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Pharmacological Research Jun 2024Neuropsychiatric disorders shorten human life spans through multiple ways and become major threats to human health. Exercise can regulate the estrogen signaling, which... (Review)
Review
Neuropsychiatric disorders shorten human life spans through multiple ways and become major threats to human health. Exercise can regulate the estrogen signaling, which may be involved in depression, Alzheimer's disease (AD) and Parkinson's disease (PD), and other neuropsychiatric disorders as well in their sex differences. In nervous system, estrogen is an important regulator of cell development, synaptic development, and brain connectivity. Therefore, this review aimed to investigate the potential of estrogen system in the exercise intervention of neuropsychiatric disorders to better understand the exercise in neuropsychiatric disorders and its sex specific. Exercise can exert a protective effect in neuropsychiatric disorders through regulating the expression of estrogen and estrogen receptors, which are involved in neuroprotection, neurodevelopment, and neuronal glucose homeostasis. These processes are mediated by the downstream factors of estrogen signaling, including N-myc downstream regulatory gene 2 (Ndrg2), serotonin (5-HT), delta like canonical Notch ligand 1 (DLL1), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), etc. In addition, exercise can act on the estrogen response element (ERE) fragment in the genes of estrogenic downstream factors like β-amyloid precursor protein cleavase 1 (BACE1). However, there are few studies on the relationship between exercise, the estrogen signaling pathway, and neuropsychiatric disorders. Hence, we review how the estrogen signaling mediates the mechanism of exercise intervention in neuropsychiatric disorders. We aim to provide a theoretical perspective for neuropsychiatric disorders affecting female health and provide theoretical support for the design of exercise prescriptions.
Topics: Humans; Estrogens; Animals; Mental Disorders; Exercise; Exercise Therapy; Signal Transduction; Receptors, Estrogen
PubMed: 38704108
DOI: 10.1016/j.phrs.2024.107201 -
Open Medicine (Warsaw, Poland) 2024Aflatoxin B (AFB) is a subsidiary poisonous metabolite, archetypally spawned by and which are often isolated in warm or tropical countries across the world. AFB is... (Review)
Review
Aflatoxin B (AFB) is a subsidiary poisonous metabolite, archetypally spawned by and which are often isolated in warm or tropical countries across the world. AFB is capable of disrupting the functioning of several reproductive endocrine glands by interrupting the enzymes and their substrates that are liable for the synthesis of various hormones in both males and females. In men, AFB is capable of hindering testicular development, testicular degeneration, and reduces reproductive capabilities. In women, a direct antagonistic interaction of AFB with steroid hormone receptors influencing gonadal hormone production of estrogen and progesterone was responsible for AFB-associated infertility. AFB is potentially teratogenic and is responsible for the development of malformation in humans and animals. Soft-tissue anomalies such as internal hydrocephalus, microphthalmia, cardiac defects, augmented liver lobes, reproductive changes, immune modifications, behavioral changes and predisposition of animals and humans to neoplasm development are AFB-associated anomalies. Substances such as esculin, selenium, gynandra extract, vitamins C and E, oltipraz, and CDDO-Im are potential therapies for AFB. Thus, this review elucidates the pivotal pathogenic roles of AFB in infertility, fetal deformities, and potential therapies because AFB toxicity is a key problem globally.
PubMed: 38283584
DOI: 10.1515/med-2024-0907 -
Biomedicine & Pharmacotherapy =... Jan 2024Excessive deposition of monosodium urate (MSU) crystal in the joint results in gout arthritis, which triggers severe pain and affects life quality. Oxidative stress is a...
Excessive deposition of monosodium urate (MSU) crystal in the joint results in gout arthritis, which triggers severe pain and affects life quality. Oxidative stress is a pivotal mechanism that contributes to etiology of gout pain and inflammation. Here we investigated whether activating Nrf2, which plays important roles in regulating endogenous antioxidant response, would attenuate gout arthritis via promoting antioxidant signaling in joint tissues. Gout arthritis model was established by intra-articular injection of MSU (500 μg/ankle) into the right ankle joint of mouse. Pharmacologically activating Nrf2 by activator oltipraz (50, 100 or 150 mg/kg, intraperitoneal) at 1 h before and 5, 23, 47 h after model establishment dose-dependently inhibited joint inflammation, mechanical and heat hypersensitivities in model mice. Oltipraz (100 mg/kg) reversed gait impairments without altering locomotor activity and reduced neutrophil infiltrations in ankle joints. In vitro studies revealed oltipraz (25 μM) inhibited MSU-induced ROS production in mouse macrophages and improved mitochondrial bioenergetics impairments caused by MSU. In vivo ROS imaging combined with biochemical assays confirmed the antioxidant effects of oltipraz on model mice. Nrf2 activation inhibited pro-inflammatory cytokine overproduction in ankle joint and attenuated the overexpression and enhancement in TRPV1 channel in DRG neurons innervating hind limb. Therapeutic effects of oltipraz were abolished by inhibiting Nrf2 or in Nrf2 knockout mice. These results suggest pharmacologically activating Nrf2 alleviates gout pain, gait impairments, inflammation and peripheral sensitization via Nrf2-dependent antioxidant mechanism. Targeting Nrf2 may represent a novel treatment option for gout arthritis.
