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Background and Purpose: Kaempferol‐3‐O‐sophoroside (PCS‐1) is the main component in Crocus sativus (Saffron), a herb with mood‐enhancing properties. AMP‐activated protein kinase (AMPK) is a potential therapeutic target for depression. This study explores the antidepressive‐like properties of PCS‐1 and its AMPK activation to confirm AMPK as a target for antidepression. Experimental Approach: Corticosterone (CORT)‐induced PC12 cell injury served as an in vitro model to evaluate the neuroprotective effect of PCS‐1. Neuro‐2a cells and primary neurons were utilized to evaluate the synaptogenesis role of PCS‐1. CORT‐induced mouse depression model and chronic unpredictable mild stress (CUMS) model were used to assess the antidepressive‐like properties of PCS‐1 through behavioural tests, magnetic resonance imaging, and biochemical index measurements. Western blot and immunofluorescence assays were used to study the mechanisms of PCS‐1. Cellular thermal shift assay was used to confirm the binding target. Key Results: PCS‐1 (12.5–50 μM) ameliorated CORT‐induced PC12 cell damage, oxidative stress and inflammation. PCS‐1 alone promoted an increase in synapses in Neuro‐2a cells and primary neurons. Oral administration of PCS‐1 (10 and 20 mg·kg−1) ameliorated weight loss, dyskinesia, and hippocampal volume reduction induced by CORT and CUMS. PCS‐1 bound to AMPK to improve the expression of brain‐derived neurotrophic factor (BDNF) and induce autophagy. Conclusion and Implications: PCS‐1 binds to AMPK to promote BDNF production and autophagy enhancement, ultimately achieving antidepressant effects. This study provides support for the clinical application of saffron petals and provides further evidence for AMPK as a potential target for antidepression. [ABSTRACT FROM AUTHOR]

Imbalance of macrophage polarization plays a critical role in the progression of rheumatoid arthritis (RA). Geniposide (GE) has been shown to exert anti-inflammatory effects. However, the effect of GE on macrophage polarization remains unclear. Here, we investigated the regulation of GE on the imbalance of macrophage polarization in RA and how it functions. We established a mouse model of collagen-induced arthritis (CIA) and isolated bone marrow-derived macrophages (BMDMs). The results confirmed that pro-inflammatory M1 macrophages were dominant in CIA mice, but the polarization imbalance of macrophages was restored to a certain extent after GE treatment. Furthermore, the membrane targeting of sphingosine kinase 1 (SphK1) was increased in BMDMs of CIA mice, as manifested by increased membrane and cytoplasmic expression of p-SphK1 and high secretion level of sphingosine-1-phosphate (S1P). RAW264.7 cells were stimulated with lipopolysaccharide (LPS)-interferon (IFN)-γ or interleukin (IL)-4 to induce M1 or M2 phenotype, respectively, to revalidate the results obtained in BMDMs. The results again observed SphK1 membrane targeting in LPS–IFN–γ-stimulated RAW264.7 cells. Selective inhibition of SphK1 by PF543 or inhibition of the S1P receptors by FTY720 both restored the proportion of M1 and M2 macrophages in LPS–IFN–γ-stimulated RAW264.7 cells, confirming that SphK1 membrane targeting mediated a proportional imbalance in M1 and M2 macrophage polarization. In addition, GE inhibited SphK1 membrane targeting and kinase activity. Taken together, results confirmed that the inhibition of SphK1 membrane targeting by GE was responsible for restoring the polarization balance of macrophages in CIA mice. • The balance of M1 and M2 macrophages was disrupted in collagen-induced arthritis (CIA) mice. • SphK1 membrane targeting mediated M1 macrophage polarization and contributed to M1/M2 macrophage imbalance. • Geniposide inhibited SphK1 membrane targeting to restore the balance of M1/M2 macrophages. [ABSTRACT FROM AUTHOR]

