Power and velocity performance of swing movement in the adolescent male volleyball players - age and positional difference.

PURPOSE: The performance of swing movement during spikes and serves plays a crucial role in determining the outcomes of volleyball matches. This study aims to explore the effects of the participation of the trunk and lower limbs' involvement on the velocity and power of the swing movement of adolescent male volleyball players, as well as the differences in power and velocity performance of the swing movement among different ages and specific positions. METHODS: The study involved 22 adolescent male volleyball players, with 11 high school students and 11 middle school students. The Kineo Globus equipment was used to assess the swing movement performance involving different segments, including arm swing movement only involving arm limb participation; upper swing movement involving trunk and arm limb participation; and whole body swing movement involving lower limb, trunk, and arm limb participation. The measured parameters included power and velocity performance levels. Before the test, each subject practiced three movement patterns twice. RESULTS: The study found that swing movement involving both the trunk and arm limbs had significantly higher average (F = 17.70, p < 0.001) and peak power performance (F = 31.47, p < 0.001), as well as in average (F = 9.14, p = 0.03) and peak velocity performance (F = 23.17, p < 0.001). There were no significant differences in average (F = 17.70; p = 0.46) and peak power (F = 31.47, p = 0.94), as well as in average (F = 9.14, p = 0.99) and peak velocity performance (F = 23.17, p = 0.90) between movements involving the whole body and those involving the trunk and upper limbs. Among different age groups, the swing movement performance of middle school athletes showed significant enhancements in both average (F = 9.20, p < 0.001) and peak power (F = 19.93, p < 0.001), as well as in average (F = 10.75, p < 0.001) and peak velocity (F = 34.35, p < 0.001) when arm swing with trunk involvement was compared to arm swing movement. High school athletes also showed significant improvements in peak velocity (F = 34.35, p < 0.001), peak power (F = 17.31, p < 0.001), and average power (F = 9.41, p < 0.001) during upper swing movements, except for average velocity performance (F = 1.56, p = 0.21), when compared to arm swing movement. The increase rate in average velocity performance of swing movements involving trunk participation was significantly higher in middle school athletes than in high school athletes (p < 0.001). Among athletes in specific positions, Middle Blocker (MB) players exhibited significantly better average power performance in swing movements involving trunk and arm limb participation compared to Outside Hitter (OH) players (p = 0.04). Furthermore, the rate of average (p = 0.01) and peak (p = 0.03) power change during upper swing movements involving lower limb participation was significantly higher among OH players than MB players. CONCLUSIONS: The involvement of the trunk segment has been observed to significantly improve power and velocity in swing movements during spike and serves among adolescent male volleyball players. This underscores the importance of coordination between the trunk and arm in influencing swing movement performance during spikes and serves. High school athletes demonstrate superior power and velocity in arm swing movements compared to middle school athletes. MB exhibits greater power in upper limb swing movements than OH, although OH players show better coordination between the arm, trunk, and lower limb segments in the swing movement. To enhance swing movement performance in adolescent male volleyball players, particularly focusing on the trunk segment was crucial. Specialized physical training programs should target improving both arm strength and rotational power of the trunk simultaneously. This approach would help in consistently enhancing coordination between the trunk and arms, ultimately leading to optimized force generation during swing movements such as spikes and serves.

Ecological insights into hematopoiesis regulation: unraveling the influence of gut microbiota.

The gut microbiota constitutes a vast ecological system within the human body, forming a mutually interdependent entity with the host. In recent years, advancements in molecular biology technologies have provided a clearer understanding of the role of the gut microbiota. They not only influence the local immune status and metabolic functions of the host's intestinal tract but also impact the functional transformation of hematopoietic stem cells (HSCs) through the gut-blood axis. In this review, we will discuss the role of the gut microbiota in influencing hematopoiesis. We analyze the interactions between HSCs and other cellular components, with a particular emphasis on the direct functional regulation of HSCs by the gut microbiota and their indirect influence through cellular components in the bone marrow microenvironment. Additionally, we propose potential control targets for signaling pathways triggered by the gut microbiota to regulate hematopoietic function, filling crucial knowledge gaps in the development of this research field.

Aryl Hydrocarbon Receptor Activation Limits the Fatty Acid Synthesis and Subsequent "miR-193a-3p-HDAC3-FASN" Signals to Alleviate Intestinal Fibrosis.