Topics: Mice; Animals; Antioxidants; Gout; NF-E2-Related Factor 2; Uric Acid; Reactive Oxygen Species; Arthritis, Gouty; Inflammation; Pain
PubMed: 38042115
DOI: 10.1016/j.biopha.2023.115957 -
Heliyon Nov 2023Our previous study has confirmed that miR338-3p/TRAP-1 axis was involved in regulation of hyperactivation in human synovial fibroblasts (HFLS) of patients with...
Our previous study has confirmed that miR338-3p/TRAP-1 axis was involved in regulation of hyperactivation in human synovial fibroblasts (HFLS) of patients with osteoarthritis (OA). Here, we aim to further investigate the underlying causes of the abnormal activation miR338-3p/TRAP-1 at the molecular level. Our results showed that the decrease of NF-E2-related factor 2(Nrf2) was the direct cause of downregulation of miR338-3p and upregulation of TRAP-1 protein expression in HFLS of OA patients. Furthermore, we also found that the phosphorylation and nuclear entry of Nrf2 protein were significantly reduced in HFLS of OA patients than that of normal individuals, and both of them were positively correlated with miR338-3p levels. Bioinformatics analysis, luciferase assay, and CHIP experiment together indicated that Nrf2 could positively regulate the transcription of miR338-3p by binding to the Transcription Factor Binding Sites (TFBS) on its promoter. It was confirmed by in vitro assays that oltipraz (agonists of Nrf2) treatment effectively inhibited the hyperactivation of HFLS induced by TGF-β1, and the effects of oltipraz could be reversed by the exogenous TRAP-1. In short, our research has revealed for the first time that Nrf2/miR338-3p/TRAP-1 pathway was involved in hyperactivation of HFLS in OA patients, Nrf2 has the potential to be used as therapy and new drug target of OA.
PubMed: 37920489
DOI: 10.1016/j.heliyon.2023.e21412 -
Antioxidants (Basel, Switzerland) Sep 2023The role(s) of nuclear factor erythroid 2-related factor 2 (NRF2) in diabetic kidney disease (DKD) is/are controversial. We hypothesized that Nrf2 deficiency in type 2...
NRF2 Deficiency Attenuates Diabetic Kidney Disease in Db/Db Mice via Down-Regulation of Angiotensinogen, SGLT2, CD36, and FABP4 Expression and Lipid Accumulation in Renal Proximal Tubular Cells.
The role(s) of nuclear factor erythroid 2-related factor 2 (NRF2) in diabetic kidney disease (DKD) is/are controversial. We hypothesized that Nrf2 deficiency in type 2 diabetes (T2D) db/db mice (db/db knockout (KO)) attenuates DKD progression through the down-regulation of angiotensinogen (AGT), sodium-glucose cotransporter-2 (SGLT2), scavenger receptor CD36, and fatty -acid-binding protein 4 (FABP4), and lipid accumulation in renal proximal tubular cells (RPTCs). Db/db KO mice were studied at 16 weeks of age. Human RPTCs (HK2) with KO via CRISPR-Cas9 genome editing and kidneys from patients with or without T2D were examined. Compared with db/db mice, db/db KO mice had lower systolic blood pressure, fasting blood glucose, kidney hypertrophy, glomerular filtration rate, urinary albumin/creatinine ratio, tubular lipid droplet accumulation, and decreased expression of AGT, SGLT2, CD36, and FABP4 in RPTCs. Male and female mice had similar results. KO attenuated the stimulatory effect of the Nrf2 activator, oltipraz, on AGT, SGLT2, and CD36 expression and high-glucose/free fatty acid (FFA)-stimulated lipid accumulation in HK2. Kidneys from T2D patients exhibited markedly higher levels of CD36 and FABP4 in RPTCs than kidneys from non-diabetic patients. These data suggest that NRF2 exacerbates DKD through the stimulation of AGT, SGLT2, CD36, and FABP4 expression and lipid accumulation in RPTCs of T2D.
