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Biomedicine & Pharmacotherapy =... Sep 2022Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Although its pathogenesis remains unclear, studies have indicated microglia-mediated...
Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Although its pathogenesis remains unclear, studies have indicated microglia-mediated neuroinflammation playing an important role. Phytosterols are a class of natural compounds presented in food, and have anti-inflammatory abilities. Recent studies suggested that phytosterols can traverse the blood-brain barrier and enter the brain, however, it remains largely unknown that whether phytosterols affect neuroinflammation in the AD pathogenesis. Here, we used APP/PS1 mice as the animal model of AD, and found that stigmasterol treatment attenuated cognitive deficits, and decreased Aβ concentration in cortex and hippocampus. Stigmasterol treatment also suppressed neuroinflammation, by reducing pro-inflammatory cytokine levels and microglia activation. Next, we simulated BV2 cells with Aβ oligomers, which induced inflammatory responses of microglia. Stigmasterol protected BV2 cells against Aβ oligomers induced inflammation, and mediated secretion of pro-inflammatory cytokines via NF-κB and NLRP3 signaling pathways by AMPK activation. Stigmasterol also alleviated the M1 polarization of BV2 cells. In general, our study demonstrates that stigmasterol ameliorated neuroinflammation in APP/PS1 mice, and suppressed inflammatory response of microglia to Aβ oligomers via AMPK/NF-κB and AMPK/NLRP3 signaling, which provides a mechanistic insight for stigmasterol in anti-inflammation and AD therapy.
Topics: AMP-Activated Protein Kinases; Alzheimer Disease; Animals; Anti-Inflammatory Agents; Cytokines; Mice; Microglia; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Stigmasterol
PubMed: 35772378
DOI: 10.1016/j.biopha.2022.113317 -
Methods in Molecular Biology (Clifton,... 2023Stigmasterol is a phytosterol contained in kraft mill effluent that is able to increase over 100% after aerobic biological treatment. This compound can act as an...
Stigmasterol is a phytosterol contained in kraft mill effluent that is able to increase over 100% after aerobic biological treatment. This compound can act as an endocrine disrupter as its structure is similar to that of cholesterol. Furthermore, stigmasterol contained in kraft mill effluent shows high toxicity (25-fold more than β-sitosterol) to aquatic organisms such as Daphnia magna. However, the operation of the aerobic treatment and biomass adaptation could be affecting their removal. The performances of activated sludge (AS), aerated lagoon (AL), and moving bed biofilm reactors (MBBR) are compared to remove the stigmasterol contained in kraft mill effluent. The AL operates at a hydraulic retention time of 6 h and removes up to 90% of phytosterols. So, a 96% of stigmasterol is removed by AL when the sterol retention load is 0.6 mg/L · d. However, stigmasterol concentrations increase from 29% to 37% at a low stigmasterol load rate (0.2 mg/L · d). On the other hand, the stigmasterol is removed between 65% and 87% by an AS under a hydraulic retention time of 3 h. Moreover, a 100% of stigmasterol can be removed by the MBBR when the hydraulic retention time is 2 days.
Topics: Stigmasterol; Biofilms; Bioreactors; Phytosterols; Acclimatization; Sewage
PubMed: 37642854
DOI: 10.1007/978-1-0716-3385-4_20 -
Chirality Feb 2022Diastereoisomeric stigmasterol oxiranes 4, 5, 8, and 9 are known phytosterol oxidation products (POPs) that have been evaluated for their cytotoxicity, although the...
Diastereoisomeric stigmasterol oxiranes 4, 5, 8, and 9 are known phytosterol oxidation products (POPs) that have been evaluated for their cytotoxicity, although the results are of limited significance since, in most cases, they were evaluated as mixtures. Consequently, to establish biological activity hierarchy of these oxides, it is critical to evaluate individual pure POPs. Therefore, we now describe the obtention of individual molecules and their absolute configuration (AC) determination. The two acetylated C-5-C-6 oxiranes 6 and 7; the two acetylated C-22-C-23 oxides 10 and 11, obtained by means of Δ double bond protection-deprotection; and the four C-5-C-6, C-22-C-23 diepoxystigmasteryl acetates 19-22 were now individually gained and their AC determined by vibrational circular dichroism. Vibrational modes associated with the C-5-C-6 and the C-22-C-23 bonds were identified in dioxiranes 19-22 and used to assign the AC of monoepoxides 6, 7, 10, and 11. The AC of biological active non-acetylated molecules follows immediately. Due to the scarce spectroscopic information available for these POPs, the H and C NMR chemical shifts of 3-22 were assigned using 1D- and 2D-NMR experiments.
