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Postmenopausal osteoporosis (PMO) is characterized by bone loss and microstructural damage, and it is most common in older adult women. Currently, there is no cure for PMO. The flavonoid chemical 7,8-dihydroxyflavone (7,8-DHF) specifically activates tropomyosin receptor kinase B (TRKB). Furthermore, 7,8-DHF has various biological characteristics, including anti-inflammatory and antioxidant effects. However, the specific implications and fundamental mechanisms of 7,8-DHF in PMO remain unclear. We used protein imprinting, flow cytometry, tissue staining, and other methods to estimate the preventive mechanisms of 7,8-DHF against hydrogen peroxide (H 2 O 2)-induced apoptosis in primary mouse bone marrow mesenchymal stem cells (BMSCs), osteogenic differentiation ability, and bone mass in ovariectomized (OVX) mice. We found that 7,8-DHF effectively prevented H 2 O 2 -induced reductions in the viability and osteogenic differentiation capacity of primary BMSCs. Mechanistically, 7,8-DHF induced the TRKB to activate the PI3K/AKT/NRF2 pathway. In vivo experiments with the OVX mouse model confirmed that 7,8-DHF can inhibit oxidative stress and promote bone formation, indicating that 7,8-DHF improves the viability and osteogenic differentiation ability of BMSCs stimulated via H 2 O 2 by activating the TRKB/PI3K/AKT and NRF2 pathways, thereby improving PMO. • 7,8-DHF can inhibit H 2 O 2 -induced oxidative stress in BMSCs and restore the osteogenic differentiation ability of BMSCs. • 7,8-DHF enhances BMSCs antioxidant stress capacity by activating the TRKB/PI3K/AKT/NRF2 signaling pathway. • 7,8-DHF can reverse the downregulation of p-TRKB expression in BMSCs of postmenopausal osteoporotic mice. • 7,8-DHF improves oxidative stress markers in postmenopausal osteoporotic mice and treats postmenopausal osteoporosis. [ABSTRACT FROM AUTHOR]

Introduction7,8-Dihydroxyflavone (7,8-DHF) is a promising translational therapy in several brain injury models, including the neonatal hypoxia-ischemia (HI) model in mice. However, the neuroprotective effect of 7,8-DHF was only observed in female, but not male, neonatal mice with HI brain injury. It is unknown whether HI-induced physiological changes affect brain distribution of 7,8-DHF differently for male versus female mice. We aimed to evaluate the impact of sex on the pharmacokinetics of 7,8-DHF in plasma and brain neonatal mice following experimentally induced HI brain injury.MethodsLeft-sided HI brain injury was induced in postnatal day 9 (P9) mice, followed by a 5 mg/kg intraperitoneal injection of 7,8-DHF. A liquid chromatography-tandem mass spectrometry method was developed to quantitate the drug concentration in plasma samples, as well as in samples from the left and right brain hemispheres. A nonlinear mixed-effects model was used to analyze the plasma and brain concentration-time data. A semi-quantitative approach was used to evaluate the concentrations of two active O-methylated metabolites of 7,8-DHF (8H7M-flavone and 7H8M-flavone) in both plasma and brain samples.ResultsOur PK analyses show that plasma 7,8-DHF concentrations followed a two-compartment PK model, with more than 95% eliminated by 3 h after the IP injection. Sex was not significantly associated with the PK of 7,8-DHF; however, HI brain injury was associated with a 21% reduction in clearance (p < 0.01). The distribution of 7,8-DHF to the brain was rapid; however, the extent of brain distribution was low with the right and left brain-to-plasma partition coefficients being 8.6% and 9.9%, respectively. Additionally, both O-methylated metabolites of 7,8-DHF were detected in the plasma and brain.ConclusionThe plasma and brain PK of 7,8-DHF in neonatal mice were similar between males and females. The low extent of 7,8-DHF brain distribution and the potential effects of the active metabolites should be considered in future studies evaluating the therapeutic effects of 7,8-DHF.

Highlights Following in vitro ischemia, the nerve growth factor receptor TrkB is activated in the presence of the TrkB agonist 7,8-DHF only in female and not in male cultured hippocampal neurons, leading to increased neuronal survival. Expression of ERα is increased following in vitro ischemia in female but not male hippocampal neurons. The female hippocampal neuronal specific responses to in vitro ischemia are blocked by pre-treatment with testosterone. The data support a model for a female-specific a neuroprotective pathway in hippocampal neurons. The pathway is activated by a TrkB agonist, dependent on ERα and blocked by testosterone.

Vitamin B6 deficiency has been linked to cognitive impairment in human brain disorders for decades. Still, the molecular mechanisms linking vitamin B6 to these pathologies remain poorly understood, and whether vitamin B6 supplementation improves cognition is unclear as well. Pyridoxal 5’-phosphate phosphatase (PDXP), an enzyme that controls levels of pyridoxal 5’-phosphate (PLP), the co-enzymatically active form of vitamin B6, may represent an alternative therapeutic entry point into vitamin B6-associated pathologies. However, pharmacological PDXP inhibitors to test this concept are lacking. We now identify a PDXP and age-dependent decline of PLP levels in the murine hippocampus that provides a rationale for the development of PDXP inhibitors. Using a combination of small-molecule screening, protein crystallography, and biolayer interferometry, we discover, visualize, and analyze 7,8-dihydroxyflavone (7,8-DHF) as a direct and potent PDXP inhibitor. 7,8-DHF binds and reversibly inhibits PDXP with low micromolar affinity and sub-micromolar potency. In mouse hippocampal neurons, 7,8-DHF increases PLP in a PDXP-dependent manner. These findings validate PDXP as a druggable target. Of note, 7,8-DHF is a well-studied molecule in brain disorder models, although its mechanism of action is actively debated. Our discovery of 7,8-DHF as a PDXP inhibitor offers novel mechanistic insights into the controversy surrounding 7,8-DHF-mediated effects in the brain.

Flavonoids, which contain a benzo‐γ‐pyrone (C6–C3–C6) skeleton, have been reported to exhibit effective antioxidant ability. This study aimed to compare the antioxidant activities of 7,8‐dihydroxyflavone (7,8‐DHF) and 7‐hydroxyflavone (7‐HF) in H2O2, lipopolysaccharide (LPS), or tert‐butyl hydroperoxide (t‐BHP)‐induced RAW264.7 cells, respectively. The antioxidant capacities of 7,8‐DHF and 7‐HF were firstly evaluated by 2,2‐azinobis‐3‐ethyl‐benzothiazoline‐6‐sulphonic acid (ABTS), 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. Then, reactive oxygen species (ROS), super oxide dismutase (SOD), and malondialdehyde (MDA) productions in H2O2, LPS, or t‐BHP‐induced RAW264.7 cells were tested and compared, respectively. Finally, the antioxidant mechanisms of 7‐HF and 7,8‐DHF were initially investigated by western blot. Our results showed that 7,8‐DHF possessed stronger free‐radical scavenging capacity than 7‐HF. Both 7,8‐DHF and 7‐HF suppressed MDA production and ROS accumulation, improved the activity of SOD in H2O2, LPS, or t‐BHP‐induced RAW264.7 cells, respectively. And 7,8‐DHF exerted a better antioxidant effect than 7‐HF, especially in t‐BHP‐induced oxidative stress. Mechanically, 7,8‐DHF prevented the activation of poly ADP‐ribosepolymerase and caspase‐3, meanwhile markedly upregulated the expression of HO‐1 protein in t‐BHP‐induced oxidative stress. These results suggested that 7,8‐DHF might serve as a potential pharmaceutical drug against oxidative stress injury. [ABSTRACT FROM AUTHOR]

7,8‐dihydroxyflavone (7,8‐DHF) is a biologically active flavone with various physiological activities, including neuroprotection, anti‐inflammation, and weight loss. Previous studies have found that the efflux protein P‐glycoprotein (P‐gp) significantly affects the transepithelial transport of 7,8‐DHF in the intestine, resulting in its low oral bioavailability. Based on this, in this study, a Caco‐2 monolayer cell model was used to investigate 14 dietary plant flavonoids as potential P‐gp inhibitors, and their effects on the transepithelial transport and in vitro digestion of 7,8‐DHF were explored. The results showed that among the 14 plant flavonoids, hesperetin, epigallocatechin gallate, fisetin, kaempferol, quercetin, and isoorientin increased and the apparent permeability coefficients (Papp) of 7,8‐DHF at AP → BL direction and lowered Papp value at BL → AP direction to varying degrees, reducing the efflux ratio of 7,8‐DHF less than 1.5. In particular, kaempferol and quercetin exhibited the best effect on promoting the transepithelial transport of 7,8‐DHF, especially when used at molar concentration ratios of 1:1 and 1:2 with 7,8‐DHF. This is beneficial for improving the oral bioavailability of 7,8‐DHF. Meanwhile, 7,8‐DHF was found to maintain structural stability in simulated saliva, gastric juice, and intestinal juice, and its stability was not affected by the coexistence of quercetin and kaempferol. Overall, this study provided a theoretical basis for seeking natural and safe P‐gp inhibitors to improve the oral absorption of natural products. [ABSTRACT FROM AUTHOR]