PubMed: 37760019
DOI: 10.3390/antiox12091715 -
Immunity Feb 2023Neuronal signals have emerged as pivotal regulators of group 2 innate lymphoid cells (ILC2s) that regulate tissue homeostasis and allergic inflammation. The molecular...
Neuronal signals have emerged as pivotal regulators of group 2 innate lymphoid cells (ILC2s) that regulate tissue homeostasis and allergic inflammation. The molecular pathways underlying the neuronal regulation of ILC2 responses in lungs remain to be fully elucidated. Here, we found that the abundance of neurotransmitter dopamine was negatively correlated with circulating ILC2 numbers and positively associated with pulmonary function in humans. Dopamine potently suppressed lung ILC2 responses in a DRD1-receptor-dependent manner. Genetic deletion of Drd1 or local ablation of dopaminergic neurons augmented ILC2 responses and allergic lung inflammation. Transcriptome and metabolic analyses revealed that dopamine impaired the mitochondrial oxidative phosphorylation (OXPHOS) pathway in ILC2s. Augmentation of OXPHOS activity with oltipraz antagonized the inhibitory effect of dopamine. Local administration of dopamine alleviated allergen-induced ILC2 responses and airway inflammation. These findings demonstrate that dopamine represents an inhibitory regulator of ILC2 responses in allergic airway inflammation.
Topics: Humans; Immunity, Innate; Dopamine; Lymphocytes; Lung; Pneumonia; Inflammation; Interleukin-33
PubMed: 36693372
DOI: 10.1016/j.immuni.2022.12.017 -
Cells Sep 2022Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, displays a highly infiltrative growth pattern and remains refractory to chemotherapy....
Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, displays a highly infiltrative growth pattern and remains refractory to chemotherapy. Phytochemicals carrying specificity and low cytotoxicity may serve as potent and safer alternatives to conventional chemotherapy for treating GBM. We have evaluated the anticancer effects of Oltipraz (Olt), a synthetic dithiolethione found in many vegetables, including crucifers. While Olt exposure was non-toxic to the HEK-293 cell line, it impaired the cell growth in three GBM cell lines (LN18, LN229, and U-87 MG), arresting those at the G2/M phase. Olt-exposed GBM cells induced the generation of reactive oxygen species (ROS), mitochondrial depolarization, caspase 3/7-mediated apoptosis, nuclear condensation, and DNA fragmentation, and decreased glutathione, a natural ROS scavenger, as well as vimentin and β-catenin, the EMT-associated markers. Its effect on a subpopulation of GBM cells exhibiting glioblastoma stem cell (GSCs)-like characteristics revealed a reduced expression of Oct4, Sox2, CD133, CD44, and a decrease in ALDH, Nestin and CD44 cells. In contrast, there was an increase in the expression of GFAP and GFAP cells. The Olt also significantly suppressed the oncosphere-forming ability of cells. Its efficacy was further validated in vivo, wherein oral administration of Olt could suppress the ectopically established GBM tumor growth in SCID mice. However, there was no alteration in body weight, organ ratio, and biochemical parameters, reflecting the absence of any toxicity otherwise. Together, our findings could demonstrate the promising chemotherapeutic efficacy of Olt with potential implications in treating GBM.
Topics: Animals; Carcinogenesis; Caspase 3; Cell Line, Tumor; Glioblastoma; Glutathione; HEK293 Cells; Humans; Mice; Mice, SCID; Neoplastic Stem Cells; Nestin; Pyrazines; Reactive Oxygen Species; Thiones; Thiophenes; Vimentin; beta Catenin
PubMed: 36231019
DOI: 10.3390/cells11193057 -
Journal of Nanobiotechnology Sep 2022Targeting cartilage is a promising strategy for the treatment of osteoarthritis, and various delivery vehicles were developed to assist the therapeutic agents into...
Targeting cartilage is a promising strategy for the treatment of osteoarthritis, and various delivery vehicles were developed to assist the therapeutic agents into cartilage. However, the underlying biomechanisms and potential bioactivities remain oversimplified. Inspired by oxidative stress in the pathogenesis of osteoarthritis, we firstly testified the antioxidant capacity of a synthetic small molecule compound, oltipraz (OL), to the chondrocytes treated by IL-1β. Then a functional reactive oxygen species (ROS) responsive nanocarrier, mesoporous silica nanoparticles (MSN) modified with methoxy polyethylene glycol-thioketal, was constructed. In vitro biomolecular results showed that compared with OL alone, MSN-OL could significantly activate Nrf2/HO-1 signaling pathway, which exhibited better ROS-scavenging proficiency and greater anti-apoptotic ability to protect mitochondrial membrane potential of chondrocytes. Further bioinformatics analysis revealed that MSN-OL suppressed clusters of genes associated with extracellular matrix organization, cell apoptosis and cellular response to oxidative stress. Animal experiments further confirmed the great cartilage-protecting ability of MSN-OL through upregulating the expression of Nrf2/HO-1 signaling pathway without obvious toxicity. In summary, this study provided a delivery system through ROS-responsive regulation of the therapeutic agents into chondrocytes of the cartilage, and confirmed the exact biological mechanisms of this innovative strategy.