Topics: Circular Dichroism; Epoxy Compounds; Molecular Structure; Stereoisomerism; Stigmasterol; Vibration
PubMed: 34788903
DOI: 10.1002/chir.23390 -
Phytomedicine : International Journal... May 2023Glutamate, an excitatory neurotransmitter, was elevated in the brain of neurodegenerative disease (ND) patients. The excessive glutamate induces Ca influx and reactive...
Stigmasterol isolated from Azadirachta indica flowers attenuated glutamate-induced neurotoxicity via downregulation of the Cdk5/p35/p25 signaling pathway in the HT-22 cells.
BACKGROUND
Glutamate, an excitatory neurotransmitter, was elevated in the brain of neurodegenerative disease (ND) patients. The excessive glutamate induces Ca influx and reactive oxygen species (ROS) production which exacerbates mitochondrial function, leading to mitophagy aberration, and hyperactivates Cdk5/p35/p25 signaling leading to neurotoxicity in ND. Stigmasterol, a phytosterol, has been reported for its neuroprotective effects; however, the underlying mechanism of stigmasterol on restoring glutamate-induced neurotoxicity is not fully investigated.
PURPOSE
We investigated the effect of stigmasterol, a compound isolated from Azadirachta indica (AI) flowers, on ameliorating glutamate-induced neuronal apoptosis in the HT-22 cells.
STUDY DESIGN
To further understand the underlying molecular mechanisms of stigmasterol, we investigated the effect of stigmasterol on Cdk5 expression, which was aberrantly expressed in glutamate-treated cells. Cell viability, Western blot analysis, and immunofluorescence are employed.
RESULTS
Stigmasterol significantly inhibited glutamate-induced neuronal cell death via attenuating ROS production, recovering mitochondrial membrane depolarization, and ameliorating mitophagy aberration by decreasing mitochondria/lysosome fusion and the ratio of LC3-II/LC3-I. In addition, stigmasterol treatment downregulated glutamate-induced Cdk5, p35, and p25 expression via enhancement of Cdk5 degradation and Akt phosphorylation. Although stigmasterol demonstrated neuroprotective effects on inhibiting glutamate-induced neurotoxicity, the efficiency of stigmasterol is limited due to its poor water solubility. We conjugated stigmasterol to soluble soybean polysaccharides with chitosan nanoparticles to overcome the limitations. We found that the encapsulated stigmasterol increased water solubility and enhanced the protective effect on attenuating the Cdk5/p35/p25 signaling pathway compared with free stigmasterol.
CONCLUSION
Our findings illustrate the neuroprotective effect and the improved utility of stigmasterol in inhibiting glutamate-induced neurotoxicity.
Topics: Humans; Down-Regulation; Stigmasterol; Azadirachta; Glutamic Acid; Neurodegenerative Diseases; Neuroprotective Agents; Reactive Oxygen Species; Neurons; Signal Transduction; Phosphorylation; tau Proteins; Flowers; Water
PubMed: 36898255
DOI: 10.1016/j.phymed.2023.154728 -
CNS Neuroscience & Therapeutics Apr 2024This study aimed to investigate the potential therapeutic applications of stigmasterol for treating neuropathic pain.
AIMS
This study aimed to investigate the potential therapeutic applications of stigmasterol for treating neuropathic pain.
METHODS
Related mechanisms were investigated by DRG single-cell sequencing analysis and the use of specific inhibitors in cellular experiments. In animal experiments, 32 male Sprague-Dawley rats were randomly divided into the sham operation group, CCI group, ibuprofen group, and stigmasterol group. We performed behavioral tests, ELISA, H&E staining and immunohistochemistry, and western blotting.
RESULTS
Cell communication analysis by single-cell sequencing reveals that after peripheral nerve injury, Schwann cells secrete IL-34 to act on CSF1R in macrophages. After peripheral nerve injury, the mRNA expression levels of CSF1R pathway and NLRP3 inflammasome in macrophages were increased in DRG. In vitro studies demonstrated that stigmasterol can reduce the secretion of IL-34 in LPS-induced RSC96 Schwann cells; stigmasterol treatment of LPS-induced Schwann cell-conditioned medium (L-S-CM) does not induce the proliferation and migration of RAW264.7 macrophages; L-S-CM reduces CSF1R signaling pathway (CSF1R, P38MAPK, and NFκB) activation, NLRP3 inflammasome activation, and ROS production. In vivo experiments have verified that stigmasterol can reduce thermal and cold hyperalgesia in rat chronic compressive nerve injury (CCI) model; stigmasterol can reduce IL-1β, IL-6, TNF-α, CCL2, SP, and PGE2 in serum of CCI rats; immunohistochemistry and western blot confirmed that stigmasterol can reduce the levels of IL-34/CSF1R signaling pathway and NLRP3 inflammasome in DRG of CCI rats.
