Syringaresinol from Cinnamomum cassia (L.) J.Presl ameliorates cognitive deficits and AD pathology via AMPK in a DM-AD mouse model.

(–)-Syringaresinol attenuates ulcerative colitis by improving intestinal epithelial barrier function and inhibiting inflammatory responses

Syringaresinol (SYR) is a dietary lignan largely known for its therapeutic effects. Thus, our present review provides an overview of the natural sources and chemistry of this molecule and discusses its biological and pharmacological properties. Indeed, SYR is widely distributed in the plant kingdom and has been reported in 87 species distributed over 40 families. Its main sources are Acanthopanax and Albizia genera. It has also been identified and purified from Cinnamomum cassia and Panax ginseng C.A. Mey. Interestingly, SYR has an important anti-inflammatory effect and is implicated in multiple mechanistic pathways, including the inhibition of iNOS, cyclooxygenase-2 (COX-2), and the decrease of NF-κB, nitric oxide (NO), PGE2, tumor necrosis factor-α (TNF-α), IL-1β, and IL-6 levels. In cancer treatment, SYR induces cell cycle arrest, increases the expression of p21waf1/cip1 and p27kip1, and causes a downregulation of cyclins and cyclin-dependent kinases (CDKs). SYR improves cardiac function via ER/SIRT1/NLRP3/GSDMD and has a protective effect against hypoxia/reoxygenation injury. Although some toxicological studies have confirmed its safety, nevertheless, further examinations are necessary to prove its pharmacological stability. Unfortunately, there is a major lack of human clinical investigations on SYR. Therefore, it is strongly advised to focus on this side to better recommend this substance as a dietary agent for various human health complications.

Syringaresinol alleviates IgG immune complex induced acute lung injury via activating PPARγ and suppressing pyroptosis

Albizia julibrissin Durazz. is one of the most popular herbs used for depression treatment, but the molecular basis for its mechanism of action has not been fully addressed. Previously, we isolated and identified two lignan glycoside derivatives that were shown to noncompetitively inhibit serotonin transporter (SERT) activity but with a relatively low inhibitory potency compared with those of conventional antidepressants. We characterized the pharmacological profile of the parental compound of these previously isolated lignan glycosides, (-)-syringaresinol (SYR), in inhibiting SERT by using biochemical, pharmacological, and behavioral approaches. SYR, as a potent inhibitor, decreases SERT Vmax but with little change in Km for its fluorescent substrate. SYR was shown to block the conformational conversion essential for substrate transport by stabilizing SERT in an outward-open and inward-closed conformation. In addition, our molecular docking and biochemical validation demonstrated that SYR binds to an allosteric site in SERT and noncompetitively inhibits SERT transport and binding activity. Furthermore, administration of SYR was indicated to exert an antidepressant-like activity and to effectively attenuate chronic unpredictable mild stress (CUMS)-induced abnormalities in behaviors and synaptic protein expression in depressive animal models. This study not only provides molecular insights into the mechanism of action of A. julibrissin in the treatment of depression, but also opens up the possibility of development of a novel class of allosteric site-targeted therapeutic agents with an underlying mechanism of action different from that of conventional antidepressants.

PTP1B(-/-) mice are resistant to diet-induced obesity due to leptin hypersensitivity and consequent increased energy expenditure. We aimed to determine the cellular mechanisms underlying this metabolic state. AMPK is an important mediator of leptin's metabolic effects. We find that alpha1 and alpha2 AMPK activity are elevated and acetyl-coenzyme A carboxylase activity is decreased in the muscle and brown adipose tissue (BAT) of PTP1B(-/-) mice. The effects of PTP1B deficiency on alpha2, but not alpha1, AMPK activity in BAT and muscle are neuronally mediated, as they are present in neuron- but not muscle-specific PTP1B(-/-) mice. In addition, AMPK activity is decreased in the hypothalamic nuclei of neuronal and whole-body PTP1B(-/-) mice, accompanied by alterations in neuropeptide expression that are indicative of enhanced leptin sensitivity. Furthermore, AMPK target genes regulating mitochondrial biogenesis, fatty acid oxidation, and energy expenditure are induced with PTP1B inhibition, resulting in increased mitochondrial content in BAT and conversion to a more oxidative muscle fiber type. Thus, neuronal PTP1B inhibition results in decreased hypothalamic AMPK activity, isoform-specific AMPK activation in peripheral tissues, and downstream gene expression changes that promote leanness and increased energy expenditure. Therefore, the mechanism by which PTP1B regulates adiposity and leptin sensitivity likely involves the coordinated regulation of AMPK in hypothalamus and peripheral tissues.