Topics: Animals; Antioxidants; Cartilage; NF-E2-Related Factor 2; Osteoarthritis; Polyethylene Glycols; Reactive Oxygen Species; Silicon Dioxide
PubMed: 36123746
DOI: 10.1186/s12951-022-01629-w -
Journal of Clinical Biochemistry and... Mar 2022Oltipraz, a synthetic dithiolethione, has chemopreventive effect through nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Nrf2 is known to be involved in...
Oltipraz, a synthetic dithiolethione, has chemopreventive effect through nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Nrf2 is known to be involved in the development of experimental steatohepatitis in rodents. In this study, to evaluate the effect of oltipraz on lipid and bile acid metabolism, wild-type and Nrf2-null mice were fed the standard diet (containing 4% soybean oil) with or without oltipraz. Based on these results, we examined the effect of oltipraz on the experimental steatohepatitis in high-fat diet (containing 4% soybean oil and 20% lard) fed Nrf2-null mice. Oltipraz induced hepatic mRNA expression of peroxisome proliferator-activated receptor α, carnitine palmityl transferase 1, and bile salt export pump by Nrf2 independent mechanisms. In Nrf2-null mice fed a high-fat diet for 12 weeks, moderate to severe inflammation and fibrosis were observed. Oral administration of oltipraz suppressed the degree of inflammation and fibrosis in Nrf2-null mouse liver fed a high-fat diet. These histopathological findings approximately corresponded to the data of mRNA expression of tumor necrosis factor α, monocyte chemoattractant protein-1, Timp-1, and collagen type 1α1. These results indicated that oltipraz administration ameliorated liver injury by Nrf2 independent manner in a model of steatohepatitis generated by Nrf2-null mice with high-fat diet.
PubMed: 35400824
DOI: 10.3164/jcbn.21-58 -
Journal of the American College of... Apr 2022Our previous studies have found that burn injury induces cardiac dysfunction through interruption of the antioxidant-response element (ARE) pathway in cardiac...
BACKGROUND
Our previous studies have found that burn injury induces cardiac dysfunction through interruption of the antioxidant-response element (ARE) pathway in cardiac mitochondria. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator that activates many antioxidant enzymes. Oltipraz (Olti) is a Nrf2 activator and a well-known inducer of NQO1 along with other enzymes that comprise the Nrf2-associated antioxidants. We propose that Nrf2 activation will induce the ARE pathway, leading to abrogation of burn-induced cardiac dysfunction.
STUDY DESIGN
In this study, we investigated the effect of Nrf2-deficiency in mice on burn-induced cardiac dysfunction. Wild-type (WT) and Nrf2-deficient mice received 30% total body surface area burn injury and were treated with or without Olti and then harvested at 3 hours and 24 hours post burn (3 hpb and 24 hpb).
RESULTS
As expected, Nrf2-deficient mice exhibited exacerbated cardiac dysfunction after burn injury, as measured by Vevo 2100 echocardiography. Electron microscopy showed that Nrf2 depletion worsened burn injury-induced cardiac mitochondrial damage. In addition, Nrf2 depletion increased cardiac mitochondrial dysfunction and myocardial fibrosis after burn injury. Treatment with Olti ameliorated the heart dysfunction in burned Nrf2-/+ mice, improved cardiac mitochondrial structure and oxidative phosphorylation, as well as decreased cardiac fibrosis. These results suggest that Nrf2 and its downstream targets modulate cardiac function after burn injury.
CONCLUSIONS
In summary, Nrf2 depletion worsens cardiac dysfunction after burn injury. Nrf2 activation, with a drug such as Olti, offers a promising therapeutic strategy for abrogating burn-induced cardiac dysfunction.
Topics: Animals; Antioxidant Response Elements; Antioxidants; Burns; Heart Diseases; Mice; NF-E2-Related Factor 2; Signal Transduction
PubMed: 35290286
DOI: 10.1097/XCS.0000000000000119