Regional difference in the distribution of alkaline phosphatase, PHOSPHO1, and calcein labeling in the femoral metaphyseal trabeculae in parathyroid hormone-administered mice.

OBJECTIVES: This study aimed to elucidate whether the administration of parathyroid hormone (PTH) results in remodeling- or modeling-based bone formation in different regions of the murine femora, and whether the PTH-driven bone formation would facilitate osteoblastic differentiation into osteocytes. METHODS: Six-week-old male C57BL/6J mice were employed to examine the distribution of alkaline phosphatase (ALP), PHOSPHO1, podoplanin, and calcein labeling in two distinct long bone regions: the metaphyseal trabeculae close to the chondro-osseous junction (COJ) and those distant from the COJ in three mouse groups, a control group receiving a vehicle (Sham group) and groups receiving hPTH (1-34) twice a day (PTH BID group) or four times a day (PTH QID group) for two weeks. RESULTS: The Sham group showed PHOSPHO1-reactive mature osteoblasts localized primarily at the COJ, whereas the PTH BID/QID groups exhibited extended lines of PHOSPHO1-reactive osteoblasts even in regions distant from the COJ. The PTH QID group displayed fragmented calcein labeling in trabeculae close to the COJ, whereas continuous labeling was observed in trabeculae distant from the COJ. Osteoblasts tended to express podoplanin and PHOSPHO1 independently in the close and distant regions of the Sham group, while osteoblasts in the PTH-administered groups showed immunoreactivity of podoplanin and PHOSPHO1 together in the close and distant regions. CONCLUSIONS: Administration of PTH may accelerate remodeling-based bone formation in regions close to the COJ while predominantly inducing modeling-based bone formation in distant regions. PTH appeared to simultaneously facilitate osteoblastic bone mineralization and differentiation into osteocytes in both remodeling- and modeling-based bone formation.

Linking stigma to social isolation among colorectal cancer survivors with permanent stomas: the chain mediating roles of stoma acceptance and valuable actions.

PURPOSE: Colorectal cancer (CRC) survivors with permanent stomas might be at higher risk of social isolation, and stigma can play an important role in the development of social isolation. However, the underlying psychological mechanisms are understudied. The current study examined how stoma acceptance and valuable actions mediated the relationships between stigma and social isolation among CRC survivors with permanent stomas. METHODS: A cross-sectional survey was conducted with a sample of 303 CRC survivors with permanent stomas. The chain mediation models were conducted using the PROCESS macro for SPSS to explore the pathways through which stigma can be associated with CRC survivors' social isolation, mediated by stoma acceptance and valuable actions. RESULTS: The results indicated that higher stigma was related to lower stoma acceptance, less personal values enactment, and higher social isolation, as well as lower objective social connectedness and subjective social belongingness among CRC survivors with permanent stomas. Additionally, the mediational analyses revealed that stoma acceptance and valuable actions jointly mediated the relationships between stigma and social isolation. CONCLUSION: Social isolation among CRC survivors during the adjustment to both stoma and stigma may be alleviated through tailored interventions that improve stoma acceptance and valuable actions. IMPLICATIONS FOR CANCER SURVIVORS: The chain mediating roles of stoma acceptance and valuable actions highlight that tailored interventions, such as acceptance and commitment therapy, can be targeted for this population, considering this population's unique needs.

Mifepristone protects acetaminophen induced liver injury through NRF2/GSH/GST mediated ferroptosis suppression.