Background: Stroke, particularly ischemic stroke, is one of the leading causes of death worldwide. Ischemic stroke causes a failure of oxidative phosphorylation and ATP synthesis, resulting in high levels of reactive oxygen species (ROS), neuroinflammatory responses, and apoptosis, all of which result in cell death. Neuroprotective agents are given to prevent the infarct area from expanding. Objective: This study aims to predict an in silico interaction by 7,8-dihydroxyflavone as neuprotective agent through TrkB signaling and inhibiting Glutaminase activity. Methods: In silico simulation with 7,8-dihydroxyflavone (DHF) as neuroprotective agent using PubChem, RCSB, Biovia Discovery Studio, PyRx, and PyMol software. This study analyzes the pharmacokinetics, pharmacodynamics, and protein-ligand interactions between 7,8-DHF as a ligand with TrkB (4AT5) and Glutaminase (5JYO) as protein target, compared to their native ligand. Results: 7,8 DHF binds to 4AT5 and 5JYO with lower bond energy (-9.4 Kcal/mol and -6.3 Kcal/mol, respectively) than the native ligand (-5 Kcal/mol and -5.9 Kcal/mol, respectively). It means that 7,8-DHF may increase protective mechanism. Conclusion: These findings tend to increase downstream signaling pathways, leading to increased TrkB expression, which induces protective mechanisms, and decreased glutamate expression, which reduces glutamate toxicity.

Background: Times New Roman 9, single space, contains the brief description of the research. Stroke is the greatest cause of disability and mortality worldwide. Several biological mechanisms underlying this disease such as failure of glutamate reuptake and ATP synthesis, resulting in high levels of reactive oxygen species (ROS), neuroinflammatory responses, and apoptosis, resulted in cell death and brain tissue damage. Neurotherapeutics agents are given to affect the pathophysiological pathways and prevent expanding infarct area. Objective: This study aims to analyze the modulation of Gluthatione S-Transferase (GST) and Tyrosine kinase receptor C (TrkC) by 7,8-DHF as neuroprotective agent in ischemic in silico. Methods: This study used in silico simulation to predict 7,8-dihydroxyflavone (DHF) as neuroprotective agent by using PubChem, RCSB, Biovia Discovery Studio, PyRx, and PyMol. This study analyzes the pharmacodynamics, pharmacokinetics, and molecular interactions between 7,8-DHF as a ligand with GST (13GS) and TrkC (6KZC) as protein target, compared to their native ligand. Results: 7,8-DHF may increase intracellular endogenous antioxidants mainly GST and stimulate TrkC to activate further neuron survival signaling. 7,8 DHF has a much lower bond energy (-8.1 Kcal/mol) when it binds to GST compared to the native ligand (-5.9 Kcal/mol). Besides, binding affinity between 7,8-DHF-TrkC was -9 Kcal/mol, while native ligand-TrkC was -10.6 Kcal/mol. This study showed that there were the same amino acid residues between 7,8-DHF-GST and 7,8-DHF-TrkC, compared to their native ligand. Conclusion: As an adaptive response to hypoxia caused by ischemic stroke, these findings are likely to induce protective mechanism through indirectly TrkC activation which regulates neurogenesis and increasing intracellular endogenous antioxidants.

The aim of this study was to investigate the effects of 7,8-dihydroxyflavone (7,8-DHF) in protecting retinal ganglion cells (RGCs) and promoting axonal regeneration, and to explore its potential molecular mechanisms. We used three-dimensional retinal culture system and optic nerve crush (ONC) rat models in this study. The pro-axonal regenerative effect of 7,8-DHF was determined with light microscopy observation and immunofluorescence staining of Thy1.1 and GAP43. The RGC protective function of 7,8-DHF was detected by RBPMS immunofluorescent staining and TUNEL staining. The inhibition effect of 7,8-DHF on astrocyte activation was measured using GFAP immunofluorescence and Western blotting. The protein levels of p-TrkB, p-AKT and p-ERK was examined by Western blotting and immunohistochemistry. Our results revealed that 7,8-DHF significantly promoted the average density and length of regenerated neurites and suppressed the apoptosis of GCL cells in three-dimensional culture system and significantly increased the number of RBPMS-positive cells and inhibited the GFAP expression and apoptosis of GCL cells in ONC rats. Our results also revealed that 7,8-DHF activates TrkB, AKT and ERK proteins in vivo, however, these activations can be inhibited byANA-12. In conclusion, 7,8-DHF protects RGCs and promotes axonal regeneration through the TrkB signaling pathway followed by AKT and ERK activation. • 7,8-Dihydroxiflavone (7,8-DHF) promotes neurite regeneration in vitro. • 7,8-DHF ameliorates the death of RGCs in vivo. • 7,8-DHF provides neuroprotection via TrkB signaling followed by AKT and ERK activation. [ABSTRACT FROM AUTHOR]

Abstract Malignant melanoma is a skin cancer with poor prognosis and high resistance to conventional treatment. 7,8-dihydroxyflavone (7,8-DHF) has shown anti-carcinogenic, anti-inflammatory, anti-oxidant, and pharmacological effects in several types of cancer. However, the relationship between ganglioside expression and the anti-cancer effects of 7,8-DHF in melanoma is not fully understood. In the present study, 7,8-DHF exhibits specific anti-proliferation, anti-migration, and G2/M phase cell-cycle arrest effects on both melanoma cancer cell lines, and induces mitochondrial dysfunction and apoptosis, making it a potent candidate for anti-melanoma treatment. Furthermore, we confirmed that 7,8-DHF significantly reduces the expression levels of ganglioside GD3 and its synthase, which are known to be closely involved in carcinogenesis. Taken together, our findings suggest that 7,8-DHF may be a potent anti-cancer drug candidate for the treatment of malignant melanoma.

The relationship between mitochondrial dysfunction and cardiovascular disease pathogenesis is well recognized. 7,8-Dihydroxyflavone (7,8-DHF), a mimetic of brain-derived neurotrophic factor, inhibits mitochondrial impairments and improves cardiac function. However, the regulatory role of 7,8-DHF in the mitochondrial function of cardiomyocytes is not fully understood. To investigate the potential mito-protective effects of 7,8-DHF in cardiomyocytes, we treated H9c2 or HL-1 cells with the mitochondrial respiratory complex I inhibitor rotenone (Rot) as an in vitro model of mitochondrial dysfunction. We found that 7,8-DHF effectively eliminated various concentrations of Rot-induced cell death and reduced lactate dehydrogenase release. 7,8-DHF significantly improved mitochondrial membrane potential and inhibited mitochondrial reactive oxygen species. Moreover, 7,8-DHF decreased routine and leak respiration, restored protein levels of mitochondrial complex I-IV, and increased ATP production in Rot-treated H9c2 cells. The protective role of 7,8-DHF in Rot-induced damage was validated in HL-1 cells. Nuclear phosphorylation protein expression of signal transducer and activator of transcription 3 (STAT3) was significantly increased by 7,8-DHF. The present study suggests that 7,8-DHF rescues Rot-induced cytotoxicity by inhibiting mitochondrial dysfunction and promoting nuclear translocation of p-STAT3 in cardiomyocytes, thus nominating 7,8-DHF as a new pharmacological candidate agent against mitochondrial dysfunction in cardiac diseases. [Display omitted] • 7,8-DHF rescued rotenone-induced cardiotoxicity in H9c2 and HL-1 cells. • 7,8-DHF maintained mitochondrial function and inhibited oxidative stress. • 7,8-DHF increased ATP production and restored AMPK protein expression. • 7,8-DHF promoted nuclear translocation of p-STAT3 (Tyr705). [ABSTRACT FROM AUTHOR]

Introduction: 7,8-dihydroxyflavone (7,8-DHF) is a low molecular weight compound that can cross the blood brain barrier and has been implicated in numerous functions and behaviours. It is thought to have neuroprotective capability and has been shown to alleviate symptoms in a wide range of diseases. Methods: 7,8-DHF was administered systemically to wildtype mice during Morris water maze training. Long-term spatial memory was assessed 28 days later. Exvivo T2-weighted (T2w) imaging was undertaken on a subset of these mice to assess brain-wide changes in volume. Results: We found that systemic 7,8-DHF administration during the training period enhanced spatial memory 28 days later. Volumetric changes were observed in numerous brain regions associated with a broad range of functions including cognition, sensory, and motor processing. Discussion: Our findings give the first whole brain overview of longterm anatomical changes following 7,8-DHF administration providing valuable information for assessing and understanding the widespread effects this drug has been shown to have in behaviour and disease. [ABSTRACT FROM AUTHOR]

