Alzheimer's disease (AD) is a fatal neurodegenerative disease characterized by progressive cognitive decline and memory loss. However, several therapeutic approaches have shown unsatisfactory ...outcomes in the clinical setting. Thus, developing alternative therapies for the prevention and treatment of AD is critical. Salidroside (SAL) is critical, an herb-derived phenylpropanoid glycoside compound, has been shown to attenuate lipopolysaccharide (LPS)-induced cognitive impairment. However, the mechanism underlying its neuroprotective effects remains unclear. Here, we show that SAL has a therapeutic effect in the senescence-accelerated mouse prone 8 (SAMP8) strain, a reliable and stable mouse model of AD.
SAMP8 mice were treated with SAL, donepezil (DNP) or saline, and cognitive behavioral impairments were assessed using the Morris water maze (MWM), Y maze, and open field test (OFT). Fecal samples were collected and analyzed by 16S rRNA sequencing on an Illumina MiSeq system. Brain samples were analyzed to detect beta-amyloid (Aβ) 1-42 (Aβ1-42) deposition by immunohistochemistry (IHC) and western blotting. The activation of microglia and neuroinflammatory cytokines was detected by immunofluorescence (IF), western blotting and qPCR. Serum was analyzed by a Mouse High Sensitivity T Cell Magnetic Bead Panel on a Luminex-MAGPIX multiplex immunoassay system.
Our results suggest that SAL effectively alleviated hippocampus-dependent memory impairment in the SAMP8 mice. SAL significantly 1) reduced toxic Aβ1-42 deposition; 2) reduced microglial activation and attenuated the levels of the proinflammatory factors IL-1β, IL-6, and TNF-α in the brain; 3) improved the gut barrier integrity and modified the gut microbiota (reversed the ratio of Bacteroidetes to Firmicutes and eliminated Clostridiales and Streptococcaceae, which may be associated with cognitive deficits); and 4) decreased the levels of proinflammatory cytokines, particularly IL-1α, IL-6, IL-17A and IL-12, in the peripheral circulation, as determined by a multiplex immunoassay.
In summary, SAL reversed AD-related changes in SAMP8 mice, potentially by regulating the microbiota-gut-brain axis and modulating inflammation in both the peripheral circulation and central nervous system. Our results strongly suggest that SAL has a preventive effect on cognition-related changes in SAMP8 mice and highlight its value as a potential agent for drug development.
Abstract
Background
Alzheimer’s disease (AD) is a neurodegenerative disease. Ferroptosis plays a critical role in neurodegenerative diseases. Nuclear factor E2-related factor 2 (Nrf2) is considered ...an important factor in ferroptosis. Studies have demonstrated that salidroside has a potential therapeutic effect on AD. The intrinsic effect of salidroside on ferroptosis is unclear. The purpose of this study was to investigate the protective effects and pharmacological mechanisms of salidroside on alleviating neuronal ferroptosis in Aβ
1−42
-induced AD mice and glutamate-injured HT22 cells.
Methods
HT22 cells were injured by glutamate (Glu), HT22 cells transfected with siRNA Nrf2, and Aβ
1−42
-induced WT and Nrf2
−/−
AD mice were treated with salidroside. The mitochondria ultrastructure, intracellular Fe
2+
, reactive oxygen species, mitochondrial membrane potential, and lipid peroxidation of HT22 cells were detected. Malondialdehyde, reduced glutathione, oxidized glutathione disulfide, and superoxide dismutase were measured. The novel object recognition test, Y-maze, and open field test were used to investigate the protective effects of salidroside on Aβ
1−42
-induced WT and Nrf2
−/−
AD mice. The protein expressions of PTGS2, GPX4, Nrf2, and HO1 in the hippocampus were investigated by Western blot.
Results
Salidroside increased the cell viability and the level of MMP of Glu-injured HT22 cells, reduced the level of lipid peroxidation and ROS, and increased GPX4 and SLC7A11 protein expressions. These changes were not observed in siRNA Nrf2 transfected HT22 cells. Salidroside improved the ultrastructural changes in mitochondria of HT22 cells and Aβ
1−42
-induced AD mice, but not in Aβ
1−42
-induced Nrf2
−/−
AD mice. Salidroside increased protein expression levels of GPX4, HO1, and NQO1 and decreased protein expression of PTGS2 in Aβ
1−42
-induced AD mice but not in Aβ
1−42
-induced Nrf2
−/−
AD mice.
Conclusions
Salidroside plays a neuroprotective role by inhibiting neuronal ferroptosis in Aβ
1−42
-induced AD mice and Glu-injured HT22 cells, and its mechanism is related to activation of the Nrf2/HO1 signaling pathway.
