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1.
Antioxidants (Basel) ; 12(2)2023 Jan 17.
Article in English | MEDLINE | ID: mdl-36829776

ABSTRACT

The incidence of traumatic brain injury (TBI) increases dramatically with advanced age and accumulating evidence indicates that age is one of the important predictors of an unfavorable prognosis after brain trauma. Unfortunately, thus far, evidence-based effective therapeutics for geriatric TBI is limited. By using middle-aged animals, we first confirm that there is an age-related change in TBI susceptibility manifested by increased inflammatory events, neuronal death and impaired functional outcomes in motor and cognitive behaviors. Since thyroid hormones function as endogenous regulators of oxidative stress, we postulate that age-related thyroid dysfunction could be a crucial pathology in the increased TBI severity. By surgically removing the thyroid glands, which recapitulates the age-related increase in TBI-susceptible phenotypes, we provide direct evidence showing that endogenous thyroid hormone-dependent compensatory regulation of antioxidant events modulates individual TBI susceptibility, which is abolished in aged or thyroidectomized individuals. The antioxidant capacity of melatonin is well-known, and we found acute melatonin treatment but not liothyronine (T3) supplementation improved the TBI-susceptible phenotypes of oxidative stress, excitotoxic neuronal loss and promotes functional recovery in the aged individuals with thyroid dysfunction. Our study suggests that monitoring thyroid function and acute administration of melatonin could be feasible therapeutics in the management of geriatric-TBI in clinic.

2.
Pharmaceutics ; 15(1)2022 Dec 31.
Article in English | MEDLINE | ID: mdl-36678774

ABSTRACT

Cerebral ischemia is an acute disorder characterized by an abrupt reduction in blood flow that results in immediate deprivation of both glucose and oxygen. The main types of cerebral ischemia are ischemic and hemorrhagic stroke. When a stroke occurs, several signaling pathways are activated, comprising necrosis, apoptosis, and autophagy as well as glial activation and white matter injury, which leads to neuronal cell death. Current treatments for strokes include challenging mechanical thrombectomy or tissue plasminogen activator, which increase the danger of cerebral bleeding, brain edema, and cerebral damage, limiting their usage in clinical settings. Monoclonal antibody therapy has proven to be effective and safe in the treatment of a variety of neurological disorders. In contrast, the evidence for stroke therapy is minimal. Recently, Clone MTS510 antibody targeting toll-like receptor-4 (TLR4) protein, ASC06-IgG1 antibody targeting acid sensing ion channel-1a (ASIC1a) protein, Anti-GluN1 antibodies targeting N-methyl-D-aspartate (NMDA) receptor associated calcium influx, GSK249320 antibody targeting myelin-associated glycoprotein (MAG), anti-High Mobility Group Box-1 antibody targeting high mobility group box-1 (HMGB1) are currently under clinical trials for cerebral ischemia treatment. In this article, we review the current antibody-based pharmaceuticals for neurological diseases, the use of antibody drugs in stroke, strategies to improve the efficacy of antibody therapeutics in cerebral ischemia, and the recent advancement of antibody drugs in clinical practice. Overall, we highlight the need of enhancing blood-brain barrier (BBB) penetration for the improvement of antibody-based therapeutics in the brain, which could greatly enhance the antibody medications for cerebral ischemia in clinical practice.

3.
Pharmaceutics ; 13(8)2021 Jul 31.
Article in English | MEDLINE | ID: mdl-34452143

ABSTRACT

The blood-brain barrier (BBB) plays a vital role in the protection and maintenance of homeostasis in the brain. In this way, it is an interesting target as an interface for various types of drug delivery, specifically in the context of the treatment of several neuropathological conditions where the therapeutic agents cannot cross the BBB. Drug toxicity and on-target specificity are among some of the limitations associated with current neurotherapeutics. In recent years, advances in nanodrug delivery have enabled the carrier system containing the active therapeutic drug to target the signaling pathways and pathophysiology that are closely linked to central nervous system (CNS) disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), brain tumor, epilepsy, ischemic stroke, and neurodegeneration. At present, among the nano formulations, solid lipid nanoparticles (SLNs) have emerged as a putative drug carrier system that can deliver the active therapeutics (drug-loaded SLNs) across the BBB at the target site of the brain, offering a novel approach with controlled drug delivery, longer circulation time, target specificity, and higher efficacy, and more importantly, reducing toxicity in a biomimetic way. This paper highlights the synthesis and application of SLNs as a novel nontoxic formulation strategy to carry CNS drugs across the BBB to improve the use of therapeutics agents in treating major neurological disorders in future clinics.