Ferroptosis is a form of iron-dependent cell death that has attracted significant attention for its potential role in numerous diseases. Targeted inhibition of ferroptosis could be of potential use in treating diseases: such as drug induced liver injury (DILI). Ferroptosis can be antagonized by the xCT/GSH/GPX4, FSP1/CoQ10, DHODH/CoQ10, GCH1/BH4, and NRF2 pathways. Identifying novel anti-ferroptosis pathways will further promote our understanding of the biological nature of ferroptosis and help discover new drugs targeting ferroptosis related human diseases. In this study, we identified the clinically used drug mifepristone (RU486) as a novel ferroptosis inhibitor. Mechanistically, RU486 inhibits ferroptosis by inducing GSH synthesis pathway, which supplies GSH for glutathione-S-transferase (GST) mediated 4-HNE detoxification. Furthermore, RU486 induced RLIP76 and MRP1 export 4-HNE conjugate contributes to its anti-ferroptosis activity. Interestingly, RU486 induced GSH/GSTs/RLIP76&MRP1 anti-ferroptosis pathway acts independent of classic anti-ferroptosis systems: including xCT/GSH/GPX4, FSP1, DHODH, GCH1, SCD1 and FTH1. Moreover, NRF2 was identified to be important for RU486's anti-ferroptosis activity by inducing downstream gene expression. Importantly, in mouse model, RU486 showed strong protection effect on acetaminophen (APAP)-induced acute liver injury, evidenced by decreased ALT, AST level and histological recovery after APAP treatment. Interestingly, RU486 also decreased oxidative markers, including 4-HNE and MDA, and induced NRF2 activation as well as GSTs, MRP1 expression. Together, these data suggest NRF2/GSH/GST/RLIP76&MRP1 mediated detoxification pathway as an important independent anti-ferroptosis pathway act both in vitro and in vivo.

Asymmetric Dearomatization of Indoles through Cobalt-Catalyzed Enantioselective C-H Functionalization Enabled by Photocatalysis.

Photocatalysis holds a pivotal position in modern organic synthesis, capable of inducing novel reactivities under mild and environmentally friendly reaction conditions. However, the merger of photocatalysis and transition-metal-catalyzed asymmetric C-H activation as an efficient and sustainable method for the construction of chiral molecules remains elusive and challenging. Herein, we develop a cobalt-catalyzed enantioselective C-H activation reaction enabled by visible-light photoredox catalysis, providing a synergistic catalytic strategy for the asymmetric dearomatization of indoles with high levels of enantioselectivity (96% to >99% ee). Mechanistic studies indicate that the excited photocatalyst was quenched by divalent cobalt species in the presence of Salox ligand, leading to the formation of catalytically active chiral Co(III) complex. Moreover, stoichiometric reactions of cobaltacycle intermediate with indole suggest that the irradiation of visible light also play a critical role in the dearomatization step.

Spectrum mapping technology based creation of a color-contrast reading environment to reach comfort and clarity.

Reading with a bit of yellowish or greenish paper, as compared to white paper, is thought to be more comfortable and friendly, and can help decrease eye fatigue to some degree. In this work, we try to map the light of different colors on a given paper within a region of interest to alter the colors presented by the paper and consequently influence the reading experience. We conducted an ergonomic experiment to study the comfort and clarity under consistent illuminance levels. We adopted 6 color series(red, yellow, green, cyan, blue, and magenta), 5 chroma levels(0, 10, 20, 30, 40), and 4 types of paper with the same hue(yellow) but different lightness(the white, light yellow, yellow, and dark yellow), and conducted pairwise selection experiments within each light color series. Results show that white and low chroma (≈10) color characteristics contribute to comfort, while higher chroma blue(30∼40) color benefits clarity. Referring to white, low chroma greenish and yellowish color characteristics are preferred in terms of comfort and clarity. This work proposes the spectrum mapping technology to endow the paper with new color effects and verifies that although spectrum compositions might differ, people's preferences and comfort perception are consistent with the same object color.

Multi-Omic Analysis Reveals Genetic Determinants and Therapeutic Targets of Chronic Kidney Disease and Kidney Function.