Glucose is an important fuel for highly active skeletal muscles. Increased adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratios during repetitive contractions trigger AMP-activated protein kinase (AMPK), indicated by phosphorylation of AMPKαThr172, which promotes glucose uptake to support heightened energy needs, but it also suppresses anabolic processes. Inhibition of AMPK can occur by protein kinase B (AKT)-mediated phosphorylation of AMPKαSer485/491, releasing its brake on growth. The influence of insulin-like growth factor I (IGF-I) on glucose uptake and its interplay with AMPK activation is not well understood. Thus, the goal of this study was to determine if increased muscle IGF-I altered AMPKα phosphorylation and activity during muscle contraction. Adult male mice harboring the rat Igf1a cDNA regulated by the fast myosin light chain promoter (mIgf1+/+) and wildtype littermates (WT) were used in the study. mIgf1+/+ mice had enhanced glucose tolerance and insulin-stimulated glucose uptake, but similar exercise capacity. Fatiguing stimulations of extensor digitorum longus (EDL) muscles resulted in upregulated AMPKα phosphorylation at both Thr172 and Ser485/491 in WT and mIgf1+/+ muscles. No differences in the phosphorylation response of the downstream AMPK target TBC1D1 were observed, but phosphorylation of raptor was significantly higher only in WT muscles. Further, total raptor content was elevated in mIgf1+/+ muscles. The results show that high muscle IGF-I can enhance glucose uptake under resting conditions; however, in contracting muscle, it is not sufficient to inhibit AMPK activity.

Exploring the protective mechanisms of syringaresinol against myocardial infarction by experimental validation and network pharmacology.

Context Type 2 Diabetes Mellitus (T2D) is a significant health concern worldwide, necessitating novel therapeutic approaches beyond conventional treatments. Objective To assess isorhamnetin’s potential in improving insulin sensitivity and mitigating T2D characteristics through oxidative and glycative stress modulation. Materials and Methods T2D was induced in mice with a high-fat diet and streptozotocin injections. Isorhamnetin was administered at 10 mg/kg for 12 weeks. HepG2 cells were used to examine in vitro effects on stress markers and insulin sensitivity. Molecular effects on the PGK1 and AKT signalling pathway were also analyzed. Results The administration of isorhamnetin significantly impacted both in vivo and in vitro models. In HepG2 cells, oxidative and glycative stresses were markedly reduced, indicating a direct effect of isorhamnetin on cellular stress pathways, which are implicated in the deterioration of insulin sensitivity. Specifically, treated cells showed a notable decrease in markers of oxidative stress, such as malondialdehyde, and advanced glycation end products, highlighting isorhamnetin’s antioxidant and antiglycative properties. In vivo, isorhamnetin-treated mice exhibited substantially lower fasting glucose levels compared to untreated T2D mice, suggesting a strong hypoglycemic effect. Moreover, these mice showed improved insulin responsiveness, evidenced by enhanced glucose tolerance and insulin tolerance tests. The molecular investigation revealed that isorhamnetin activated PGK1, leading to the activation of the AKT signalling pathway, crucial for promoting glucose uptake and reducing insulin resistance. This molecular action underscores the potential mechanism through which isorhamnetin exerts its beneficial effects in T2D management. Discussion The study underscores isorhamnetin’s multifaceted role in T2D management, emphasizing its impact on oxidative and glycative stress reduction and molecular pathways critical for insulin sensitivity. Conclusion Isorhamnetin presents a promising avenue for T2D treatment, offering a novel approach to enhancing insulin sensitivity and managing glucose levels through the modulation of key molecular pathways. Further research is needed to translate these findings into clinical practice.

Glabridin protects against paraquat-induced acute lung injury by targeting ME1 to mitigate oxidative stress, mitochondrial dysfunction, and cGAS-STING activation.