BACKGROUND: Dietary interventions are crucial in modulating inflammation in humans. Strawberries are enjoyed by people of different ages as a result of their attractive phenotype and taste. In addition, the active compounds in strawberries may contribute to the reduction of inflammation. When developing new strawberry cultivars to address agricultural and environmental threats, the bioactivity of strawberries must be improved to maintain their health benefits. RESULTS: We determined the phytochemical contents of extracts from a new Korean strawberry cultivar, with the CN7 cultivar extract possessing the highest total polyphenol and flavonoid contents compared to the CN5 and Seolhyang cultivar extracts. The new Korean strawberry cultivars reduced the expression of inflammatory‐related genes in lipopolysaccharide (LPS)‐induced RAW264.7 cells via the nuclear factor‐kappa B signaling pathway, indicating an anti‐inflammatory effect. The CN7 cultivar showed greater bioactivity potential and the highest ellagic acid content; hence, we assessed the effect of the CN7 cultivar in an LPS‐stimulated mouse model. The CN7 cultivar treatment demonstrated its effectiveness in reducing inflammation via the downregulation of inflammatory cytokines secretion and gene expression. CONCLUSION: The results obtained in the present study have revealed the observable differences of the newly developed strawberry cultivars with Seolhyang in mitigating inflammation induced by LPS. The enhanced phytochemical content of the CN7 cultivar extract may contribute to its improved anti‐inflammatory effect. Therefore, it is crucial to maintain the nutritive benefits of strawberry during the development of new cultivation. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a neurasthenic disease, which is the second-largest burden of disease globally. Increasing studies have revealed that depression is associated with abnormalities in gut microbiota and metabolites. Several species of bacteria have been classified as psychobiotics, which confer mental health benefits through interactions with commensal gut microbiota. Therefore, it is essential to identify new psychobiotics and elucidate their mechanisms in the treatment of depression. This study aims to evaluate the antidepressant effect of Akkermansia muciniphila (AKK) in a mouse model of depression induced by chronic restraint stress (CRS). C57BL/6 male mice were divided into three groups: mice subjected to CRS, mice not subjected to CRS, and mice treated with AKK for 3 weeks. Behavioral tests were performed, and hormone, neurotransmitter, and brain-derived neurotrophic factor (BDNF) levels were measured. Cecal microbiota was analyzed using 16S rRNA gene sequencing, and serum metabolites were detected using untargeted metabolomics. In addition, correlations between altered gut microbiota and metabolites with significant variations in serum associated with AKK ameliorating depression were analyzed using Pearson's correlation coefficient. The results revealed that AKK significantly ameliorated depressive-like behavior and restored abnormal variations in depression-related molecular (corticosterone, dopamine, and BDNF). Moreover, AKK altered chronic stress–induced gut microbial abnormalities. Untargeted metabolomics analysis revealed 23 potential biomarkers in serum that could be associated with the mechanisms underlying CRS-induced depression and the therapeutic effects of AKK. Pearson's correlation coefficient analysis revealed that AKK predominantly upregulated β-alanyl-3-methyl-l-histidine and edaravone to relieve depression. Furthermore, β-alanyl-3-methyl-l-histidine and edaravone exhibited the antidepressant phenotype in mice subjected to CRS. In conclusion, the study demonstrated that AKK ameliorates chronic stress–induced depressive symptoms in mice by regulating gut microbiota and metabolites. Key points: • AKK reduces depressive-like behaviors induced by chronic stress. • AKK regulates the gut microbial structure and metabolomics of serum under the chronic stress. • Antidepressant effect of AKK correlates with the increase of β-alanyl-3-methyl-l-histidine and edaravone. [ABSTRACT FROM AUTHOR]