4.
J Cell Mol Med ; 25(15): 7418-7425, 2021 08.
Article in English | MEDLINE | ID: mdl-34216182

ABSTRACT

We previously showed a hydroxamic acid-based histone deacetylase inhibitor (HDACi), compound 13, provides neuroprotection against chronic cerebral hypoperfusion (CCH) both in vitro under oxygen-glucose deprivation (OGD) conditions and in vivo under bilateral common carotid artery occlusion (BCCAO) conditions. Intriguingly, the protective effect of this HDACi is via H3K14 or H4K5 acetylation-mediated differential BDNF isoform activation. BDNF is involved in cell proliferation and differentiation in development, synaptic plasticity and in learning and memory related with receptors or synaptic proteins. B6 mice underwent BCCAO and were randomized into 4 groups; a sham without BCCAO (sham), BCCAO mice injected with DMSO (DMSO), mice injected with HDACi-compound 13 (compound 13) and mice injected with suberoylanilide hydroxamic acid (SAHA). The cortex and hippocampus of mice were harvested at 3 months after BCCAO, and levels of BDNF, AMPA receptor and dopamine receptors (D1, D2 and D3) were studied using Western blotting analysis or immunohistochemistry. We found that the AMPA receptor plays a key role in the molecular mechanism of this process by modulating HDAC. This protective effect of HDACi may be through BDNF; therefore, activation of this downstream signalling molecule, for example by AMPA receptors, could be a therapeutic target or intervention applied under CCH conditions.


Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Dementia, Vascular/drug therapy , Histone Deacetylase Inhibitors/therapeutic use , Neuroprotective Agents/therapeutic use , Receptors, AMPA/metabolism , Animals , Arterial Occlusive Diseases/complications , Carotid Arteries/pathology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Dementia, Vascular/etiology , Dementia, Vascular/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Histone Deacetylase Inhibitors/pharmacology , Mice , Mice, Inbred C57BL , Neuroprotective Agents/pharmacology
5.
Mar Drugs ; 17(6)2019 Jun 17.
Article in English | MEDLINE | ID: mdl-31213027

ABSTRACT

Activated human monocytes/macrophages, which increase the levels of matrix metalloproteinases (MMPs) and pro-inflammatory cytokines, are the essential mechanisms for the progression of sepsis. In the present study, we determined the functions and mechanisms of hirsutanolA (HA), which is isolated from the red alga-derived marine fungus Chondrostereum sp. NTOU4196, on the production of pro-inflammatory mediators produced from lipopolysaccharide (LPS)-treated THP-1 cells. Our results showed that HA suppressed LPS-triggered MMP-9-mediated gelatinolysis and expression of protein and mRNA in a concentration-dependent manner without effects on TIMP-1 activity. Also, HA significantly attenuated the levels of TNF-α, IL-6, and IL-1ß from LPS-treated THP-1 cells. Moreover, HA significantly inhibited LPS-mediated STAT3 (Tyr705) phosphorylation, IκBα degradation and ERK1/2 activation in THP-1 cells. In an LPS-induced endotoxemia mouse model, studies indicated that HA pretreatment improved endotoxemia-induced acute sickness behavior, including acute motor deficits and anxiety-like behavior. HA also attenuated LPS-induced phospho-STAT3 and pro-MMP-9 activity in the hippocampus. Notably, HA reduced pathologic lung injury features, including interstitial tissue edema, infiltration of inflammatory cells and alveolar collapse. Likewise, HA suppressed the induction of phospho-STAT3 and pro-MMP-9 in lung tissues. In conclusion, our results provide pharmacological evidence that HA could be a useful agent for treating inflammatory diseases, including sepsis.