Obesity-induced inflammation and insulin resistance are mediated by macrophage infiltration into adipose tissue. We investigated the effects of 7,8-dihydroxyflavone (7,8-DHF), a flavone found in plants, on the inflammatory response and insulin resistance induced by the interaction between adipocytes and macrophages. Hypertrophied 3T3-L1 adipocytes were cocultured with RAW 264.7 macrophages and treated with 7,8-DHF (3.12, 12.5, and 50 μM). The inflammatory cytokines and free fatty acid (FFA) release were evaluated by assay kits, and signaling pathways were determined by immunoblotting. Coculture of adipocytes and macrophages increased inflammatory mediators, such as nitric oxide (NO), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) and FFA secretion but suppressed the production of anti-inflammatory adiponectin. 7,8-DHF counteracted the coculture-induced changes (p < 0.001). 7,8-DHF also inhibited c-Jun N-terminal kinase (JNK) activation and blocked nuclear factor kappa B (NF-κB) nuclear translocation in the coculture system (p < 0.01). In addition, adipocytes cocultured with macrophages did not increase glucose uptake and Akt phosphorylation in response to insulin. However, 7,8-DHF treatment recovered the impaired responsiveness to insulin (p < 0.01). These findings show that 7,8-DHF alleviates inflammation and adipocyte dysfunction in the coculture of hypertrophied 3T3-L1 adipocytes and RAW 264.7 macrophages, indicating its potential as a therapeutic agent for obesity-induced insulin resistance. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders are generally characterized by progressive neuronal loss and cognitive decline, with underlying mechanisms involving oxidative stress, protein aggregation, neuroinflammation, and synaptic dysfunction. Currently, the available treatment options only improve the symptoms of the disease but do not stop disease progression; neurodegeneration. This underscores the urgent need for novel therapeutic strategies targeting multiple neurodegenerative pathways alongside the conventional therapeutic strategies available. Emerging evidence demonstrates that flavones a subgroup of flavonoids found abundantly in various dietary sources, have surfaced as promising candidates for neuroprotection due to their multifaceted pharmacological properties. Flavones possess the potency to modulate these pathophysiological processes through their antioxidant, anti-inflammatory, and neurotrophic activities. Additionally, flavones have been shown to interact with various cellular targets, including receptors and enzymes, to confer neuroprotection. Though there are ample evidence available, the nutraceutical and neuroprotective pharmacodynamics of flavones have not been very well established. Hence, the current review aims to explores the therapeutic potential of flavones as nutraceuticals with neuroprotective effects, focusing on their ability to modulate key pathways implicated in neurodegenerative diseases. The current article also aims to actuate supplementary research into flavones as potential agents for alleviating neurodegeneration and improving patient outcomes in neurodegenerative disorders globally. • Globally neurodegenerative disorders have become the leading cause of disability. • Pharmacodynamic properties of flavones are responsible for its therapeutic effects. • Flavones possess neurotrophic, neuroprotective, and neuro-regenerative effects. • 7,8-DHF selectively binds to TrkB receptor and attenuates neurodegeneration. • Scientific exploration of flavones holds great promise to treat neurodegeneration. [ABSTRACT FROM AUTHOR]

Introduction: 7,8-dihydroxyflavone (7,8-DHF) is a low molecular weight compound that can cross the blood brain barrier and has been implicated in numerous functions and behaviours. It is thought to have neuroprotective capability and has been shown to alleviate symptoms in a wide range of diseases.Methods: 7,8-DHF was administered systemically to wildtype mice during Morris water maze training. Long-term spatial memory was assessed 28 days later. Ex-vivo T2-weighted (T2w) imaging was undertaken on a subset of these mice to assess brain-wide changes in volume.Results: We found that systemic 7,8-DHF administration during the training period enhanced spatial memory 28 days later. Volumetric changes were observed in numerous brain regions associated with a broad range of functions including cognition, sensory, and motor processing.Discussion: Our findings give the first whole brain overview of long-term anatomical changes following 7,8-DHF administration providing valuable information for assessing and understanding the widespread effects this drug has been shown to have in behaviour and disease.

The BDNF-TrkB signaling pathway and its downstream cascade disorders participate in learning and memory impairments. The BDNF - TrkB signaling pathway and its downstream cascades are involved in the generation of synapses which then regulate learning and memory. Intraperitoneal injection of LPS damages the BDNF - TrkB signaling pathway and its downstream cascade, leading to cognitive dysfunction. 7,8-DHF can penetrate the blood–brain barrier and activate TrkB receptors, alleviating learning and memory deficits. [Display omitted] • The BDNF-TrkB pathway and downstream cascades are involved in cognitive deficits. • 7,8-DHF could alleviate cognitive deficits via acting on the TrkB in LPS mice. • The mPFC, hippocampus and EC regions are associated with learning and memory. • 7,8-DHF might serve as a potential treating target in neurodegenerative diseases. Accumulating evidence suggests that neuroinflammation is the main mechanism in cognitive dysfunction and that brain-derived neurotrophic factor (BDNF) is involved in learning and memory by binding to tyrosine kinase B (TrkB) receptors. Herein, we tested the roles of the BDNF - TrkB signaling pathway and its downstream cascade in lipopolysaccharide (LPS) induced cognitive dysfunction in mice. Mice were treated with LPS (0.25 mg/kg) for 7 days, and learning and memory function was evaluated by the novel object recognition test (NORT). Western blotting was performed to elucidate roles of the BDNF - TrkB signaling pathway and its downstream cascades in LPS mice. The NORT showed that LPS induced learning and memory deficits in mice. The levels of IL-1β, IL-6, and TNF-α in the serum and central nervous system decreased in LPS mice. In addition, LPS reduced the protein levels of BDNF, p-TrkB, Bcl-2, p-ERK1/2, p-CaMK2, p-CREB and p-GluR1 and increased the expression of Bax in the hippocampus and medial prefrontal cortex regions. In the entorhinal cortex, the protein levels of BDNF, p-TrkB, Bcl-2, p-CaMK2 and p-CREB were decreased, and the protein level of Bax was increased in LPS mice. Interestingly, 7,8-DHF alleviated these disorders in LPS mice and improved learning and memory function; however, the TrkB antagonist ANA12 effectively reversed effects of 7,8-DHF. Therefore, we conclude that the BDNF - TrkB signaling pathway and its downstream cascades disorders in different regions are main mechanisms of cognitive dysfunction, and 7,8-DHF maybe useful as a new treatment for preventing or treating cognitive dysfunction induced by neuroinflammation in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

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Infection during pregnancy is a substantial risk factor for the unborn child to develop autism or schizophrenia later in life, and is thought to be driven by maternal immune activation (MIA). MIA can be modelled by exposing pregnant mice to Polyinosinic: polycytidylic acid (Poly-I:C), a viral mimetic that induces an immune response and recapitulates in the offspring many neurochemical features of ASD and schizophrenia, including altered BDNF-TrkB signalling and disruptions to excitatory/inhibitory balance. Therefore, we hypothesised that a BDNF mimetic, 7,8-Dihydroxyflavone (7,8-DHF), administered prophylactically to the dam may prevent the neurobehavioural sequelae of disruptions induced by MIA. Dams were treated with 7,8-DHF in the drinking water (0.08 mg/ML) from gestational day (GD) 9–20 and were exposed to Poly-I:C at GD17 (20 mg/kg, i.p.). Foetal brains were collected 6 h post Poly-I:C exposure for RT-qPCR analysis of BDNF, cytokine, GABAergic and glutamatergic gene targets. A second adult cohort were tested in a battery of behavioural tests relevant to schizophrenia and the prefrontal cortex and ventral hippocampus dissected for RT-qPCR analysis. Foetal brains exposed to Poly-I:C showed increased IL-6, but reduced expression of Ntrk2 and multiple GABAergic and glutamatergic markers. Anxiety-like behaviour was observed in adult offspring prenatally exposed to poly-I:C, which was accompanied by altered expression of Gria2 in the prefrontal cortex and Gria4 in the ventral hippocampus. While 7–8 DHF normalised the expression of some glutamatergic (Grm5) and GABAergic (Gabra1) genes in Poly-I:C exposed offspring, it also led to substantial alterations in offspring not exposed to Poly-I:C. Furthermore, mice exposed to 7,8-DHF prenatally showed increased pre-pulse inhibition and reduced working memory in adulthood. These data advance understanding of how 7,8-DHF and MIA prenatal exposure impacts genes critical to excitatory/inhibitory pathways and related behaviour. • Maternal immune activation (MIA) reduced foetal brain GABAergic marker expression • MIA reduced expression of multiple glutamate receptors in foetal brains • Maternal 7,8-DHF treatment prevented MIA-induced disruptions to Gabra1 and Grm5 • Maternal 7,8-DHF alone disrupted multiple GABAergic and glutamatergic markers. • Maternal 7,8-DHF treatment did not prevent behavioural disturbances induced by MIA. [ABSTRACT FROM AUTHOR]