Intestinal fibrosis is a common complication of Crohn's disease and characterized by excessive extracellular matrix (ECM) deposition. The aryl hydrocarbon receptor (AhR) detects micronutrients and microbial metabolites in diet and can attenuate intestinal fibrosis with unclear mechanisms. In this study, AhR activation was demonstrated to downregulate the transcription of collagen I and fibronectin in a Sp1- but not Sp3- or AP-1-dependent manner. A suppressed fatty acid synthesis was highlighted using untargeted metabolomics analyses, and synthetic products, palmitic acid (PA), were used as the intermediary agent. After a screening study, fatty acid synthase (FASN) was identified as the main targeted protein, and AhR activation regulated "HDAC3-acetylation" signals but not glycosylation to enhance FASN degradation. Furthermore, results of bioinformatics analysis and others showed that after being activated, AhR targeted miR-193a-3p to control HDAC3 transcription. Collectively, AhR activation inhibited ECM deposition and alleviated intestinal fibrosis by limiting fatty acid synthesis subsequent to the inhibition of "miR-193a-3p-HDAC3-FASN" signals.

Bergenin attenuates triptolide-caused premature ovarian failure in mice based on the antioxidant activity.

Tripterygium wilfordii (TW) preparations have been utilized in China for treating rheumatoid arthritis and autoimmune diseases. However, their clinical use is limited due to reproductive toxicity, notably premature ovarian failure (POF). Our study aimed to investigate the effect and mechanism of bergenin in attenuating POF induced by triptolide in mice. POF was induced in female ICR mice via oral triptolide administration (50 µg/kg) for 60 days. Mice received bergenin (25, 50, 100 mg/kg, i.g.) or estradiol valerate (EV) (0.1 mg/kg, i.g.) daily, 1 h before triptolide treatment. In vitro, ovarian granulosa cells (OGCs) were exposed to triptolide (100 nM) and bergenin (1, 3, 10 µM). Antioxidant enzyme activity, protein expression, apoptosis rate, and reactive oxygen species (ROS) levels were assessed. The results showed that triptolide-treated mice exhibited evident atrophy, along with an increase in atretic follicles. Bergenin (50, 100 mg/kg) and EV (0.1 mg/kg), orally administered, exerted significant anti-POF effect. Bergenin and EV also decreased apoptosis in mouse ovaries. In vitro, bergenin (1, 3, 10 µM) attenuated triptolide-induced OGCs apoptosis by reducing levels of apoptosis-related proteins. Additionally, bergenin reduced oxidative stress through downregulation of antioxidant enzymes activity and overall ROS levels. Moreover, the combined use with Sh-Nrf2 resulted in a reduced protection of bergenin against triptolide-induced apoptosis of OGCs. Together, bergenin counteracts triptolide-caused POF in mice by inhibiting Nrf2-mediated oxidative stress and preventing OGC apoptosis. Combining bergenin with TW preparations may effectively reduce the risk of POF.

Anti-aging effects of icariin and the underlying mechanisms: A mini-review.

Aging is an extremely intricate and progressive phenomenon that is implicated in many physiological and pathological conditions. Icariin (ICA) is the main active ingredient of Epimedium and has exhibited multiple bioactivities, such as anti-tumor, neuroprotective, antioxidant, anti-inflammatory, and anti-aging properties. ICA could extend healthspan in both invertebrate and vertebrate models. In this review, the roles of ICA in protection from declined reproductive function, neurodegeneration, osteoporosis, aging intestinal microecology, and senescence of cardiovascular system will be summarized. Furthermore, the underlying mechanisms of ICA-mediated anti-aging effects will be introduced. Finally, we will discuss some key aspects that constrain the usage of ICA in clinical practice and the corresponding strategies to solve these issues.

3D reconstruction of a gastrulating human embryo.

Progress in understanding early human development has been impeded by the scarcity of reference datasets from natural embryos, particularly those with spatial information during crucial stages like gastrulation. We conducted high-resolution spatial transcriptomics profiling on 38,562 spots from 62 transverse sections of an intact Carnegie stage (CS) 8 human embryo. From this spatial transcriptomic dataset, we constructed a 3D model of the CS8 embryo, in which a range of cell subtypes are identified, based on gene expression patterns and positional register, along the anterior-posterior, medial-lateral, and dorsal-ventral axis in the embryo. We further characterized the lineage trajectories of embryonic and extra-embryonic tissues and associated regulons and the regionalization of signaling centers and signaling activities that underpin lineage progression and tissue patterning during gastrulation. Collectively, the findings of this study provide insights into gastrulation and post-gastrulation development of the human embryo.