Subject(s)
Acute Lung Injury/drug therapy , Cytokines/metabolism , Illness Behavior/drug effects , Matrix Metalloproteinase 9/metabolism , Sesquiterpenes/pharmacology , Acute Lung Injury/etiology , Acute Lung Injury/metabolism , Animals , Cell Line, Tumor , Endotoxemia/complications , Endotoxemia/metabolism , Humans , Lipopolysaccharides/pharmacology , Lung/drug effects , Lung/metabolism , Male , Mice , Mice, Inbred C57BL , Signal Transduction/drug effects , THP-1 Cells/drug effects , THP-1 Cells/metabolism
6.
Mediators Inflamm ; 2018: 9541459, 2018.
Article in English | MEDLINE | ID: mdl-29849502

ABSTRACT

Much evidence has indicated that matrix metalloproteinases (MMPs) participate in the progression of neuroinflammatory disorders. The present study was undertaken to investigate the inhibitory effect and mechanism of the antipsychotic haloperidol on MMP activation in the stimulated THP-1 monocytic cells. Haloperidol exerted a strong inhibition on tumor necrosis factor- (TNF-) α-induced MMP-9 gelatinolysis of THP-1 cells. A concentration-dependent inhibitory effect of haloperidol was observed in TNF-α-induced protein and mRNA expression of MMP-9. On the other hand, haloperidol slightly affected cell viability and tissue inhibition of metalloproteinase-1 levels. It significantly inhibited the degradation of inhibitor-κB-α (IκBα) in activated cells. Moreover, it suppressed activated nuclear factor-κB (NF-κB) detected by a mobility shift assay, NF-κB reporter gene, and chromatin immunoprecipitation analyses. Consistent with NF-κB inhibition, haloperidol exerted a strong inhibition of lipopolysaccharide- (LPS-) induced MMP-9 gelatinolysis but not of transforming growth factor-ß1-induced MMP-2. In in vivo studies, administration of haloperidol significantly attenuated LPS-induced intracerebral MMP-9 activation of the brain homogenate and the in situ in C57BL/6 mice. In conclusion, the selective anti-MMP-9 activation of haloperidol could possibly involve the inhibition of the NF-κB signal pathway. Hence, it was found that haloperidol treatment may represent a bystander of anti-MMP actions for its conventional psychotherapy.


Subject(s)
Haloperidol/pharmacology , Matrix Metalloproteinase 9/metabolism , NF-kappa B/metabolism , Animals , Cell Survival/drug effects , Chromatin Immunoprecipitation , Humans , I-kappa B Proteins/metabolism , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred C57BL , Signal Transduction/drug effects
7.
Int J Mol Sci ; 18(7)2017 Jun 29.
Article in English | MEDLINE | ID: mdl-28661460

ABSTRACT

Dysregulated human monocytes/macrophages can synthesize and secrete matrix metalloproteinases (MMPs), which play important roles in the progression of sepsis. In this study, we investigated the effects and mechanism of a novel histone deacetylase (HDAC8) inhibitor, (E)-N-hydroxy-4-methoxy-2-(biphenyl-4-yl)cinnamide (WK2-16), on MMP-9 production and activation in stimulated human monocytic THP-1 cells. Our results demonstrated that the acetylation level of structural maintenance of chromosomes 3 (SMC3) was up-regulated by WK2-16 in THP-1 cells. Consistently, an in vitro enzyme study demonstrated that WK2-16 selectively inhibited HDAC8 activity. Moreover, the WK2-16 concentration dependently suppressed MMP-9-mediated gelatinolysis induced by tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS). Additionally, WK2-16 significantly inhibited both MMP-9 protein and mRNA expression without cellular toxicity. Nevertheless, WK2-16 suppressed the extracellular levels of interleukin (IL)-6 from LPS-stimulated THP-1 cells. For the signaling studies, WK2-16 had no effect on LPS/TLR4 downstream signaling pathways, such as the NF-κB and ERK/JNK/P38 MAPK pathways. On the other hand, WK2-16 enhanced the recruitment of acetylated Yin Yang 1 (YY1) with HDAC1. Finally, in vivo studies indicated that WK2-16 could reduce the serum levels of TNF-α and IL-6 in endotoxemic mice. These results suggested that HDAC8 inhibition might provide a novel therapeutic strategy of hypercytokinemia in sepsis.