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by progressive degeneration of both upper and lower motor neurons, resulting in paralysis and eventually leads to death from respiratory failure typically within 3 to 5 years of symptom onset. The aim of this work was to predict the pharmacokinetics and identify unique protein targets that are associated with potential anti-ALS phytochemicals and FDA-approved drugs, by in silico approaches. Materials and methods: Standard computational tools (webserver and software) were used, and the methods used are clustering analysis, pharmacokinetics and molecular target predictions, and molecular docking simulation. Results and discussion: The results show that riluzole, ß-asarone, cryptotanshinone, harmine and 7,8-dihydroxyflavone have similar pharmacokinetics properties. Riluzole and harmine show 95% probability of target on norepinephrine transporter. Huperzine-A and cryptotanshinone show 100% probability of target on acetylcholinesterase. 7,8-dihydroxyflavone shows 35% probability of target on several carbonic anhydrases, 40% probability of target on CYP19A1, and 100% probability of target on inhibitor of nuclear factor kappa B kinase beta subunit and neurotrophic tyrosine kinase receptor type 2, respectively. Harmine also shows 95% probability of target on dual specificity tyrosine-phosphorylation-regulated kinases, threonine-protein kinases (haspin and PIM3), adrenergic receptors, cyclin-dependent kinases (CDK5 and CDK9), monoamine oxidase A, casein kinase I delta, serotonin receptors, dual specificity protein kinases (CLK1, CLK2, and CLK4), and nischarin, respectively. Also, the results of gene expression network show possible involvement of CDK1, CDK2, CDK4, ERK1, ERK2 and MAPK14 signaling pathways. This study shows that riluzole and harmine have closely similar physicochemical and pharmacokinetics properties as well as molecular targets, such as norepinephrine transporter (SLC6A2). Harmine, huperzine-A and cryptotanshinone could modulate acetylcholinesterase (AChE), which is involved in ALS-pathogenesis. The impact of 7,8-dihydroxyflavone on several carbonic anhydrases (CA) I, II, VII, IX, XII, and XIV, as well as CYP19A1, could help in remediating the respiratory failure associated with ALS. Conclusion: Overall, harmine is found to be superior to riluzole, and the combination of harmine with 7,8-dihydroxyflavone can provide more effective treatment for ALS than the current regime. Further work is needed to validate the predicted therapeutic targets of harmine identified in this study on ALS model or clinical trials, using in silico, in vitro and in vivo techniques. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the most common motor-associated neurodegenerative disease. Although the pathogenesis of PD is still wrapped in the mist, accumulating evidence indicates that mitochondrial dysfunction contributes to the onset and progression of PD. We previously reported that the lysosomal protease asparagine endopeptidase (AEP) cleaves α-synuclein in the brains of PD patients. The major product, α-synuclein 1–103, significantly promotes PD-like histological changes and motor dysfunction. However, the underlying molecular mechanisms remain unknown. Here we show that α-synuclein 1–103 fragment interacts with mitochondria and induces morphological and functional abnormalities of mitochondria. Furthermore, we investigated the protective effects of 7,8-dihydroxyflavone (7,8-DHF) on mitochondrial dysfunction induced by α-synuclein 1–103 fragment. We found that 7,8-DHF ameliorated α-synuclein 1–103-induced mitochondrial impairment and motor dysfunction. These results indicate that 7,8-DHF represents a novel oral bioactive therapeutic agent for treating PD.

Abstract Glaucoma is the leading cause of irreversible blindness globally and is associated with retinal ganglion cell (RGC) death. Brain‐derived neurotrophic factor (BDNF) is a potent neurotrophin that promotes neuronal survival via its receptor, tropomyosin receptor kinase B (TrkB) encoded by NTRK2. Our current understanding of the mechanism of action and therapeutic potential of the BDNF pathway is limited by the lack of knowledge of its interaction with TrkB at atomic resolution. We developed an artificial intelligence (AI) model to predict the three‐dimensional protein structures of BDNF and TrkB, as well as their interaction. The AI model was further applied to compare small‐molecule drugs that mimic BDNF–TrkB interaction, leading to the identification of 7,8‐dihydroxyflavone (DHF) as an agonist of TrkB. We verified the neuroprotective effects of DHF in an in vivo acute glaucoma model in which RGC apoptosis caused by acute elevation of intraocular pressure was prevented by the intraocular application of DHF and to a lesser extent by BDNF. Our results provide AI‐enabled prediction of ligand–receptor interactions between BDNF and TrkB at the atomic level and demonstrate the great potential for AI‐enabled drug discovery.

Purpose: Chronic intermittent hypoxia (CIH) plays a key role in the complications of obstructive sleep apnea (OSA), which is strongly associated with retinal and optic nerve diseases. Additionally, the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling pathway plays an important protective role in neuronal injury. In the present study, we investigated the role of 7,8-dihydroxyflavone (7,8-DHF) in regulating CIH-induced injury in mice retinas and rat primary retinal ganglion cells (RGCs). Methods: C57BL/6 mice and in vitro primary RGCs were exposed to CIH or normoxia and treated with or without 7,8-DHF. The mice eyeballs or cultured cells were then taken for histochemistry, immunofluorescence or biochemistry, and the protein expression of the BDNF/TrkB signaling pathway analysis. Results: Our results showed that CIH induced oxidative stress (OS) in in vivo and in vitro models and inhibited the conversion of BDNF precursor (pro-BDNF) to a mature form of BDNF, which increased neuronal cell apoptosis. 7,8-DHF reduced the production of reactive oxygen species (ROS) caused by CIH and effectively activated TrkB signals and downstream protein kinase B (Akt) and extracellular signal-regulated kinase (Erk) survival signaling pathways, which upregulated the expression of mature BDNF. ANA-12 (a TrkB specific inhibitor) blocked the protective effect of 7,8-DHF. Conclusion: In short, the activation of the BDNF/TrkB signaling pathway alleviated CIH-induced oxidative stress damage of the optic nerve and retinal ganglion cells. 7,8-DHF may serve as a promising agent for OSA related neuropathy. [ABSTRACT FROM AUTHOR]

Background. 7,8-dihydroxyflavone (7,8-DHF), a selective agonist of tropomyosin related kinase receptor B (TrkB), is known to exert protective effects in neurodegenerative diseases. However, the role of 7,8-DHF in TrkB signaling after ischemic stroke has remained elusive. Methods. In the vitro model of ischemic stroke, we investigated the neuroprotective effect of 7,8-DHF through activation of TrkB signaling. Neurons subjected to oxygen and glucose deprivation/reperfusion were treated with the protein kinase inhibitor K252a and a knockdown of TrkB. Cell counting kit-8 (CCK-8) assay, Flow Cytometric Analysis (FACS), TdT-mediated dUTP nick end labeling (TUNEL) assay were conducted for measuring cell viability and numbers of apoptotic cells. And apoptosis-associated proteins were analyzed by Western blotting. Results. Compared with the Control group, OGD/R group revealed lower cell viability by CCK-8 assay FACS and TUNEL assay showed increased rates of neuronal apoptosis. However, 7,8-DHF treatment increased cell viability and reduced neuronal apoptosis. Western blotting indicated upregulated Bax and cleaved caspase-3 and but downregulated Bcl-2 following OGD/R. Whereas 7,8-DHF treatment downregulated Bax and cleaved caspase-3 but upregulated Bcl-2. These changes were accompanied by a significant increase in the phosphorylation of TrkB and Akt following 7,8-DHF administration. However, the administration of K252a and knockdown of TrkB could alleviate those effects. Conclusion. Our study demonstrates that activation of TrkB signaling by 7,8-DHF protects neurons against OGD/R injury via the TrkB/Akt pathway, which provides the evidence for the role of TrkB signaling in OGD-induced neuronal damage and may become a potential therapeutic target for ischemic stroke. [ABSTRACT FROM AUTHOR]

In this work, the lactoferrin (LF) was glycosylated by dextran (molecular weight 10, 40, and 70 kDa, LF 10K, LF 40K, and LF 70K) via Maillard reaction as a stabilizer to establish zein/glycosylated LF nanoparticles and encapsulate 7,8-dihydroxyflavone (7,8-DHF). Three zein/glycosylated LF nanoparticles (79.27–87.24 nm) with low turbidity (