Retrospective study on the effect of Niaoduqing particles on outcome of non-diabetic patients with stage IV chronic kidney disease.

This study was to investigate the improvement value of Niaoduqing particles in the outcome of non-diabetic patients with stage IV chronic kidney disease (CKD). The non-diabetic patients with stage IV CKD who were to receive Niaoduqing particles were set as the study group (252 cases), and the patients with the same disease who only received Western medicine in the public database were set as the control group (220 cases). The follow-up visits were 3 months/time for 1 year. Deaths due to various causes, doubling of creatinine levels, and end-stage renal disease were used as hard end points to stop follow-up. The clinical indexes of the 2 groups were observed and compared. The results showed that the rate of compound outcome was significantly lower in the study group (28.17%) than in the control group (36.82%), the glomerular filtration rate was significantly higher than that in the control group, and the levels of uric acid and urea were significantly lower than that in the control group (P < .05). Niaoduqing particles can reduce creatinine and urea nitrogen, stabilize renal function, delay dialysis time, and improve the incidence of compound outcome in patients with non-diabetic stage IV CKD, which is worthy of clinical promotion.

Wnt, notch signaling and exercise: what are their functions?

In the last decade, the study of Wnt and Notch signaling in cell biology has led to significant progress in understanding embryogenesis, bone development, muscle healing, neurogenesis, and tumorigenesis. It has been found that regular physical activity can counteract the decline of skeletal muscle caused by aging, which is linked to osteoporosis, regenerative neurogenesis, hippocampal function, cognitive ability, and the creation of neuromuscular junctions. Despite these discoveries, there is still uncertainty about how cell biology and exercise can impact the Wnt and Notch signaling pathways in the locomotor system. This review aims to summarize the potential influence of exercise on Wnt and Notch signaling.

Arctigenin promotes mucosal healing in ulcerative colitis through facilitating focal adhesion assembly and colonic epithelial cell migration via targeting focal adhesion kinase.

Colonic mucosal defect constitutes the major reason of recurrence and deterioration of ulcerative colitis (UC), and mucosal healing has become the therapeutic endpoint of UC. Unfortunately, specific promoter of mucosal healing is still absent. Our previous researches demonstrated that arctigenin could alleviate colitis symptoms in mice, but whether it has a positive impact on colonic mucosal healing remains unclear. This study explores whether and how arctigenin promotes mucosal healing. Orally administered arctigenin was shown to alleviate colitis in mice primarily by enhancing mucosal healing. In vitro, arctigenin was shown to promote the wound healing by accelerating colonic epithelial cell migration but not proliferation. Acceleration of the focal adhesion turnover, especially assembly, is crucial for arctigenin promoting the cell migration. Arctigenin was able to activate focal adhesion kinase (FAK) in colonic epithelial cells through directly binding with Tyr251 site of FAK, as evidenced by surface plasmon resonance assay and site-directed mutagenesis experiment. In the colonic epithelial cells of UC patients and colitis mice, FAK activation was significantly down-regulated compared with the controls. Arctigenin promoted colonic epithelial cell migration and mucosal healing in dextran sulphate sodium (DSS)-induced colitis mice dependent on activating FAK, as confirmed by combined use with FAK inhibitor. In summary, arctigenin can directly promote mucosal healing in colitis mice through facilitating focal adhesion turnover, especially assembly, and consequent migration of epithelial cells via targeting FAK. Arctigenin may be developed as a mucosal healing promoter, and FAK is a potential therapeutic target for UC and other mucosal defect-related diseases.

Physical education and student well-being: Promoting health and fitness in schools.

The school students are facing mental health issues, and their performance is not improving in China. Health education policies are not implemented at the school level in China. However, scholars focus on college students' health education, but the school student is neglected. The research's primary objective is to answer the question: What is the impact of health education on the psychological well-being of school students? A sample of 549 10th grade students is collected from China's public and private sector institutes. The partial least square-structural equation modelling (PLS-SEM) is employed to analyze the data. The outcomes highlighted that the impact of health education is significant on the psychological well-being of school students in China. Furthermore, the study introduced that the moderating role of sustainable health exercise and sports participation is critical as it positively influences the relationship between health education and psychological wellbeing. This research improves literature as the novel contribution are highlighted in theory. Furthermore, the government education policies must be reframed under the light of this research' findings to improve students' health.