Graphical Abstract
Acne is a kind of common, chronic skin condition caused by the inflammation of the sebaceous glands in hair follicles. Recent studies have demonstrated that baicalin (BA) possesses potential ...anti-inflammatory properties. In this study, we evaluated the anti-inflammatory activity of BA in vitro and in vivo. Heat-killed Propionibacterium acnes-induced THP-1 cells and live P. acnes-injected male Sprague Dawley rats were used for establishing the acne model. The rate of ear swelling was calculated, and the severity was determined by hematoxylin and eosin staining. The production of cytokines interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF-α) in the cell supernatant and ear tissue homogenates was measured by ELISA. Protein levels of JNK, ERK, P38, IκBα, P65, Nod-like receptor pyrin domain-containing 3 (NLRP3), pro-caspase-1, and IL-1β in THP-1 cells and ear tissues were detected by western blotting. NLRP3 and IL-1β were detected by immunohistochemistry, and the NLRP3, IL-1β and pro-caspase-1 mRNAs were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The results showed that BA decreased the expression of pro-inflammatory cytokines in vitro and in vivo. Moreover, BA down-regulated the phosphorylation of JNK, ERK1/2, and κBα and inhibited the nuclear translocation of p65. Furthermore, BA inhibited the activation of NLRP3 inflammasome, at both the gene and protein levels. Taken together, the results demonstrated that BA might exert its anti-inflammatory activity by inhibiting NF-κB/MAPK signaling pathways and consequently suppressing the activation of the NLRP3 inflammasome both in vivo and in vitro.
Abstract
Neuronal iron overload contributes to synaptic damage and neuropsychiatric disorders. However, the molecular mechanisms underlying iron deposition in depression remain largely unexplored. ...Our study aims to investigate how nuclear factor-erythroid 2 (NF-E2)-related factor 2 (
Nrf2
) ameliorates hippocampal synaptic dysfunction and reduces brain functional connectivity (FC) associated with excessive iron in depression. We treated mice with chronic unpredictable mild stress (CUMS) with the iron chelator deferoxamine mesylate (DFOM) and a high-iron diet (2.5% carbonyl iron) to examine the role of iron overload in synaptic plasticity. The involvement of
Nrf2
in iron metabolism and brain function was assessed using molecular biological techniques and in vivo resting-state functional magnetic resonance imaging (rs-fMRI) through genetic deletion or pharmacologic activation of
Nrf2
. The results demonstrated a significant correlation between elevated serum iron levels and impaired hippocampal functional connectivity (FC), which contributed to the development of depression-induced CUMS. Iron overload plays a crucial role in CUMS-induced depression and synaptic dysfunction, as evidenced by the therapeutic effects of a high-iron diet and DFOM. The observed iron overload in this study was associated with decreased
Nrf2
levels and increased expression of transferrin receptors (TfR). Notably, inhibition of iron accumulation effectively attenuated CUMS-induced synaptic damage mediated by downregulation of brain-derived neurotrophic factor (BDNF).
Nrf2
−/−
mice exhibited compromised FC within the limbic system and the basal ganglia, particularly in the hippocampus, and inhibition of iron accumulation effectively attenuated CUMS-induced synaptic damage mediated by downregulation of brain-derived neurotrophic factor (BDNF). Activation of
Nrf2
restored iron homeostasis and reversed vulnerability to depression. Mechanistically, we further identified that
Nrf2
deletion promoted iron overload via upregulation of TfR and downregulation of ferritin light chain (FtL), leading to BDNF-mediated synapse damage in the hippocampus. Therefore, our findings unveil a novel role for
Nrf2
in regulating iron homeostasis while providing mechanistic insights into poststress susceptibility to depression. Targeting
Nrf2
-mediated iron metabolism may offer promising strategies for developing more effective antidepressant therapies.
A series of novel dual A
2A
/A
2B
AR antagonists based on the triazole-pyrimidine-methylbenzonitrile core were designed and synthesised. The A
2A
AR antagonist cAMP functional assay results were ...encouraging for most target compounds containing quinoline or its open-ring bioisosteres. In addition, compound 7i displayed better inhibitory activity on A
2B
AR (IC
50
14.12 nM) and higher potency in IL-2 production than AB928. Moreover, molecular docking studies were carried out to explain the rationality of molecular design and the activity of compound 7i. Further studies on 7f and 7i revealed good liver microsomes stabilities and acceptable in vivo PK profiles. This study provides insight into the future development of dual A
2A
/A
2B
AR antagonists for cancer immunotherapy.
Cathelicidins, a class of gene-encoded effector molecules of vertebrate innate immunity, provide a first line of defense against microbial invasions. Although cathelicidins from mammals, birds, ...reptiles and fishes have been extensively studied, little is known about cathelicidins from amphibians. Here we report the identification and characterization of two cathelicidins (cathelicidin-RC1 and cathelicidin-RC2) from the bullfrog Rana catesbeiana. The cDNA sequences (677 and 700 bp, respectively) encoding the two peptides were successfully cloned from the constructed lung cDNA library of R. catesbeiana. And the deduced mature peptides are composed of 28 and 33 residues, respectively. Structural analysis indicated that cathelicidin-RC1 mainly assumes an amphipathic alpha-helical conformation, while cathelicidin-RC2 could not form stable amphipathic structure. Antimicrobial and bacterial killing kinetic analysis indicated that the synthetic cathelicidin-RC1 possesses potent, broad-spectrum and rapid antimicrobial potency, while cathelicidin-RC2 exhibited very weak antimicrobial activity. Besides, the antimicrobial activity of cathelicidin-RC1 is salt-independent and highly stable. Scanning electron microscopy (SEM) analysis indicated that cathelicidin-RC1 kills microorganisms through the disruption of microbial membrane. Moreover, cathelicidin-RC1 exhibited low cytotoxic activity against mammalian normal or tumor cell lines, and low hemolytic activity against human erythrocytes. The potent, broad-spectrum and rapid antimicrobial activity combined with the salt-independence, high stability, low cytotoxic and hemolytic activities make cathelicidin-RC1 an ideal template for the development of novel peptide antibiotics.