We recently reported that intraperitoneal injection of 7,8-dihydroxyflavone (7,8-DHF), a brain-derived neurotrophic factor-mimicking small compound, could attenuate alcohol-related behaviors in a two-bottle choice ethanol consumption procedure (IA2BC) in rats via tropomyosin receptor kinase B in the ventral tegmental area (VTA), which is closely related to alcohol use disorder. However, the detailed mechanisms underlying the regulation of 7,8-DHF on alcohol drinking behavior remain elusive. In this study, we determined the role of nitric oxide (NO), a pleiotropic signaling molecule, in the VTA in the action of 7,8-DHF upon alcohol drinking behavior. Intermittent alcohol exposure led to the overexpression of NO in the VTA, especially 72 h after withdrawal from four weeks of ethanol exposure in IA2BC rats. A higher amount of alcohol intake was also found at the same time point, consistent with the overexpression of NO in the VTA. Microinjection of NG-Nitro-l-Arginine Methyl Ester, (NO synthase inhibitor) or 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (NO scavenger) into the VTA inhibited alcohol intake, whereas application of S-Nitroso-N-acetyl-DL-penicillamine (SNAP, the NO donor) in the VTA further enhanced alcohol consumption in IA2BC rats. Interestingly, either 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (a sGC inhibitor) or KT5823 [a selective protein kinase G (PKG) inhibitor] blocked NO's enhancing effect on ethanol intake. Intraperitoneal injection of 7,8-DHF reduced the overexpression of NO; SNAP microinjected into the VTA reversed the inhibitory effects of 7,8-DHF on alcohol consumption. Our findings suggest that NO-cGMP-PKG might be involved in regulation of 7,8-DHF on alcohol consumption in IA2BC rats. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease with memory loss and cognitive decline. Neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau protein are one of the pathological hallmarks of several neurodegenerative diseases including AD. Heat shock protein family B (small) member 1 (HSPB1) is a molecular chaperone that promotes the correct folding of other proteins in response to environmental stress. Nuclear factor erythroid 2-like 2 (NRF2), a redox-regulated transcription factor, is the master regulator of the cellular response to excess reactive oxygen species. Tropomyosin-related kinase B (TRKB) is a membrane-bound receptor that, upon binding brain-derived neurotrophic factor (BDNF), phosphorylates itself to initiate downstream signaling for neuronal survival and axonal growth. In this study, four natural flavones such as 7,8-dihydroxyflavone (7,8-DHF), wogonin, quercetin, and apigenin were evaluated for Tau aggregation inhibitory activity and neuroprotection in SH-SY5Y neuroblastoma. Among the tested flavones, 7,8-DHF, quercetin, and apigenin reduced Tau aggregation, oxidative stress, and caspase-1 activity as well as improved neurite outgrowth in SH-SY5Y cells expressing ΔK280 TauRD-DsRed folding reporter. Treatments with 7,8-DHF, quercetin, and apigenin rescued the reduced HSPB1 and NRF2 and activated TRKB-mediated extracellular signal-regulated kinase (ERK) signaling to upregulate cAMP-response element binding protein (CREB) and its downstream antiapoptotic BCL2 apoptosis regulator (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of these three flavones. Our results suggest 7,8-DHF, quercetin, and apigenin targeting HSPB1, NRF2, and TRKB to reduce Tau aggregation and protect cells against Tau neurotoxicity and may provide new treatment strategies for AD. [ABSTRACT FROM AUTHOR]

Background: Whether 7,8-dihydroxyflavone (7,8-DHF), a tyrosine kinase receptor B (TrkB) agonist, modulates colonic smooth muscle motility and/or alleviates constipation has not yet been studied. Aims: Here, we aimed to determine how 7,8-DHF influences carbachol (CCh)-stimulated contraction of colonic strips and the in vivo effect of 7,8-DHF on constipation. Methods: Muscle strips were isolated from rat colons for recording contractile tension and performing western blotting. Constipation was induced in rats with loperamide. Results: Although it specifically activated TrkB, 7,8-DHF applied alone neither activated PLCγ1 in the colonic strips nor induced colonic strip contraction. However, 7,8-DHF enhanced CCh-stimulated PLCγ1 activation and strip contraction. The PLCγ1 antagonist U73122 suppressed both CCh-stimulated and 7,8-DHF-enhanced/CCh-stimulated contraction. While clarifying the underlying mechanism, we revealed that 7,8-DHF augmented muscarinic M3 receptor expression in the colonic strips. The M3-selective antagonist tarafenacin specifically inhibited the 7,8-DHF-enhanced/CCh-stimulated contraction of the colonic strips. Since 7,8-DHF increased Akt phosphorylation, and LY294002 (an antagonist of PI3K upstream of Akt) dramatically inhibited both 7,8-DHF-augmented M3 expression and 7,8-DHF-enhanced/CCh-stimulated contractions, we assumed that 7,8-DHF/TrkB/Akt was associated with the modulation of M3 expression in the colonic strips. ANA-12, a specific TrkB antagonist, not only inhibited TrkB activation by 7,8-DHF but also suppressed 7,8-DHF-enhanced cholinergic contraction, 7,8-DHF/CCh-mediated activation of PLCγ1/Akt, and M3 overexpression in colonic strips. In vivo 7,8-DHF, also by promoting intestinal motility and M3 expression, significantly alleviated loperamide-induced functional constipation in rats. Conclusions: Our results suggest that 7,8-DHF regulates colonic motility possibly via a TrkB/Akt/M3 pathway and may be applicable for alleviating constipation. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with memory loss and cognitive decline. Neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau protein are one of the pathological hallmarks of several neurodegenerative diseases including AD. Heat shock protein family B (small) member 1 (HSPB1) is a molecular chaperone that promotes the correct folding of other proteins in response to environmental stress. Nuclear factor erythroid 2-like 2 (NRF2), a redox-regulated transcription factor, is the master regulator of the cellular response to excess reactive oxygen species. Tropomyosin-related kinase B (TRKB) is a membrane-bound receptor that, upon binding brain-derived neurotrophic factor (BDNF), phosphorylates itself to initiate downstream signaling for neuronal survival and axonal growth. In this study, four natural flavones such as 7,8-dihydroxyflavone (7,8-DHF), wogonin, quercetin, and apigenin were evaluated for Tau aggregation inhibitory activity and neuroprotection in SH-SY5Y neuroblastoma. Among the tested flavones, 7,8-DHF, quercetin, and apigenin reduced Tau aggregation, oxidative stress, and caspase-1 activity as well as improved neurite outgrowth in SH-SY5Y cells expressing ΔK280 TauRD-DsRed folding reporter. Treatments with 7,8-DHF, quercetin, and apigenin rescued the reduced HSPB1 and NRF2 and activated TRKB-mediated extracellular signal-regulated kinase (ERK) signaling to upregulate cAMP-response element binding protein (CREB) and its downstream antiapoptotic BCL2 apoptosis regulator (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of these three flavones. Our results suggest 7,8-DHF, quercetin, and apigenin targeting HSPB1, NRF2, and TRKB to reduce Tau aggregation and protect cells against Tau neurotoxicity and may provide new treatment strategies for AD.

Cardiac lipotoxicity is a prevalent consequence of lipid metabolism disorders occurring in cardiomyocytes, which in turn precipitates the onset of heart failure. Mimetics of brain-derived neurotrophic factor (BDNF), such as 7,8-dihydroxyflavone (DHF) and 7,8,3′-trihydroxyflavone (THF), have demonstrated significant cardioprotective effects. However, it remains unclear whether these mimetics can protect cardiomyocytes against lipotoxicity. The aim of this study was to examine the impact of DHF and THF on the lipotoxic effects induced by palmitic acid (PA), as well as the concurrent mitochondrial dysfunction. H9c2 cells were subjected to treatment with PA alone or in conjunction with DHF or THF. Various factors such as cell viability, lactate dehydrogenase (LDH) release, death ratio, and mitochondrial function including mitochondrial membrane potential (MMP), mitochondrial-derived reactive oxygen species (mito-SOX) production, and mitochondrial respiration were assessed. PA dose-dependently reduced cell viability, which was restored by DHF or THF. Additionally, both DHF and THF decreased LDH content, death ratio, and mito-SOX production, while increasing MMP and regulating mitochondrial oxidative phosphorylation in cardiomyocytes. Moreover, DHF and THF specifically activated Akt signaling. The protective effects of DHF and THF were abolished when an Akt inhibitor was used. In conclusion, BDNF mimetics attenuate PA-induced injury in cardiomyocytes by alleviating mitochondrial impairments through the activation of Akt signaling. • BDNF mimetics repressed PA-induced injury in cardiomyocytes. • BDNF mimetics inhibited oxidative stress and mitochondrial dysfunction. • BDNF mimetics activated Akt and HO-1 in PA-treated cardiomyocytes. • Akt inhibitor abolished the protective effects of BDNF mimetics. [ABSTRACT FROM AUTHOR]