Chronic kidney disease (CKD) presents a significant global health challenge, characterized by complex pathophysiology. This study utilized a multi-omic approach, integrating genomic data from the CKDGen consortium alongside transcriptomic, metabolomic, and proteomic data to elucidate the genetic underpinnings and identify therapeutic targets for CKD and kidney function. We employed a range of analytical methods including cross-tissue transcriptome-wide association studies (TWASs), Mendelian randomization (MR), summary-based MR (SMR), and molecular docking. These analyses collectively identified 146 cross-tissue genetic associations with CKD and kidney function. Key Golgi apparatus-related genes (GARGs) and 41 potential drug targets were highlighted, with MAP3K11 emerging as a significant gene from the TWAS and MR data, underscoring its potential as a therapeutic target. Capsaicin displayed promising drug-target interactions in molecular docking analyses. Additionally, metabolome- and proteome-wide MR (PWMR) analyses revealed 33 unique metabolites and critical inflammatory proteins such as FGF5 that are significantly linked to and colocalized with CKD and kidney function. These insights deepen our understanding of CKD pathogenesis and highlight novel targets for treatment and prevention.

Electropolymerization of a Carbonyl-Modified Dihydropyrazine Derivative for Aqueous Zinc Batteries with Ultrahigh Cycling Stability.

The design of aqueous zinc-ion batteries (ZIBs) that have high specific capacity and long-term stability is essential for future large-scale energy storage systems. Cathode materials with extended π-conjugation and abundant active sites are desirable to enhance the charge storage performance and the cycling stability of the aqueous ZIB. Based on this concept, 6,9-dihydropyrazino[2,3-g]quinoxaline-2,3,7,8(1H,4H)-tetrone was chosen as the monomer to be electropolymerized onto carbon cloth (PDHPQ-Tetrone/CC). When used as the cathode material for aqueous ZIBs, an exceptional cycling life (>20,000 cycles) at a current density of 10 A g-1 was achieved, with the specific capacity maintained at 82.8% and with the Coulombic efficiency at around 100% throughout cycling. At the charge-discharge current density of 0.1 A g-1, the ZIB with PDHPQ-Tetrone/CC achieved a high specific capacity of 248 mAh g-1. Kinetic analyses showed that both surface-capacitive-controlled processes and semi-infinite diffusion-controlled processes contribute to the stored charge. The charge storage mechanism was investigated with ex situ characterizations and involves the redox processes of carbonyl/hydroxyl and amino/imino groups coupled with insertion and extraction of both Zn2+ and H+.

Chronic increasing nitrogen and endogenous phosphorus release from sediment threaten to the water quality in a semi-humid region reservoir.

The water quality in the drinking water reservoir directly affects people's quality of life and health. When external pollution input is effectively controlled, endogenous release is considered the main cause of water quality deterioration. As the major nitrogen (N) and phosphorus (P) sources in reservoirs, sediment plays a vital role in affecting the water quality. To understand the spatial and temporal variation of N and P in the sediment, this study analyzed the current characteristics and cumulative effects of a semi-humid reservoir, Yuqiao Reservoir, in North China. The N and P concentrations in the reservoir sediment were decreased along the flow direction, while the minimum values were recorded at the central sediment profile. External input and algal deposition were the main factors leading to higher sediment concentrations in the east (Re-E) and west (Re-W) areas of reservoir sediment profiles. According to the long-term datasets, the peaks of both sediment total nitrogen content and deposition rate were observed in the 2010s, which has increased about three times and six times than in the1990s, respectively. Therefore, the increase in phosphorus concentration may be the main reason for eutrophication in water in recent years. The mineralization of organic matter has a significant promoting effect on releasing N and P from sediments, which will intensify eutrophication in water dominated by P and bring huge challenges to water environment management. This study highlights that the current imbalance in N and P inputs into reservoirs and the endogenous P release from sediment will have a significant impact on water quality.

Immunohistochemical and Morphometric Assessment on the Biological Function and Vascular Endothelial Cells in the Initial Process of Cortical Porosity in Mice With PTH Administration.