CONCLUSION
Stigmasterol alleviates neuropathic pain by reducing Schwann cell-macrophage cascade in DRG by modulating IL-34/CSF1R axis.
Topics: Rats; Male; Animals; Rats, Sprague-Dawley; NLR Family, Pyrin Domain-Containing 3 Protein; Stigmasterol; Inflammasomes; Peripheral Nerve Injuries; Lipopolysaccharides; Neuralgia; Hyperalgesia; Interleukins; Macrophages; Schwann Cells
PubMed: 38572785
DOI: 10.1111/cns.14657 -
BioMed Research International 2018The therapeutic potential of stigmasterol, a natural steroid alcohol with established immune-modulatory properties, was assessed on allergic cutaneous responses. We...
The therapeutic potential of stigmasterol, a natural steroid alcohol with established immune-modulatory properties, was assessed on allergic cutaneous responses. We examined its suppressive effect on immunoglobulin E (IgE)-mediated active cutaneous anaphylaxis (ACA), compound 48/80 (C48/80)-induced pruritus, and irritant dermatitis induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Stigmasterol at 10-100 mg/kg significantly inhibited ACA with reduction in reaction area and concentration of the extravasated Evans blue dye. Given at 50 and 100 mg/kg, stigmasterol significantly inhibited C48/80-induced scratching behaviour when compared to saline-treated C48/80-injected control. Skin histopathology of injected sites confirmed that stigmasterol reduced mast cell trafficking and degranulation associated with C48/80-induced pruritus. Stigmasterol controlled inflammatory features such as ear skin oedema and neutrophilia and also reduced serum levels of TNF induced by topical application of TPA. Epidermal layer thickening and inflammatory cell infiltration of ear skin tissue were significantly reduced by stigmasterol. Taken together, stigmasterol demonstrates significant potential as a molecule of interest in allergic skin disease therapy.
Topics: Animals; Drug Eruptions; Ghana; Hypersensitivity; Mast Cells; Mice; Mice, Inbred ICR; Rats; Rats, Wistar; Rodentia; Skin; Stigmasterol
PubMed: 30140696
DOI: 10.1155/2018/3984068 -
Acta Crystallographica. Section C,... Mar 2002The title compound, stigmasta-5,22-dien-3beta-ol hemihydrate, C(29)H(48)O x 0.5H(2)O, previously thought to be the monohydrate, has two sterol molecules and one water...
The title compound, stigmasta-5,22-dien-3beta-ol hemihydrate, C(29)H(48)O x 0.5H(2)O, previously thought to be the monohydrate, has two sterol molecules and one water molecule in the asymmetric unit. In both sterol molecules, the methyl group of the ethyl substituent at the end of the hydrocarbon chain is disordered over two sites. The OH group of molecule A donates a hydrogen bond to a water molecule and accepts a hydrogen bond from the OH group of molecule B. The OH group of molecule B accepts two hydrogen bonds from water molecules.
Topics: Asteraceae; Crystallography, X-Ray; Hydrogen Bonding; Models, Molecular; Molecular Conformation; Stigmasterol
PubMed: 11870303
DOI: 10.1107/s0108270102000434 -
The Journal of Nutrition Jul 2023Hepatic cholesterol accumulation is a significant risk factor in the progression of nonalcoholic fatty liver disease (NAFLD) to steatohepatitis. However, the precise...
BACKGROUND
Hepatic cholesterol accumulation is a significant risk factor in the progression of nonalcoholic fatty liver disease (NAFLD) to steatohepatitis. However, the precise mechanism by which stigmasterol (STG) mitigates this process remains unclear.
OBJECTIVES
This study aimed to investigate the potential mechanism underlying the protective effect of STG in mice with NAFLD progressing to steatohepatitis while being fed a high-fat and high-cholesterol (HFHC) diet.
METHODS
Male C57BL/6 mice were fed an HFHC diet for 16 wk to establish the NAFLD model. Subsequently, the mice received STG or a vehicle via oral gavage while continuing the HFHC diet for an additional 10 wk. The study evaluated hepatic lipid deposition and inflammation as well as the expression of key rate-limiting enzymes involved in the bile acid (BA) synthesis pathways. BAs in the colonic contents were quantified using ultra-performance liquid chromatography-tandem mass spectrometry.