A polypeptide derived from pilose antler ameliorates CUMS-induced depression-like behavior by SENP2-PLCß4 signaling axis.

Neurogenesis is known to be closely associated with depression. We aimed to investigate whether a polypeptide monomer derived from pilose antler (polypeptide sequence LSALEGVFYP, PAP) exerts an antidepressant effect by influencing neurogenesis, and to elucidate the mechanism of its antidepressant action. Behavioral tests were performed to observe the antidepressant effect of PAP. Neurogenesis in the dentate gyrus (DG) region of hippocampus was observed by immunofluorescence. The expression of key proteins of Sentrin/SUMO-specific proteases 2 (SENP2)- Phosphoinositide-specific phospholipase C beta 4 (PLCß4) pathway was accessed by co-immunoprecipitation (Co-IP), and the calcium homeostasis associated proteins were observed via Western blot (WB). Subsequently, temozolomide (TMZ) pharmacologically blocked neurogenesis to verify the antidepressant effect of PAP on neurogenesis. The mechanism of PAP antidepressant effect was verified by constructing a sh-SENP2 virus vector to silence SENP2 protein. Finally, corticosterone (CORT)-induced PC12 cell model was used to verify whether PAP was involved in the process of deconjugated PLCß4 SUMOylated. The results showed that PAP improved depression-like behavior and neurogenesis induced by chronic unpredictable mild stimulation (CUMS). In addition, PAP acted on SENP2-PLCß4 pathway to deconjugate the SUMOylation of PLCß4 and affect calcium homeostasis. Pharmacological blockade of neurogenesis by TMZ treatment impaired the antidepressant efficacy of PAP. Knockout of SENP2 in the CUMS model attenuated the antidepressant response of PAP, and the impaired neurogenesis was not ameliorated by PAP treatment. In summary, PAP acted on the SENP2-PLCß4 signaling pathway to inhibit the SUMOylation of PLCß4 and maintain calcium homeostasis, thereby protecting neurogenesis and playing an antidepressant role.

Spatiotemporal transcriptome atlas reveals the regional specification of the developing human brain.

Different functional regions of brain are fundamental for basic neurophysiological activities. However, the regional specification remains largely unexplored during human brain development. Here, by combining spatial transcriptomics (scStereo-seq) and scRNA-seq, we built a spatiotemporal developmental atlas of multiple human brain regions from 6-23 gestational weeks (GWs). We discovered that, around GW8, radial glia (RG) cells have displayed regional heterogeneity and specific spatial distribution. Interestingly, we found that the regional heterogeneity of RG subtypes contributed to the subsequent neuronal specification. Specifically, two diencephalon-specific subtypes gave rise to glutamatergic and GABAergic neurons, whereas subtypes in ventral midbrain were associated with the dopaminergic neurons. Similar GABAergic neuronal subtypes were shared between neocortex and diencephalon. Additionally, we revealed that cell-cell interactions between oligodendrocyte precursor cells and GABAergic neurons influenced and promoted neuronal development coupled with regional specification. Altogether, this study provides comprehensive insights into the regional specification in the developing human brain.

Shikonin exerts an anti-leukemia effect against FLT3-ITD mutated acute myeloid leukemia cells via targeting FLT3 tyrosine kinase and its downstream pathways.

INTRODUCTION: Acute myeloid leukemia (AML) with internal tandem duplication (ITD) mutations in Fms-like tyrosine kinase 3 (FLT3) has an unfavorable prognosis. Recently, using newly emerging inhibitors of FLT3 has led to improved outcomes of patients with FLT3-ITD mutations. However, drug resistance and relapse continue to be significant challenges in the treatment of patients with FLT3-ITD mutations. This study aimed to evaluate the anti-leukemic effects of shikonin (SHK) and its mechanisms of action against AML cells with FLT3-ITD mutations in vitro and in vivo. METHODS: The CCK-8 assay was used to analyze cell viability, and flow cytometry was used to detect cell apoptosis and differentiation. Western blotting and real-time polymerase chain reaction (RT-PCR) were used to examine the expression of certain proteins and genes. Leukemia mouse model was created to evaluate the anti-leukemia effect of SHK against FLT3-ITD mutated leukemia in vivo. RESULTS: After screening a series of leukemia cell lines, those with FLT3-ITD mutations were found to be more sensitive to SHK in terms of proliferation inhibition and apoptosis induction than those without FLT3-ITD mutations. SHK suppresses the expression and phosphorylation of FLT3 receptors and their downstream molecules. Inhibition of the NF-κB/miR-155 pathway is an important mechanism through which SHK kills FLT3-AML cells. Moreover, a low concentration of SHK promotes the differentiation of AML cells with FLT3-ITD mutations. Finally, SHK could significantly inhibit the growth of MV4-11 cells in leukemia bearing mice. CONCLUSION: The findings of this study indicate that SHK is a promising drug for the treatment of FLT3-ITD mutated AML.