The total flavone of Abelmoschus manihot (TFA), a compound extracted from the flowers of Abelmoschus manihot (L.) Medic, has been widely used for the treatment of Crohn's disease, chronic glomerulonephritis and other diseases. The aim of this study was to investigate the effect of TFA on the gut microbiota and intestinal barrier in dextran sulfate sodium (DSS)-induced experimental colitis. C57BL/6J mice were treated with 2.5% DSS in drinking water to induce colitis. Mice were orally administered TFA (62.5 mg/kg, 125 mg/kg) or prednisone acetate (PAT, 2.5 mg/kg) once daily for 7 days. Biological samples were collected for analysis of inflammatory cytokines, gut microbiota and intestinal barrier integrity. TFA-H (125 mg/kg) markedly attenuated DSS-induced colon shortening and histological injury in experimental colitis. The therapeutic effect was similar to that of PAT administration. TFA-H notably modulated the dysbiosis of gut microbiota induced by DSS and greatly enriched Akkermansia muciniphila (A. muciniphila). Moreover, TFA-H remarkably ameliorated the colonic inflammatory response and intestinal epithelial barrier dysfunction. Interestingly, TFA directly promotes the growth of A. muciniphila in vitro. Taken together, the results revealed for the first time that TFA, as a prebiotic of A. muciniphila, improved DSS-induced experimental colitis, at least partly by modulating the gut microflora profile to maintain colonic integrity and inhibit the inflammatory response. [ABSTRACT FROM AUTHOR]

Botulinum neurotoxin (BoNT) is a neurotoxin produced by Clostridium botulinum in an anaerobic environment. BoNT is the most toxic protein among bacteria, animals, plants, and chemical substances reported to date. BoNTs are 150 kDa proteins composed of three major functional domains: catalytic (L domain, 50 kDa), translocation (HN domain, 50 kDa), and receptor-binding (Hc domain, 50 kDa) domains. Most studies have focused on the use of the Hc domain as an antigen because it is capable of generating robust protective immunity and contains some functional neutralizing epitopes. In the present study, we produced and characterized a recombinant L-HN fusion fragment of the parent BoNT/B (BL-HN) composed of L and HN domains with a deletion in the Hc domain (BHc). When the BL-HN protein was expressed in E. coli, it retained its stable structure and antigenicity. As a vaccine antigen, the recombinant BL-HN protein was found to induce sufficient protection against native BoNT/B in a mouse model. The BL-HN subunit vaccine could also induce a strong humoral immune response and generate sufficient neutralizing antibodies in immunized mice. Therefore, BL-HN may retain the native neurotoxin structure and critical epitopes responsible for inducing serum neutralizing antibodies. Studies of the dose-dependent immunoprotective effects further confirmed that the BL-HN antigen could provide potent protective immunity. This finding suggests that BL-HN can play an important role in immune protection against BoNT/B. Therefore, the BL-HN fusion fragment provides an excellent platform for the design of recombinant botulinum vaccines and neutralizing antibodies. [ABSTRACT FROM AUTHOR]

Advanced age is the strongest risk factor for osteoporosis. The immunomodulator drug rapamycin extends lifespan in numerous experimental model organisms and is being investigated as a potential therapeutic to slow human aging, but little is known about the effects of rapamycin on bone. We evaluated the impact of rapamycin treatment on bone mass, architecture, and indices of bone turnover in healthy adult (16–20 weeks old at treatment initiation) female wild-type (ICR) and Nrf2−/− mice, a mouse model of oxidative damage and aging-related disease vulnerability. Rapamycin (4 mg/kg bodyweight) was administered by intraperitoneal injection every other day for 12 weeks. Mice treated with rapamycin exhibited lower femur bone mineral content, bone mineral density, and bone volume compared to vehicle-treated mice. In midshaft femur diaphysis (cortical bone), rapamycin-treated mice had lower cortical volume and thickness, and in the distal femur metaphysis (cancellous bone), rapamycin-treated mice had higher trabecular spacing and lower connectivity density. Mice treated with rapamycin exhibited lower bone volume, bone volume fraction, and trabecular thickness in the 5th lumbar vertebra. Rapamycin-treated mice had lower levels of bone formation in the distal femur metaphysis compared to vehicle-treated mice which occurred co-incidentally with increased serum CTX-1, a marker of global bone resorption. Rapamycin had no impact on tibia inflammatory cytokine gene expression, and we found no independent effects of Nrf2 knockout on bone, nor did we find any interactions between genotype and treatment. These data show that rapamycin may have a negative impact on the skeleton of adult mice that should not be overlooked in the clinical context of its usage as a therapy to retard aging and reduce the incidence of age-related pathologies. • We tested the impact of rapamycin on the skeleton in young adult wild type and Nrf2 knockout mice. • Rapamycin treatment altered bone microarchitecture and impaired bone accrual independent of Nrf2. • Nrf2 status had no impact on skeletal outcomes. • There was no effect of rapamycin on gene expression of inflammatory mediators. [ABSTRACT FROM AUTHOR]