RESULTS
Compared with the vehicle control group, STG significantly reduced hepatic cholesterol accumulation (P < 0.01) and suppressed the gene expression of NLRP3 inflammasome and interleukin-18 (P < 0.05) in the livers of HFHC diet-fed mice. The total fecal BA content in the STG group was nearly double that of the vehicle control group. Additionally, the administration of STG increased the concentrations of representative hydrophilic BAs in the colonic contents (P < 0.05) along with the upregulation of gene and protein expression of CYP7B1 (P < 0.01). Furthermore, STG enhanced the α-diversity of the gut microbiota and partially reversed the alterations in the relative abundance of the gut microbiota induced by the HFHC diet.
CONCLUSIONS
STG mitigates steatohepatitis by enhancing the alternative pathway for BA synthesis.
Topics: Mice; Male; Animals; Non-alcoholic Fatty Liver Disease; Stigmasterol; Cholesterol, Dietary; Diet, High-Fat; Mice, Inbred C57BL; Liver; Cholesterol; Hypercholesterolemia; Bile Acids and Salts
PubMed: 37269906
DOI: 10.1016/j.tjnut.2023.05.026 -
Methods in Molecular Biology (Clifton,... 2017Stigmasterol is a phytosterol contained in Kraft mill effluent that is able to increase over 100% after aerobic biological treatment. This compound can act as an...
Stigmasterol is a phytosterol contained in Kraft mill effluent that is able to increase over 100% after aerobic biological treatment. This compound can act as an endocrine disrupter as its structure is similar to that of cholesterol. Furthermore, stigmasterol contained in Kraft mill effluent shows high toxicity (25-fold that of β-sitosterol) to aquatic organisms such as Daphnia magna (24-48 h). However, the operation of the aerobic treatment and biomass adaptation could be affecting their removal. The performances of activated sludge (AS), aerated lagoon (AL), and moving bed biofilm reactors (MBBR) are compared for removing stigmasterol contained in Kraft mill effluent. The AL operates at a hydraulic retention time of 6 h and removes up to 90% of phytosterols. So, a 96% of stigmasterol is removed by AL when the sterol retention load is 0.6 mg/L/day. However, stigmasterol concentrations increase from 29% to 37% at a low stigmasterol load rate (0.2 mg/L/day). On the other hand, the stigmasterol is removed between 65% and 87% by an AS under a hydraulic retention time of 3 h. Moreover, a 100% of stigmasterol can be removed by the MBBR when the hydraulic retention time is 2 days.
Topics: Aerobiosis; Animals; Biofilms; Bioreactors; Cholesterol; Daphnia; Endocrine Disruptors; Stigmasterol
PubMed: 28710626
DOI: 10.1007/978-1-4939-7183-1_10 -
Bioengineered Dec 2021Stigmasterol (STM), one of the main active components of , has been shown to effectively inhibit proinflammatory factors and matrix degradation in chondrocytes. However,...
Stigmasterol (STM), one of the main active components of , has been shown to effectively inhibit proinflammatory factors and matrix degradation in chondrocytes. However, the effect of STM on interleukin (IL)-1β-induced chondrocytes and its specific mechanism remain unclear. The purpose of the present study was to explore the effect and mechanism of sterol regulatory element binding transcription factor 2 (SREBF2) on IL-1β induced chondrocytes in the presence of STM. CCK-8 was used to detect the effect of STM on the cell viability of mouse chondrogenic cells (ATDC5). After ATDC5 cells were induced by IL-1β, the expression of SREBF2 in osteoarthritis cells was detected by RT-qPCR. The content of iron ion in the cells was detected by using an iron colorimetric assay kit. After further transfection of a SREBF2 overexpressing vector (Oe-SREBF2) or addition of a ferroptosis inhibitor, the expression levels of inflammation and matrix degradation-related proteins were detected via Western blotting. The levels of oxidative stress in cells were determined by using an ELISA kit. The results revealed that STM had no significant effect on the viability of ATDC5 cells. STM reduced IL-1β-induced ATDC5 cell damage and ferroptosis through SREBF2 and enhanced the inhibitory effect of ferroptosis inhibitors on IL-1β-induced ATDC5 cell injury. The present data suggest that STM attenuated chondrocyte injury induced by IL-1β by regulating ferroptosis via down-regulation of SREBF2, and may have potential as a novel therapeutic method for knee osteoarthritis.
Topics: Animals; Cell Line; Cell Survival; Chondrocytes; Down-Regulation; Ferroptosis; Interleukin-1beta; Mice; Sterol Regulatory Element Binding Protein 2; Stigmasterol
PubMed: 34806937
DOI: 10.1080/21655979.2021.2000742