To clarify the cellular mechanism of cortical porosity induced by intermittent parathyroid hormone (PTH) administration, we examined the femoral cortical bone of mice that received 40 µg/kg/day (four times a day) human PTH (hPTH) (1-34). The PTH-driven cortical porosity initiated from the metaphyseal region and chronologically expanded toward the diaphysis. Alkaline phosphatase (ALP)-positive osteoblasts in the control mice covered the cortical surface, and endomucin-positive blood vessels were distant from these osteoblasts. In PTH-administered mice, endomucin-reactive blood vessels with TRAP-positive penetrated the ALP-positive osteoblast layer, invading the cortical bone. Statistically, the distance between endomucin-positive blood vessels and the cortical bone surface abated after PTH administration. Transmission electron microscopic observation demonstrated that vascular endothelial cells often pass through the flattened osteoblast layer and accompanied osteoclasts in the deep region of the cortical bone. The cell layers covering mature osteoblasts thickened with PTH administration and exhibited ALP, α-smooth muscle actin (αSMA), vascular cell adhesion molecule-1 (VCAM1), and receptor activator of NF-κB ligand (RANKL). Within these cell layers, osteoclasts were found near endomucin-reactive blood vessels. In PTH-administered femora, osteocytes secreted Dkk1, a Wnt inhibitor that affects angiogenesis, and blood vessels exhibited plasmalemma vesicle-associated protein, an angiogenic molecule. In summary, endomucin-positive blood vessels, when accompanied by osteoclasts in the ALP/αSMA/VCAM1/RANKL-reactive osteoblastic cell layers, invade the cortical bone, potentially due to the action of osteocyte-derived molecules such as DKK1.

Coherence measurements of polaritons in thermal equilibrium reveal a power law for two-dimensional condensates.

We have created a spatially homogeneous polariton condensate in thermal equilibrium, up to very high condensate fraction. Under these conditions, we have measured the coherence as a function of momentum and determined the total coherent fraction of this boson system from very low density up to density well above the condensation transition. These measurements reveal a consistent power law for the coherent fraction as a function of the total density over nearly three orders of its magnitude. The same power law is seen in numerical simulations solving the two-dimensional Gross-Pitaevskii equation for the equilibrium coherence.

In-locus gene silencing in plants using genome editing.

Gene silencing is crucial in crop breeding for desired trait development. RNA interference (RNAi) has been used widely but is limited by ectopic expression of transgenes and genetic instability. Introducing an upstream start codon (uATG) into the 5'untranslated region (5'UTR) of a target gene may 'silence' the target gene by inhibiting protein translation from the primary start codon (pATG). Here, we report an efficient gene silencing method by introducing a tailor-designed uATG-containing element (ATGE) into the 5'UTR of genes in plants, occupying the original start site to act as a new pATG. Using base editing to introduce new uATGs failed to silence two of the tested three rice genes, indicating complex regulatory mechanisms. Precisely inserting an ATGE adjacent to pATG achieved significant target protein downregulation. Through extensive optimization, we demonstrated this strategy substantially and consistently downregulated target protein expression. By designing a bidirectional multifunctional ATGE4, we enabled tunable knockdown from 19% to 89% and observed expected phenotypes. Introducing ATGE into Waxy, which regulates starch synthesis, generated grains with lower amylose, revealing the value for crop breeding. Together, we have developed a programmable and robust method to knock down gene expression in plants, with potential for biological mechanism exploration and crop enhancement.

Effect of Crystallinity on the Field Emission Characteristics of Carbon Nanotube Grown on W-Co Bimetallic Catalyst.

Carbon nanotube (CNT) is an excellent field emission material. However, uniformity and stability are the key issues hampering its device application. In this work, a bimetallic W-Co alloy was adopted as the catalyst of CNT in chemical vapor deposition process. The high melting point and stable crystal structure of W-Co helps to increase the grown CNT diameter uniformity and homogeneous crystal structure. High-crystallinity CNTs were grown on the W-Co bimetallic catalyst. Its field emission characteristics demonstrated a low turn-on field, high current density, stable current stability, and uniform emission distribution. The Fowler-Nordheim (FN) and Seppen-Katamuki (SK) analyses revealed that the CNT grown on the W-Co catalyst has a relatively low work function and high field enhancement factor. The high crystallinity and homogeneous crystal structure of CNT also reduce the body resistance and increase the emission current stability and maximum current. The result provides a way to synthesis a high-quality CNT field emitter, which will accelerate the development of cold cathode vacuum electronic device application.

