryl C Zeldin Source Type: research
Developing insulin-like peptide 5-based antagonists for the G protein-coupled receptor, RXFP4
Biochem Pharmacol. 2024 Apr 26:116239. doi: 10.1016/j.bcp.2024.116239. Online ahead of print.ABSTRACTHuman insulin-like peptide 5 (INSL5) is a gut hormone produced by colonic L-cells, and its biological functions are mediated by Relaxin Family Peptide Receptor 4 (RXFP4). Our preliminary data indicated that RXFP4 agonists are potential drug leads for the treatment of constipation. More recently, we designed and developed a novel RXFP4 antagonist, A13-nR that was shown to block agonist-induced activity in cells and animal models. We showed that A13-nR was able to block agonist-induced increases in colon motility in mice of b...
Source: Biochemical Pharmacology - April 28, 2024 Category: Drugs & Pharmacology Authors: Hongkang Wu Thomas N G Handley Bradley L Hoare Herodion A Hartono Daniel J Scott David K Chalmers Ross A D Bathgate Mohammed Akhter Hossain Source Type: research
ONC212 enhances YM155 cytotoxicity by triggering SLC35F2 expression and NOXA-dependent MCL1 degradation in acute myeloid leukemia cells
In this study, we investigated the apoptotic mechanism of ONC212 in acute myeloid leukemia (AML) cells. ONC212 induces apoptosis, MCL1 downregulation, and mitochondrial depolarization in AML U937 cells. Ectopic MCL1 expression alleviates mitochondria-mediated apoptosis in ONC212-treated U937 cells. ONC212 triggers AKT phosphorylation, inducing NOX4-dependent ROS production and promoting HuR transcription. HuR-mediated ATF4 mRNA stabilization stimulates NOXA and SLC35F2 expression; ONC212-induced upregulation of NOXA leads to MCL1 degradation. The synergistic effect of ONC212 on YM155 cytotoxicity was dependent on increased...
Source: Biochemical Pharmacology - April 28, 2024 Category: Drugs & Pharmacology Authors: Jing-Ting Chiou Long-Sen Chang Source Type: research
Sesamin ameliorates nonalcoholic hepatic steatosis by inhibiting CD36-mediated hepatocyte lipid accumulation in vitro and in vivo
In this study, we observed the anti-hepatic steatosis effects of Ses in palmitate/oleate (PA/OA)-incubated primary mouse hepatocytes, AML12 hepatocytes, and HepG2 cells, as well as in high-fat, high-cholesterol diet-induced NASH mice. RNA sequencing analysis revealed that cluster of differentiation 36 (CD36), a free fatty acid (FA) transport protein, was involved in the Ses-mediated inhibition of hepatic fat accumulation. Moreover, the overexpression of CD36 significantly increased hepatic steatosis in both Ses-treated PA/OA-incubated HepG2 cells and NASH mice. Furthermore, Ses treatment suppressed insulin-induced de novo ...
Source: Biochemical Pharmacology - April 28, 2024 Category: Drugs & Pharmacology Authors: Ya-Ping Bai Teng Zhang Zheng-Yan Hu Yan Zhang De-Guo Wang Meng-Yun Zhou Ying Zhang Fang Zhang Xiang Kong Source Type: research
Overexpression of soluble epoxide hydrolase reduces post-ischemic recovery of cardiac contractile function
Biochem Pharmacol. 2024 Apr 26:116237. doi: 10.1016/j.bcp.2024.116237. Online ahead of print.ABSTRACTCytochromes P450 can metabolize endogenous fatty acids, such as arachidonic acid, to bioactive lipids such as epoxyeicosatrienoic acids (EETs) that have beneficial effects. EETs protect hearts against ischemic damage, heart failure or fibrosis; however, their effects are limited by hydrolysis to less active dihydroxy oxylipins by soluble epoxide hydrolase (sEH), encoded by the epoxide hydrolase 2 gene (EPHX2, EC 3.3.2.10). Pharmacological inhibition or genetic disruption of sEH/EPHX2 have been widely studied for their impac...
Source: Biochemical Pharmacology - April 28, 2024 Category: Drugs & Pharmacology Authors: Matthew L Edin Artiom Gruzdev J Alyce Bradbury Joan P Graves Ginger W Muse David R Goulding Fred B Lih Laura M DeGraff Darryl C Zeldin Source Type: research
Development of a synthetic relaxin-3/INSL5 chimeric peptide ligand for NanoBiT complementation binding assays
In this study, we have utilized NanoBiT complementation to develop a SmBiT-conjugated tracer for use with LgBiT-fused RXFP3 and RXFP4. The low affinity between LgBiT:SmBiT should result in a low non-specific luminescence signal and enable the quantification of binding without the tedious separation of non-bound ligands. We used solid-phase peptide synthesis to produce a SmBiT-labelled RXFP3/4 agonist, R3/I5, where SmBiT was conjugated to the B-chain N-terminus via a PEG12 linker. Both SmBiT-R3/I5 and R3/I5 were synthesized and purified in high purity and yield. Stable HEK203T cell lines expressing LgBiT-RXFP3 and LgBiT-RXF...
Source: Biochemical Pharmacology - April 27, 2024 Category: Drugs & Pharmacology Authors: Hongkang Wu Bradley L Hoare Thomas N G Handley Mohammed Akhter Hossain Ross A D Bathgate Source Type: research