Abstract Background Intracerebral hemorrhage (ICH) induces a complex sequence of apoptotic cascades that contribute to secondary neuronal damage. Tropomyosin-related kinase receptor B (TrkB) signaling plays a crucial role in promoting neuronal survival following brain damage. Methods The present study investigated the protective effects and underlying mechanisms of TrkB activation by the specific TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), in a model of collagenase-induced ICH and in neuronal cultures. Mice subjected to collagenase-induced ICH were intraperitoneally injected with either 7,8-DHF or vehicle 10 min after ICH and, subsequently, daily for 3 days. Behavioral studies, brain edema measurement, and histological analysis were conducted. Levels of TrkB signaling-related molecules and apoptosis-related proteins were analyzed by western blots. Results Treatment with 20 mg/kg 7,8-DHF significantly improved functional recovery and reduced brain damage up to 28 days post-ICH. Reduction in neuronal death, apoptosis, and brain edema were also observed in response to 7,8-DHF treatment at 3 days post-ICH. These changes were accompanied by a significant increase in the phosphorylation of TrkB and Akt (Ser473/Thr308) at 1 and 3 days, but had no effect on Erk 44/42 phosphorylation. 7,8-DHF also enhanced the phosphorylation of Ask-1 Ser967 and FOXO-1, downstream targets of Akt at 1 and 3 days. Moreover, 7,8-DHF increased brain-derived neurotrophic factor levels at 1 day. In primary cultured neurons stimulated with hemin, 7,8-DHF promoted survival and reduced apoptosis. Furthermore, delaying the administration of 7,8-DHF to 3 h post-ICH reduced brain tissue damage and neuronal death. Conclusions Our findings demonstrate that the activation of TrkB signaling by 7,8-DHF protects against ICH via the Akt, but not the Erk, pathway. These data provide new insights into the role of TrkB signaling deficit in the pathophysiology of ICH and highlight TrkB/Akt as possible therapeutic targets in this disease.

Imbalances in bone formation and resorption cause osteoporosis. Mounting evidence supports that brain-derived neurotrophic factor (BDNF) implicates in this process. 7,8-Dihydroxyflavone (7,8-DHF), a plant-derived small molecular TrkB agonist, mimics the functions of BDNF. We show that both BDNF and 7,8-DHF promoted the proliferation, osteogenic differentiation, and mineralization of MC3T3-E1 cells. These effects might be attributed to the activation of the Wnt/β-catenin signaling pathway as the expression of cyclin D1, phosphorylated-glycogen synthase kinase-3β (p-GSK3β), β-catenin, Runx2, Osterix, and osteoprotegerin (OPG) was all significantly up-regulated. Knockdown of β-catenin restrained the up-regulation of Runx2 and Osterix stimulated by 7,8-DHF. In particular, blocking TrkB by its specific inhibitor K252a suppressed 7,8-DHF-induced osteoblastic proliferation, differentiation, and expression of osteoblastogenic genes. Moreover, BDNF and 7,8-DHF repressed osteoclastic differentiation of RAW264.7 cells. The transcription factor c-fos and osteoclastic genes such as tartrate-resistant acid phosphatase (TRAP), matrix metalloprotein-9 (MMP-9), Adamts5 were inhibited by 7,8-DHF. More importantly, 7,8-DHF attenuated bone loss, improved trabecular microarchitecture, tibial biomechanical properties, and bone biochemical indexes in an ovariectomy (OVX) rat model. The current work highlights the dual regulatory effects that 7,8-DHF exerts on bone remodeling.

Rationale: Intracerebroventricular (ICV) streptozotocin (STZ) mimics sporadic Alzheimer's disease (SAD) characterized by tau pathology and neurodegeneration arising from oxidative stress, mitochondrial dysfunction, and insulin resistance. 7,8-Dihydroxyflavone (7,8-DHF) is a flavonoid having antioxidant property interlinked with mitochondrial functioning and insulin actions. Objectives: To evaluate the neuroprotective and cognitive enhancement properties of 7,8-DHF in an ICV-STZ rat model of SAD. Methods: ICV-STZ (3 mg/kg) was injected into male Wistar rats. Cognitive functions were evaluated by Morris water maze (MWM) and novel object recognition (NOR). 7,8-DHF (5 mg/kg, 10 mg/kg, and 20 mg/kg) and rivastigmine (2 mg/kg) were given orally for 21 days. Reduced glutathione (GSH), catalase, superoxide dismutase (SOD), glutathione peroxidase (GPX), lipid peroxidation (LPO), protein carbonylation (PCO), and nitrite assays were performed. Mitochondrial enzyme complex I, II, III, and IV, and acetylcholinesterase (AchE) activities were determined. ELISA for the insulin-degrading enzyme (IDE) and p-tau was done. Histopathology was investigated by hematoxylin and eosin staining. Results: 7,8-DHF treatment attenuated ICV-STZ-induced cognitive deficit in MWM and NOR. Moreover, in the cortex and hippocampus regions of the brain, GSH, catalase, SOD, GPX, LPO, PCO, and nitrite levels were reversed. Mitochondrial enzyme complex I, II, III, and IV, and acetylcholinesterase (AchE) activities were also normalized. IDE and p-tau protein were found to be significantly altered. 7,8-DHF provided protection from neuronal cell death examined in histopathology. Conclusions: Conclusively, 7,8-DHF was found to be neuroprotective in the ICV-STZ rat model by ameliorating oxidative stress, mitochondrial dysfunction, and insulin resistance, thereby improving cognitive functions evident with the behavioral results. [ABSTRACT FROM AUTHOR]

Objective: 7,8-Dihydroxyflavone (7,8-DHF), a small molecular mimetic of brain-derived neurotrophic factor (BDNF), alleviates high-fat diet-induced obesity in female mice in a sex-specific manner by activating muscular tropomyosin-related kinase B (TrkB). However, the underlying molecular mechanism for this sex difference is unknown. Moreover, muscular estrogen receptor α (ERα) plays a critical role in metabolic diseases. Impaired ERα action is often accompanied by metabolic syndrome (MetS) in postmenopausal women. This study investigated whether muscular ERα is involved in the metabolic effects of 7,8-DHF. Methods: For the in vivo studies, 72 female C57BL/6J mice were given a low-fat diet or high-fat diet, and both received daily intragastric administration of vehicle or 7,8-DHF for 24 weeks. The hypothalamic-pituitary-ovarian (HPO) axis function was assessed by investigating typical sex-related serum hormones and the ovarian reserve. Indicators of menopausal MetS, including lipid metabolism, insulin sensitivity, bone density, and serum inflammatory cytokines, were also evaluated. The expression levels of ERα and other relevant signaling molecules were also examined. In vitro, the molecular mechanism involved in the interplay of ERα and TrkB receptors was verified in differentiated C2C12 myotubes using several inhibitors and a lentivirus short hairpin RNA-knockdown strategy. Results: Long-term oral administration of 7,8-DHF acted as a protective factor for the female HPO axis function, protecting against ovarian failure, earlier menopause, and sex hormone disorders, which was paralleled by the alleviation of MetS coupled with the production of ERα-rich, TrkB-activated, and uncoupling protein 1 (UCP1) high thermogenic skeletal muscle tissues. 7,8-DHF-stimulated transactivation of ERα at serine 118 (S118) and tyrosine 537 (Y537), which was crucial to activate the BDNF/TrkB signaling cascades. In turn, activation of BDNF/TrkB signaling was also required for the ligand-independent activation of ERα, especially at the Y537 phosphorylation site. In addition, Src family kinases played a core role in the interplay of ERα and TrkB, synergistically activating the signaling pathways related to energy metabolism. Conclusions: These findings revealed a novel role of 7,8-DHF in protecting the function of the female HPO axis and activating tissue-specific ERα, which improves our understanding of this sex difference in 7,8-DHF-mediated maintenance of metabolic homeostasis and provides new therapeutic strategies for managing MetS in women.