Temporal dynamics of Grime's CSR strategies in plant communities during 60 years of succession.

Grime's competitive, stress-tolerant, ruderal (CSR) theory predicts a shift in plant communities from ruderal to stress-tolerant strategies during secondary succession. However, this fundamental tenet lacks empirical validation using long-term continuous successional data. Utilizing a 60-year longitudinal data of old-field succession, we investigated the community-level dynamics of plant strategies over time. Our findings reveal that while plant communities generally transitioned from ruderal to stress-tolerant strategies during succession, initial abandonment conditions crucially shaped early successional strategies, leading to varied strategy trajectories across different fields. Furthermore, we found a notable divergence in the CSR strategies of alien and native species over succession. Initially, alien and native species exhibited similar ruderal strategies, but in later stages, alien species exhibited higher ruderal and lower stress tolerance compared to native species. Overall, our findings underscore the applicability of Grime's predictions regarding temporal shifts in CSR strategies depending on both initial community conditions and species origin.

Cobalt-Catalyzed Domino Transformations via Enantioselective C-H Activation/Nucleophilic [3 + 2] Annulation toward Chiral Bridged Bicycles.

Selective synthesis of chiral bridged (hetero)bicyclic scaffolds via asymmetric C-H activation constitutes substantial challenges due to the multiple reactivities of strained bicyclic structures. Herein, we develop the domino transformations through an unprecedented cobalt-catalyzed enantioselective C-H activation/nucleophilic [3 + 2] annulation with symmetrical bicyclic alkenes. The methods offer straightforward access to a wide range of chiral molecules bearing [2.2.1]-bridged bicyclic cores with four and five consecutive stereocenters in a single step. Two elaborate salicyloxazoline (Salox) ligands were synthesized based on the rational design and mechanistic understanding. The well-defined chiral pockets generated from asymmetric coordination around the trivalent cobalt catalyst direct the orientation of bicyclic alkenes, leading to excellent enantioselectivity.

Analysis of vertical differentiation of vegetation in Taishan World Heritage site based on cloud model.

While the forests on Mount Taishan are predominantly man-made, there is a notable vertical variation in vegetation. This study employs the method of cloud model, quantifying uncertainty (fuzziness and randomness) of things. Utilizing digital elevation model (DEM) and vegetation distribution data, we constructed elevation cloud models for Mount Taishan's deciduous broad-leaved, temperate coniferous, and mixed coniferous-broadleaved forests. Using three numerical features of the cloud model-Expectation (EX), Entropy (EN), and Hyper-entropy (HE)-we quantitatively analyzed the macro regularity and local heterogeneity of Mount Taishan's forests vertical distribution from the perspective of uncertainty theory. The results indicate: (1) The EX of the core zone elevation of deciduous broad-leaved forest is 716.65 m, temperate coniferous forest is 1053.51 m, and mixed coniferous-broadleaved forest is 1384.09 m. The variation range of the core zone distribution height is smaller in the mixed coniferous-broadleaved forest (EN: 53.74 m) compared to deciduous broad-leaved forest (EN: 99.63 m) and temperate coniferous forest (EN: 121.70 m). (2) The fuzziness and randomness of the distribution height of the lower extension zones of deciduous broad-leaved forest and temperate coniferous forest (EN: 75.15 m, 184.56 m; HE: 24.09 m, 63.54 m) are greater than those of the upper extension zones (EN: 44.75 m, 42.49 m; HE: 14.48 m, 13.23 m). (3) The distribution fuzziness and randomness within temperate coniferous forests exceed those of deciduous broad-leaved forests. Within the core zones, the uncertainty regarding the vertical distribution of vegetation across different aspects remains consistent, which retains the characteristic of man-made forests. However, in transition areas, there is significant disparity, reflecting the adaptive relationship between vegetation and its environment to some extent. In the upper and lower extension zones of deciduous broad-leaved forests, the EX values for the vertical distribution height of mixed coniferous and broad-leaved forests differ significantly from those of deciduous broad-leaved forests (the difference is 22.82-39.15 m), yet closely resemble those of temperate coniferous forests (the difference is 4.79-7.94 m). This suggests a trend wherein deciduous broad-leaved tree species exhibit a proclivity to encroach upon coniferous forest habitats. The elevation cloud model of vertical vegetation zones provides a novel perspective and method for the detailed analysis of Mount Taishan's vegetation vertical differentiation.