Syringaresinol derived from Panax ginseng berry attenuates oxidative stress-induced skin aging via autophagy

AMPK was shown to negatively regulate FcεRI activation, and FcεR-mediated Fyn activation can counteract the LKB1/AMPK axis in mast cells. However, the relationship between the major Src family kinase Lyn and AMPK remains poorly defined. Here, we investigate the molecular mechanism for AMPK inhibition by FcεRI-Lyn signaling in rat RBL-2H3 cells. We found that FcεRI activation could rapidly inhibit AMPK activation through increased AMPK phosphorylation at the inhibitory Ser485/491 residues without a change at the activating Th172 residue, and this was accompanied by a reduction of ACC phosphorylation. Using specific inhibitors and gene silencing, we found that such AMPK inhibition involved a signaling cascade through Lyn-Syk-Akt. When AMPK was activated by AICAR, A769662 and metformin, FcεRI-mediated Syk, ERK, JNK and p38 activation, and TNFα release were all inhibited. Consistently, AMPK inhibition by compound C increased FcεRI-mediated Lyn activation. Moreover, AMPK activation dominantly impaired IgE-induced recruitment of signal proteins to the FcεRI by blocking the formation of FcεRIβ-Lyn-Syk, FcεRIγ-Lyn-Syk, and AMPK-FcεRIβ complexes. In vitro kinase assay further revealed the ability of AMPKα2 to phosphorylate FcεRIβ in the complex. In vivo, AMPK activation by metformin could readily reduce vascular permeability and ear swelling in a mouse model of passive cutaneous anaphylaxis mediated by IgE. In summary, our findings demonstrate that IgE-mediated FcεRI activation results in AMPK inhibition through activation of Lyn-Syk-Akt pathway, and as such FcεRI receptor can efficiently propagate Lyn-mediated allergic signaling and response. These results provide important insights into the use of AMPK activators for the treatment of allergic diseases. AMPK is inhibited by FcεRI via Lyn-Syk-Akt signaling in RBL-2H3 cells. AMPK inhibition supports FcεRI-mediated Lyn signaling and allergic response. Metformin has inhibitory effect on passive cutaneous anaphylaxis.

We recently demonstrated that AMPK inhibition in spermatozoa regulates motility, plasma membrane organization, acrosome integrity and mitochondrial membrane potential. As AMPK activity varies in different energy conditions induced by sperm environment, this work investigates the functional effects of AMPK activation in boar spermatozoa. Spermatozoa were incubated under non-stimulating (TBM) or Ca(2+) and [Formula: see text]-stimulating (TCM) media in the presence/absence of AMPK activator, A769662, for different times. AMPK activity, evaluated as Thr(172) phosphorylation by western blot, is effectively increased by A769662 in spermatozoa. AMPK activation significantly reduces the percentage of motile spermatozoa under Ca(2+) and/or [Formula: see text]-stimulating conditions. Moreover, AMPK activation in spermatozoa incubated in TBM or TCM significantly reduces curvilinear VCL, straight-line VSL and average VAP velocities, which subsequently lead to a significant decrease in the percentage of rapid spermatozoa (VAP > 80 μm/s). The effect of AMPK activation on motility is intensified by the absence of BSA in the incubation medium. AMPK activation for a short time prevents the decline in cell viability and in the sperm population displaying high mitochondrial membrane potential which is induced by Ca(2+) and [Formula: see text]. Sustained (24 h) AMPK activation under TBM or TCM significantly increases both lipid disorganization and phosphatidylserine externalization in the sperm plasma membrane, and diminishes the acrosome membrane integrity. In summary, AMPK activation modifies essential sperm processes such as motility, viability, mitochondrial membrane potential, acrosome membrane integrity, and organization and fluidity of plasma membrane. As these spermatozoa processes are required under different environmental conditions when transiting through the female reproductive tract to achieve fertilization, we conclude that balanced levels of AMPK activity are essential for regulating sperm function.

Gastrodin ameliorates postoperative cognitive dysfunction in aged mice by promoting nuclear translocation of Nrf2 through activation of AMPK

Metformin affects macrophages’ phenotype and improves the activity of glutathione peroxidase, superoxide dismutase, catalase and decreases malondialdehyde concentration in a partially AMPK-independent manner in LPS-stimulated human monocytes/macrophages

Syringaresinol attenuates sepsis-induced cardiac dysfunction by inhibiting inflammation and pyroptosis in mice