Subject(s)
Cytokines/drug effects , Cytokines/metabolism , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/drug effects , Histone Deacetylases/metabolism , Lipopolysaccharides/pharmacology , Matrix Metalloproteinase 9/drug effects , Matrix Metalloproteinase 9/metabolism , Repressor Proteins/drug effects , Repressor Proteins/metabolism , Acetylation , Animals , Cell Cycle Proteins/metabolism , Cell Survival/drug effects , Chondroitin Sulfate Proteoglycans/metabolism , Chromosomal Proteins, Non-Histone/metabolism , Cyclooxygenase 2/drug effects , Down-Regulation , Endotoxemia , Histone Deacetylase 1/drug effects , Humans , Interleukin-6 , JNK Mitogen-Activated Protein Kinases/drug effects , MAP Kinase Signaling System/drug effects , Male , Mice , Mice, Inbred C57BL , Monocytes/metabolism , NF-kappa B/metabolism , RNA, Messenger/biosynthesis , RNA, Messenger/drug effects , Sepsis/drug therapy , Signal Transduction/drug effects , THP-1 Cells/drug effects , Tubulin/metabolism , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/pharmacology , YY1 Transcription Factor/metabolism , p38 Mitogen-Activated Protein Kinases/drug effects
8.
Phytomedicine ; 19(3-4): 270-7, 2012 Feb 15.
Article in English | MEDLINE | ID: mdl-22244537

ABSTRACT

There is much evidence indicating that human leukemic cells and monocytes/macrophages synthesize, and secrete, several matrix metalloproteinases (MMPs), and participate in the degradation of extracellular matrix components in tissue lesions. In this study, we investigated the effects and mechanisms of andrographolide, extracted from the herb Andrographis paniculata, on human monocytic MMPs expression and activation. Andrographolide (1-50 µM) exhibited concentration-dependent inhibition of MMP-9 activation, induced by either tumor necrosis factor-α (TNF-α), or lipopolysaccharide (LPS), in THP-1cells. In addition, andrographolide did not present an inhibitory effect on MMP-9 enzymatic activity at a concentration of 50 µM. By contrast, enzyme-linked immunosorbent assay (ELISA) showed that andrographolide partially affect TIMP-1 levels. Western blot analysis showed that both TNF-α, and LPS stimulators attenuated MMP-9 protein expression in a concentration-dependent manner. Using reverse transcription polymerase chain reaction (RT-PCR), we found that andrographolide suppressed expression of MMP-9 messenger RNA. Furthermore, we also found that andrographolide could significantly inhibit the degradation of inhibitor-κB-α (IκB-α) induced by TNF-α. We used electrophoretic mobility shift assay and reporter gene detection to show that andrographolide also markedly inhibited NF-κB signaling, anti-translocation and anti-activation. In conclusion, we demonstrate that andrographolide attenuates MMP-9 expression, and its main mechanism might involve the NF-κB signal pathway. These results provide new opportunities for the development of new anti-inflammatory and leukemic therapies.


Subject(s)
Diterpenes/pharmacology , Matrix Metalloproteinase 9/metabolism , Monocytes/drug effects , NF-kappa B/metabolism , Protease Inhibitors/pharmacology , Andrographis/chemistry , Cell Line , Cell Survival , Dose-Response Relationship, Drug , Electrophoretic Mobility Shift Assay , Enzyme Activation/drug effects , Enzyme-Linked Immunosorbent Assay , Genes, Reporter , Humans , I-kappa B Proteins/metabolism , Lipopolysaccharides/adverse effects , MAP Kinase Signaling System , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase Inhibitors , Monocytes/metabolism , NF-KappaB Inhibitor alpha , NF-kappa B/antagonists & inhibitors , NF-kappa B/genetics , Protein Transport , Proteolysis/drug effects , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tissue Inhibitor of Metalloproteinase-1/metabolism , Transcriptional Activation/drug effects , Transfection , Tumor Necrosis Factor-alpha/adverse effects
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