Gene associations of lipid traits, lipid-lowering drug-target genes and endometriosis.

RESEARCH QUESTION: Does the observed correlation between dyslipidaemia and endometriosis indicate a bidirectional causal association? DESIGN: Bidirectional Mendelian randomization was used to investigate the causal association between lipid traits and endometriosis. Drug-target Mendelian randomization was used to explore potential drug-target genes for managing endometriosis. In cases where lipid-mediated effects via specific drug targets were significant, aggregate analyses, such as summary-data-based Mendelian randomization and colocalization methods, were introduced to validate the outcomes. Mediation analyses supplemented these evaluations. RESULTS: The bidirectional Mendelian randomization results suggested that genetically predicted triglyceride (OR 1.15, 95% CI 1.08-1.23), high-density lipoprotein cholesterol (OR 0.87, 95% CI 0.81-0.94), low-density lipoprotein cholesterol (OR 1.20, 95% CI 1.06-1.34) and apolipoprotein A (OR 0.90, 95% CI 0.83-0.96) concentrations were causally associated with endometriosis. Reverse Mendelian randomization results revealed that genetically proxied endometriosis was causally associated with triglyceride concentration (OR 1.02, 95% CI 1.01-1.02). In drug-target Mendelian randomization, genetic mimicry in proprotein convertase subtilisin/kexin type 9 (PCSK9) (OR 1.40, 95% CI 1.13-1.72), apolipoprotein B (APOB) (OR 1.49, 95% CI 1.21-1.86) and angiopoietin-related protein 3 (ANGPTL3) (OR 1.57, 95% CI 1.14-2.16) was significantly associated with the risk of endometriosis stages 1-2. CONCLUSION: There is a potential bidirectional causal association between endometriosis and dyslipidaemia. Genetic mimicry of PCSK9, APOB and ANGPTL3 is associated with the risk of early-stage endometriosis. The development of lipid-lowering drugs to treat endometriosis is of potential clinical interest.

Omega-3 polyunsaturated fatty acids play a protective role in a mouse model of Parkinson's disease by increasing intestinal inducible Treg cells.

Parkinson's disease (PD) is defined as a progressive neurodegenerative disease in middle-aged and elderly people. The therapeutic effect of ω-3 PUFAs in several neurodegenerative diseases has been well recognized. Nevertheless, whether nutrition supplementing ω-3 PUFAs exerts a neuroprotective role in PD remains elusive. Bioinformatics revealed 2D chemical structural formula of three components. Mice received indicated treatment with saline, MPTP or ω-3 PUFAs according to grouping. Behavioral function of mice was measured through motor tests such as rearing, akinesia, and rotarod tests. OFT test measured anxiety-like behaviors of mice. Western blotting and TUNEL staining measured dopaminergic fibers and neurons of mice. Western blotting measured inflammation and apoptosis-related protein levels in mouse tissue. FACS measured iTreg cell proportion in colon and brain tissues of mice. ω-3 PUFAs repaired MPTP-stimulated motor function damage in PD mice. ω-3 PUFAs mitigated MPTP-stimulated comorbid anxiety in PD mice. ω-3 PUFAs relieved MPTP-stimulated deficits of dopaminergic fibers and neurons in PD mice. ω-3 PUFAs repressed MPTP-stimulated inflammation and apoptosis pathway activation in PD mice. ω-3 PUFAs repaired MPTP-stimulated immune function damage in PD mice. ω-3 PUFAs exert a protective role in PD mice through alleviating motor function impairment and neuroinflammation by increasing intestinal inducible Treg cells, which may provide a new direction for seeking targeted therapy plans for PD in humans.