Synaptic impairment may be the main cause of cognitive dysfunction in brain aging that is probably due to a reduction in synaptic contact between the axonal buttons and dendritic spines. Rho proteins including the small GTPase Rac1 have become key regulators of neuronal morphogenesis that supports synaptic plasticity. Small Rho- and Ras-GTPases are post-translationally modified by the isoprenoids geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP), respectively. For all GTPases, anchoring in the plasma membrane is essential for their activation by guanine nucleotide exchange factors (GEFs). Rac1-specific GEFs include the protein T lymphoma invasion and metastasis 1 (Tiam1). Tiam1 interacts with the TrkB receptor to mediate the brain-derived neurotrophic factor (BDNF)-induced activation of Rac1, resulting in cytoskeletal rearrangement and changes in cellular morphology. The flavonoid 7,8-dihydroxyflavone (7,8-DHF) acts as a highly affine-selective TrkB receptor agonist and causes the dimerization and autophosphorylation of the TrkB receptor and thus the activation of downstream signaling pathways. In the current study, we investigated the effects of 7,8-DHF on cerebral lipid isoprenoid and Rho protein levels in male C57BL/6 mice aged 3 and 23 months. Aged mice were daily treated with 100 mg/kg b.w. 7,8-DHF by oral gavage for 21 days. FPP, GGPP, and cholesterol levels were determined in brain tissue. In the same tissue, the protein content of Tiam1 and TrkB in was measured. The cellular localization of the small Rho-GTPase Rac1 and small Rab-GTPase Rab3A was studied in total brain homogenates and membrane preparations. We report the novel finding that 7,8-DHF restored levels of the Rho proteins Rac1 and Rab3A in membrane preparations isolated from brains of treated aged mice. The selective TrkB agonist 7,8-DHF did not affect BDNF and TrkB levels, but restored Tiam1 levels that were found to be reduced in brains of aged mice. FPP, GGPP, and cholesterol levels were significantly elevated in brains of aged mice but not changed by 7,8-DHF treatment. Hence, 7,8-DHF may be useful as pharmacological tool to treat age-related cognitive dysfunction although the underlying mechanisms need to be elucidated in detail. [ABSTRACT FROM AUTHOR]

Striatal neurons depends on an afferent supply of brain-derived neurotrophic factor-(BDNF) that explicitly interacts with tropomyosin receptor kinase B (TrkB) receptor and performs sundry functions including synaptic plasticity, neuronal differentiation and growth. Therefore, we aimed to scrutinize an active molecule that functions identical to BDNF in activating TrkB receptor and it's downstream targets for restoring neuronal survival in Huntington disease (HD). Data from in vitro Neuro-2a cell line showed that treatment with 7,8-dihydroxyflavone (7,8-DHF), improved 3-nitropropionic acid (3-NP) induced neuronal death by stabilizing the loss of mitochondrial membrane potential and transiently increased the activity of cAMP-response element-binding protein (CREB) and BDNF via TrkB receptor activation. Consistent with in vitro findings, our in vivo results stated that treatment with 7,8-DHF at a dose of 10 mg/kg body weight ameliorated various behavior alterations caused by 3-NP intoxication. Further histopathological and electron microscopy evidences from striatal region of 3-NP mice brain treated with 7,8-DHF showed more improved neurons with intact mitochondria and less autophagic vacuoles. Protein expression analysis of both in vitro and in vivo study showed that 7,8-DHF promotes neuronal survival through upregulation and phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt at serine-473/threonine-308). Akt phosphorylation additionally phosphorylates Bad at serine-136 and inhibits its translocation to mitochondria thereby promoting mitochondrial biogenesis, enhanced ATP production and inhibit apoptosis mediated neuronal death. These aforementioned findings help in strengthening our hypothesis and has come up with a novel neuroprotective mechanism of 7,8-DHF against 3-NP induced neuronal death. [ABSTRACT FROM AUTHOR]

Vitamin B6 deficiency has been linked to cognitive impairment in human brain disorders for decades. Still, the molecular mechanisms linking vitamin B6 to these pathologies remain poorly understood, and whether vitamin B6 supplementation improves cognition is unclear as well. Pyridoxal 5'-phosphate phosphatase (PDXP), an enzyme that controls levels of pyridoxal 5'-phosphate (PLP), the co-enzymatically active form of vitamin B6, may represent an alternative therapeutic entry point into vitamin B6-associated pathologies. However, pharmacological PDXP inhibitors to test this concept are lacking. We now identify a PDXP and age-dependent decline of PLP levels in the murine hippocampus that provides a rationale for the development of PDXP inhibitors. Using a combination of small-molecule screening, protein crystallography, and biolayer interferometry, we discover, visualize, and analyze 7,8-dihydroxyflavone (7,8-DHF) as a direct and potent PDXP inhibitor. 7,8-DHF binds and reversibly inhibits PDXP with low micromolar affinity and sub-micromolar potency. In mouse hippocampal neurons, 7,8-DHF increases PLP in a PDXP-dependent manner. These findings validate PDXP as a druggable target. Of note, 7,8-DHF is a well-studied molecule in brain disorder models, although its mechanism of action is actively debated. Our discovery of 7,8-DHF as a PDXP inhibitor offers novel mechanistic insights into the controversy surrounding 7,8-DHF-mediated effects in the brain., Competing Interests: MB, CZ, LW, AK, KH, SB, MN, CV, Jv, HS, EJ No competing interests declared, AG A.G. is a recipient of a research project grant from Boehringer Ingelheim International GmbH. This project funding is independent of and has no overlap with the work described in this manuscript, (© 2024, Brenner, Zink, Witzinger et al.)

Fragile X syndrome (FXS) is associated with deficits in various types of learning, including those that require the hippocampus. Relatedly, hippocampal long-term potentiation (LTP) is impaired in the Fmr1 knockout (KO) mouse model of FXS. Prior research found that infusion of brain-derived neurotrophic factor (BDNF) rescues LTP in the KOs. Here, we tested if, in Fmr1 KO mice, up-regulating BDNF production or treatment with an agonist for BDNF's TrkB receptor restores synaptic plasticity and improves learning. In hippocampal slices, bath infusion of the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) completely restored otherwise impaired hippocampal field CA1 LTP of Fmr1 KOs without effect in wild types (WTs). Similarly, acute, semi-chronic, or chronic treatments with 7,8-DHF rescued a simple hippocampus-dependent form of spatial learning (object location memory: OLM) in Fmr1 KOs without effect in WTs. The agonist also restored object recognition memory, which depends on cortical regions. Semi-chronic, but not acute, treatment with the ampakine CX929, which up-regulates BDNF expression, lowered the training threshold for OLM in WT mice and rescued learning in the KOs. Positive results were also obtained in a test for social recognition. An mGluR5 antagonist did not improve learning. Quantification of synaptic immunolabeling demonstrated that 7,8-DHF and CX929 increase levels of activated TrkB at excitatory synapses. Moreover, CX929 induced a robust synaptic activation of the TrkB effector ERK1/2. These results suggest that enhanced synaptic BDNF signaling constitutes a plausible strategy for treating certain aspects of the cognitive disabilities associated with FXS.

Low bioavailability and stability of 7,8-dihydroxyflavone (7,8-DHF) hinder its potential application in prevention of humans’ disease. 7,8-DHF loaded nanoliposomes decorated by original, crosslinked and glycosylated lactoferrin (LF) were fabricated. The mean particle size of spherical crosslinked and glycosylated LF coating liposomes were larger than uncoated liposomes with a low polydispersity index, and the former had higher encapsulation efficiency (Above 98%). Crosslinked and glycosylated LF coating liposomes had higher antioxidant activity, storage stability, slow-release ability, bioaccessibility and transepithelial transport compared to free 7,8-DHF and 7,8-DHF loaded liposome. Effective hydrogen bonding between phospholipid and 7,8-DHF, while electrostatic interaction and hydrogen bonding between LF proteins and phospholipid existed. The encapsulated 7,8-DHF was in an amorphous state rather than a crystalline form as detected by differential scanning calorimetry. Collectively, crosslinked or glycosylated LF coating liposomes are promising delivery systems for protecting and transporting 7,8-DHF or other relative bioactive components.

Alcohol use–associated disorders are highly comorbid with anxiety disorders; however, their mechanism remains unknown. The amygdala plays a central role in anxiety. We recently found that 7,8-dihydroxyflavone (7,8-DHF) significantly reduces withdrawal symptoms in a rat model of chronic intermittent alcohol (ethanol) exposure. This study aimed to determine the role of 7,8-DHF in regulating anxiety induced by chronic alcohol exposure and its associated underlying mechanism. Male C57BL/6J mice were exposed to chronic intermittent alcohol for 3 weeks followed by alcohol withdrawal for 12 h with or without 7,8-DHF administered intraperitoneally. All mice were tested using an open field test and elevated plus maze to assess anxiety-like behaviors. Synaptic activity and intrinsic excitability in basal and lateral amygdala (BLA) neurons were assessed using electrophysiological recordings. 7,8-DHF alleviated alcohol-induced anxiety-like behavior and attenuated alcohol-induced enhancement of activities in BLA pyramidal neurons. Furthermore, 7,8-DHF prevented alcohol withdrawal–evoked augmentation of glutamatergic transmission in the amygdala and had no effect on GABAergic transmission in the amygdala, as demonstrated by unaltered frequency and amplitude of spontaneous inhibitory postsynaptic currents. Microinjection of K252a, a tropomyosin-related kinase B (TrkB) antagonist, into the BLA blocked the effects of 7,8-DHF on anxiety-like behavior and neuronal activity in the BLA. Our findings suggest that 7,8-DHF alleviates alcohol-induced anxiety-like behavior induced by chronic alcohol exposure through regulation of glutamate transmission involving TrKB in the BLA. [ABSTRACT FROM AUTHOR]