Pyrophosphate (PPi) anions are crucial in numerous biological and ecological processes involved in energy conversion, enzymatic reactions, and metabolic regulation along with adenosine. They are also ...significant biological markers for various processes related to diseases. Fluorescent PPi sensors would enable visual and/or biological detection in convenient settings. However, the current availability of commercial sensors has been limited to costly enzymes that are not compatible for imaging. Sensor development has also encountered challenges such as poor selectivity and stability and limited practical applications. In this review, we analyze the situation of PPi sensing via commercial kits and focus on sensors that use metal complexes. We address their designs, sensing mechanisms, selectivities, and detection limits. Finally, we discuss limitations and perspectives for PPi detection and imaging.
We focus on the designs, sensing mechanisms, selectivities, and detection limits of PPi sensors based on metal complexes. We initially analyzed commercial PPi‐sensing kits. We discussed limitations and perspectives, providing support for PPi detection and molecular imaging.
20(S)-protopanaxadiol (20(S)-PPD), one of the main active metabolites of ginseng, performs a broad spectrum of anti-tumor effects. Our aims are to search out new strategies to enhance anti-tumor ...effects of natural products, including 20(S)-PPD. In recent years, fasting has been shown to be multi-functional on tumor progression. Here, the effects of fasting combined with 20(S)-PPD on hepatocellular carcinoma growth, apoptosis, migration, invasion and cell cycle were explored.
CCK-8 assay, trypan blue dye exclusion test, imagings photographed by HoloMonitorTM M4, transwell assay and flow cytometry assay were performed for functional analyses on cell proliferation, morphology, migration, invasion, apoptosis, necrosis and cell cycle. The expressions of genes on protein levels were tested by western blot. Tumor-bearing mice were used to evaluate the effects of intermittent fasting combined with 20(S)-PPD.
We firstly confirmed that fasting-mimicking increased the anti-proliferation effect of 20(S)-PPD in human HepG2 cells in vitro. In fasting-mimicking culturing medium, the apoptosis and necrosis induced by 20(S)-PPD increased and more cells were arrested at G0-G1 phase. Meanwhile, invasion and migration of cells were decreased by down-regulating the expressions of matrix metalloproteinase (MMP)-2 and MMP-9 in fasting-mimicking medium. Furthermore, the in vivo study confirmed that intermittent fasting enhanced the tumor growth inhibition of 20(S)-PPD in H22 tumor-bearing mice without obvious side effects.
Fasting significantly sensitized HCC cells to 20(S)-PPD in vivo and in vitro. These data indicated that dietary restriction can be one of the potential strategies of chinese medicine or its active metabolites against hepatocellular carcinoma.
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Angucyclines and angucyclinones represent the largest family of type II PKS-engineered natural products. Chemical analysis of a marine
Streptomyces
sp. KCB-132 yielded three new members, ...actetrophenone A (1) and actetrophenols A–B (2–3). Their structures were elucidated by NMR spectroscopy, X-ray crystallography and CD calculations. Actetrophenone A (1) is the first representative of a novel-type angucyclinone bearing a nonaromatic D-ring. Actetrophenol A (2) features a highly reduced and aromatized four-ring system, which is unprecedented for natural products. While (
R
a
)- and (
S
a
)-actetrophenol B (3) bear an unprecedented
N
-acetyltryptamine-substituted tetraphene core skeleton, this is the first report of a pair of atropisomeric isomers in the angucyclinone family. Actetrophenol A (2) exhibits remarkable antibiotic activity, notably including potent activity to multiple resistant
Staphylococcus aureus
and
Enterococcus faecium
with MIC values of 4 μg/ml, in contrast, the positive control antimicrobial agent penicillin was inactive up to 32 μg/ml.
Chemical investigation of a marine-derived
Streptomyces
sp. KCB-132, cultivated in liquid ISP2 medium, had led to the discovery of three C-ring cleavage angucyclinone
N
-heterocycles, pratensilins ...A–C, with a novel spiro indolinone-naphthofuran skeleton. Addition of 50 μM LaCl
3
to the same medium and subsequent chemical analysis of this strain returned a new member of this rare class, pratensilin D (
1
), along with two new angucyclinone derivatives, featuring ether-bridged (
2
) and A-ring cleavage (
3
) structural properties. Their structures and absolute configurations were assigned by spectroscopic analysis, single-crystal X-ray diffractions, and equivalent circulating density (ECD) calculations. (+)- and (–)-
1
, a pair of enantiomeric nitrogen-containing angucyclinones, exhibited different strengths of antibacterial and cytotoxic activities.
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