20(S)-Protopanaxadiol Exerts Antidepressive Effects in Chronic Corticosterone-Induced Rodent Animal Models as an Activator of Brain-Type Creatine Kinase.

20(S)-Protopanaxadiol (PPD) is one of the bioactive ingredients in ginseng and possesses neuroprotective properties. Brain-type creatine kinase (CK-BB) is an enzyme involved in brain energy homeostasis via the phosphocreatine-creatine kinase system. We previously identified PPD as directly bound to CK-BB and activated its activity in vitro. In this study, we explored the antidepressive effects of PPD that target CK-BB. First, we conducted time course studies on brain CK-BB, behaviors, and hippocampal structural plasticity responses to corticosterone (CORT) administration. Five weeks of CORT injection reduced CK-BB activity and protein levels and induced depression-like behaviors and hippocampal structural plasticity impairment. Next, a CK inhibitor and an adeno-associated virus-targeting CKB were used to diminish CK-BB activity or its expression in the brain. The loss of CK-BB in the brain led to depressive behaviors and morphological damage to spines in the hippocampus. Then, a polyclonal antibody against PPD was used to determine the distribution of PPD in the brain tissues. PPD was detected in the hippocampus and cortex and observed in astrocytes, neurons, and vascular endotheliocytes. Finally, different PPD doses were used in the chronic CORT-induced depression model. Treatment with a high dose of PPD significantly increased the activity and expression of CK-BB after long-term CORT injection. In addition, PPD alleviated the damage to depressive-like behaviors and structural plasticity induced by repeated CORT injection. Overall, our study revealed the critical role of CK-BB in mediating structural plasticity in CORT-induced depression and identified CK-BB as a therapeutic target for PPD, allowing us to treat stress-related mood disorders.

Regulatory effects of mangiferin on LPS-induced inflammatory responses and intestinal flora imbalance during sepsis.

Studies suggest that mangiferin (MAF) has good therapeutic effects on chronic bronchitis and hepatitis. Also, it is one of the antiviral ingredients in Anemarrhena asphodeloides Bunge. However, its effect on the LPS-induced inflammation and intestinal flora during sepsis remains unclear yet. In the present study, LPS-stimulated inflammation RAW264.7 cells and LPS-induced sepsis mice were used to evaluate the efficacy of MAF in vitro and in vivo. 16S rDNA sequencing was performed to analyze the characteristics of intestinal flora of the sepsis mice. It has been demonstrated that MAF (12.5 and 25 µg/mL) significantly inhibited protein expressions of TLR4, MyD88, NF-κB, and TNF-α in the LPS-treated cells and reduced the supernatant TNF-α and IL-6 levels. In vivo, MAF (20 mg/kg) markedly protected the sepsis mice and reduced the serum TNF-α and IL-6 levels. Also, MAF significantly downregulated the protein expressions of TLR4, NF-κB, and MyD88 in the livers. Importantly, MAF significantly attenuated the pathological injuries of the livers and small intestines. Further, MAF significantly increased proportion of Bacteroidota and decreased the proportions of Firmicutes, Desulfobacterota, Actinobacteriota, and Proteobacteria at phylum level, and it markedly reduced the proportions of Escherichia-Shigella, Pseudoalteromonas, Staphylococcus at genus level. Moreover, MAF affects some metabolism-related pathways such as citrate cycle (TCA cycle), lipoic acid metabolism, oxidative phosphorylation, bacterial chemotaxis, fatty acid biosynthesis, and peptidoglycan biosynthesis of the intestinal flora. Thus, it can be concluded that MAF as a treatment reduces the inflammatory responses in vitro and in vivo by inhibiting the TLR4/ MyD88/NF-κB pathway, and corrects intestinal flora imbalance during sepsis to some degree.