Rationale: Alcoholism and obesity impart a deleterious impact on human health and affects the quality of life. Chronic consumption of alcohol and western diet has been reported to cause memory deficits. 7,8-dihydroxyflavone (7,8-DHF), a TrkB agonist, comprises antioxidant and anti-inflammatory properties in treating various neurological disorders. Objectives: The current study was aimed to determine the protective effect and molecular mechanism of 7,8-DHF against alcohol and high-fat diet (HFD)-induced memory deficits in rats. Methods: The adult male Wistar rats were given alcohol (3–15%) and HFD ad libitum for 12 weeks in different experimental groups. 7,8-DHF (5 mg/kg) was intraperitoneally injected daily for the last 4 weeks (9th–12th week). Results: The alcohol and HFD administration caused cognitive impairment as evaluated through the Morris water maze (MWM) test in alcohol, HFD, and alcohol + HFD-fed animals. The last 4-week treatment of 7,8-DHF (5 mg/kg; i.p.) attenuated alcohol and HFD-induced memory loss. 7,8-DHF treatment also restored the glutathione (GSH) level along with attenuation of nitrite, malondialdehyde content (markers of oxidative and nitrosative stress), and reduction of the acetylcholinesterase activity in the hippocampus of alcohol and HFD-fed animals. Furthermore, the administration of 7,8-DHF caused downregulation of NF-κB, iNOS, and caspase-3 and upregulation of Nrf2, HO-1, and BDNF mRNA level in rat hippocampus. Conclusion: 7,8-DHF administration conferred beneficial effects against alcohol and HFD-induced memory deficit via its unique antioxidant, anti-inflammatory, anti-apoptotic potential, along with the activation of TrkB/BDNF signaling pathway in the hippocampus. [ABSTRACT FROM AUTHOR]

• DHF causes motor and striatal TH recovery in a progressive MPTP animal model of PD. • DHF induced motor recovery is not facilitated by restoration of dopamine within the nigrostriatal pathway. • DHF treated mice had an increased expression of the sprouting factor, SCG10, in the striatum and midbrain. • Using a restorative PD animal model, DHF may be a useful treatment for patients with PD. Parkinson's disease (PD) is caused by neurodegeneration of nigrostriatal neurons, resulting in dopamine (DA) stimulated motor deficits. Like brain derived neurotrophic factor (BDNF), 7,8-dihydroxyflavone (DHF) is an agonist of the tropomyosin receptor kinase-B (TrkB) and stimulates the same secondary cascades that promote neuronal growth, survival and differentiation. We used our progressive mouse model of PD by administering increasing doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over 4 weeks (5 days/week), and then treated mice with DHF for 4 weeks after the cessation of the toxin injections (i.e., restoration). Mice treated with DHF recovered motorically, even after MPTP administration. Despite a 75% loss of tyrosine hydroxylase (TH) expression in the dorsolateral (DL) striatum in the MPTP group, mice treated with DHF had a recovery comparable to that found in the respective control. There was no recovery of DA tissue levels within the DL striatum. In both the DL striatum and substantia nigra (SN)/midbrain, phosphorylated TrkB and secondary messengers were significantly increased following DHF compared to the MPTP only group. Expression of the sprouting biomarker, superior cervical ganglion 10 (SCG10), was increased ∼20% in the DL striatum and 66% in the SN/midbrain in mice treated with DHF compared to the MPTP only group. We report that after 4 weeks of progressive MPTP administration, DHF can restore motor deficits and TH within the DL striatum in a TrkB-dependent manner. Our data suggests that DHF may help alleviate motor symptoms of PD and restore the loss of DA terminals within the striatum. [ABSTRACT FROM AUTHOR]

7,8-dihydroxyflavone (7,8-DHF), a tyrosine kinase B (TrkB) receptor agonist, can mimick physiological actions of brain-derived neurotrophic factor (BDNF) to attenuate neurogenic disease. However, its use as a functional food, is limited by its low-water solubility, chemical instability, and poor bioavailability. The purpose of this work is to fabricate stable 7,8-DHF loaded zein/lactoferrin (LF) composite nanoparticles (zein/LF-DHF) to overcome these challenges. Results showed that mean particle size of zein/LF nanoparticles was about 74 nm with low polydispersity index (<0.200) and turbidity (<0.300) values. Zein/LF nanoparticles had good stability against pH (3.0–9.0), ionic strengths (0–500 mM NaCl at neutral pH) and long-term storage. Zein/LF nanoparticles showed spherical structures formed by hydrogen bonding and hydrophobic interactions, however, LF changed surface morphology of zein nanoparticles as observed by scanning electron microscope. X-ray diffraction indicated 7,8-DHF was presented in an amorphous state inside zein/LF nanoparticles. Most importantly, zein/LF-DHF had good redispersibility, and increased the encapsulation efficiency, chemical stability, water solubility and bioaccessibility of 7,8-DHF. Collectively, zein/LF nanoparticles are promising delivery systems for 7,8-DHF in functional foods. Unlabelled Image • Lactoferrin (LF) acted as a powerful stabilizer to fabricate zein nanoparticles. • 7,8-Dihydroxyflavone (7,8-DHF) was firstly encapsulated in zein/LF nanoparticles. • Zein/LF-DHF had good redispersibility in water. • Zein/LF-DHF increased encapsulation efficiency and chemical stability of 7,8-DHF. • Zein/LF-DHF enhanced water solubility and bioaccessibility of 7,8-DHF. [ABSTRACT FROM AUTHOR]

Down syndrome (DS), a major genetic cause of intellectual disability, is characterized by numerous neurodevelopmental defects. Previous in vitro studies highlighted a relationship between bioenergetic dysfunction and reduced neurogenesis in progenitor cells from the Ts65Dn mouse model of DS, suggesting a critical role of mitochondrial dysfunction in neurodevelopmental alterations in DS. Recent in vivo studies in Ts65Dn mice showed that neonatal supplementation (Days P3–P15) with the polyphenol 7,8-dihydroxyflavone (7,8-DHF) fully restored hippocampal neurogenesis. The current study was aimed to establish whether brain mitochondrial bioenergetic defects are already present in Ts65Dn pups and whether early treatment with 7,8-DHF positively impacts on mitochondrial function. In the brain and cerebellum of P3 and P15 Ts65Dn pups we found a strong impairment in the oxidative phosphorylation apparatus, resulting in a deficit in mitochondrial ATP production and ATP content. Administration of 7,8-DHF (dose: 5 mg/kg/day) during Days P3–P15 fully restored bioenergetic dysfunction in Ts65Dn mice, reduced the levels of oxygen radicals and reinstated the hippocampal levels of PGC-1α. No pharmacotherapy is available for DS. From current findings, 7,8-DHF emerges as a treatment with a good translational potential for improving mitochondrial bioenergetics and, thus, mitochondria-linked neurodevelopmental alterations in DS.

In this study, two polysaccharides [sodium alginate (ALG) and sodium carboxymethyl cellulose (CMC)] were selected to establish zein/sophorolipid/ALG (ALG/S/Z) and zein/sophorolipid/ALG (CMC/S/Z) nanoparticles to encapsulate 7,8-dihydroxyflavone (7,8-DHF), respectively. The results showed that polysaccharide types significantly affected performance of ternary nanoparticles, including CMC/S/Z possessed lower polydispersity index, particle size and turbidity, but higher zeta potential, encapsulation efficiency and loading capacity compared to ALG/S/Z. Compared to zein/sophorolipid nanoparticles (S/Z), both ALG/S/Z and CMC/S/Z had better stability against low pH (pH 3~4) and high ionic strengths (150~200 mM NaCl). Hydrophobic effects, electrostatic interactions and hydrogen bonding were confirmed in ternary nanoparticles fabrication via Fourier-transform infrared spectroscopy. Circular dichroism revealed that CMC and ALG had no evident impact on secondary structure of zein in S/Z, but changed surface morphology of S/Z as observed by scanning electron microscope. Encapsulated 7,8-DHF exhibited an amorphous state in ternary nanoparticles as detected by X-ray diffraction and differential scanning calorimetry. Furthermore, compared to S/Z, ALG/S/Z, and CMC/S/Z remarkably improved the storage stability and bioaccessibility of 7,8-DHF. CMC/S/Z possessed a greater storage stability for 7,8-DHF, however, ALG/S/Z exhibited a better in vitro bioaccessibility of 7,8-DHF. This research provides a theoretical reference for zein-based delivery system application.