Oxidative disruption of dopaminergic neurons is regarded as a crucial pathogenesis in Parkinson's disease (PD), eventually causing neurodegenerative progression. (-)-Clausenamide (Clau) is an alkaloid isolated from plant Clausena lansium (Lour.) , which is well-known as a scavenger of lipid peroxide products and exhibiting neuroprotective activities both in vivo and in vitro, yet with the in-depth molecular mechanism unrevealed. In this study, we evaluated the protective effects and mechanisms of Clau on dopaminergic neuron. Our results showed that Clau directly interacted with the Ser663 of ALOX5, the PKC α -phosphorylation site, and thus prevented the nuclear translocation of ALOX5, which was essential for catalyzing the production of toxic lipids 5-HETE. LC-MS/MS-based phospholipidomics analysis demonstrated that the oxidized membrane lipids were involved in triggering ferroptotic death in dopaminergic neurons. Furthermore, the inhibition of ALOX5 was found to significantly improving behavioral defects in PD mouse model, which was confirmed associated with the effects of attenuating the accumulation of lipid peroxides and neuronal damages. Collectively, our findings provide an attractive strategy for PD therapy by targeting ALOX5 and preventing ferroptosis in dopaminergic neurons. [Display omitted] • Clau reduced the motor impairment of PD model mice by inhibiting ferroptosis in dopaminergic neurons. • Clau inhibited lipid peroxidation and ferroptosis by blocking ALOX5 phosphorylation and nuclear translocation. • Clau interfered with ALOX5 function by binding to its Ser663 site and preventing the phosphorylation by PKCα. [ABSTRACT FROM AUTHOR]

[Display omitted] A total number of 18 different isoforms of histone deacetylases (HDACs) which were categorized into 4 classes have been identified in human. HDAC3 is categorized as class I HDACs and is closely related to the occurrence and development of atherosclerosis. Recent evidence has pointed to endothelial-to-mesenchymal transition (EndMT) as a key process in vascular inflammation in atherosclerosis. However, little is known about the effect of HDAC3 on EndMT in atherosclerosis. Therefore, we aimed to investigate the effect of HDAC3 specific inhibitor on EndMT in ApoE−/− mice fed a Western diet and human umbilical vein endothelial cells (HUVECs) induced by inflammatory cytokines. Firstly, we found that HDAC3 expression was up-regulated and EndMT occurred in the aortas of ApoE−/− mice compared with C57BL/6J mice. However, HDAC3 specific inhibitor RGFP966 alleviated atherosclerotic lesions and inhibited EndMT of the atherosclerotic plaque in ApoE−/− mice. Then, in vitro study showed that inflammatory cytokines TNF-α and IL-1β co-treatment increased the expression of HDAC3 and induced EndMT in HUVECs. HDAC3 inhibition by siRNA or specific inhibitor RGFP966 suppressed EndMT in HUVECs stimulated with TNF-α and IL-1β. By contrast, HDAC3 overexpression by adenovirus further promoted EndMT of HUVECs. In addition, we found that HDAC3 also regulated the inflammatory response of HUVECs by modulating the expression of inflammatory cytokines and the number of monocytes attached to HUVECs. These above results suggest that HDAC3 inhibitor suppresses EndMT via modulating inflammatory response in ApoE−/− mice and HUVECs. [ABSTRACT FROM AUTHOR]