3, 3'-diindolylmethane, a natural aryl hydrocarbon receptor agonist, alleviates ulcerative colitis by enhancing "glycolysis-lactate-STAT3″ and TIP60 signals-mediated Treg differentiation.

BACKGROUND: Aryl hydrocarbon receptor (AhR) plays an important role in the occurrence and development of ulcerative colitis (UC). In this study, the effect and mechanism of 3, 3'-diindolylmethane (DIM), the classical AhR agonist, on UC was investigated from the angle of recovering the balance of Th17/Treg. METHODS: The in vivo colitis model was established in mice by using dextran sulfate sodium, and CD4+ T cells were used to simulate the in vitro differentiation of Treg and Th17 cells. The proportions and related factors of Th17 and Treg cells were measured using flow cytometry, Q-PCR and western blotting. The glycolysis was evaluated by examining the glucose uptake, glucose consumption and lactate production using kits or immunofluorescence. The activation of AhR was detected by western blotting and the XRE-luciferase reporter gene. The co-immunoprecipitation, transfection or other methods were selected to investigate and identify the signaling molecular pathway. RESULTS: DIM significantly attenuated symptoms of colitis mice by rebuilding the balance of Th17/Treg in anoxic colons. In hypoxia, a more potent promotion of Treg differentiation was showed by DIM relative to normoxia, and siFoxp3 prevented DIM-suppressed Th17 differentiation. DIM repressed the excessive glycolysis in hypoxia evidenced by down-regulated glucose uptake, lactate production, Glut1 and HK2 levels. Interestingly, IL-10, the function-related factor of Treg cells, showed the feedback effect of DIM-suppressed glycolysis. Besides, 2-deoxy-D-glucose, HK2 plasmid and IL-10 antibody prevented increase of DIM on the expression of Foxp3 at the transcriptional level and subsequent Treg differentiation through the lactate-STAT3 pathway, and reasons for the direct improvement of DIM on Foxp3 protein was attributed to promoting the formation of HIF-1α/TIP60 complexes as well as subsequent acetylation and protein stability. Finally, AhR dependence and mechanisms for DIM-improved Treg differentiation in vitro and in vivo were well confirmed by using plasmids or inhibitors. CONCLUSIONS: DIM enhances activation of AhR and subsequent "glycolysis-lactate-STAT3″ and TIP60 signals-mediated Treg differentiation.

The roles of ubiquitination in AML.

Acute myeloid leukemia (AML) is a heterogeneously malignant disorder resulting in poor prognosis. Ubiquitination, a major post-translational modification (PTM), plays an essential role in regulating various cellular processes and determining cell fate. Despite these initial insights, the precise role of ubiquitination in AML pathogenesis and treatment remains largely unknown. In order to address this knowledge gap, we explore the relationship between ubiquitination and AML from the perspectives of signal transduction, cell differentiation, and cell cycle control; and try to find out how this relationship can be utilized to inform new therapeutic strategies for AML patients.

Chinese experience on comparison of clinical efficacy and safety of hemodialysis and peritoneal dialysis in the treatment of diabetic kidney failure: a systematic review and meta-analysis.

Objective: This meta-analysis aims to compare the efficacy and safety of peritoneal dialysis (PD) and hemodialysis (HD) in the treatment of diabetic kidney failure. Methods: Five databases were selected to retrieve research on PD and HD for diabetic kidney failure until 6 August 2022. A fixed-effects or random-effects model was utilized to calculate the standardized mean difference (SMD) or odds ratio (OR) based on the heterogeneity among studies. Results: Sixteen studies were included. The results showed that patients with diabetic kidney failure treated with PD had lower levels of albumin, total protein, and systolic blood pressure (SBP) and higher levels of urine volume, creatinine, and blood urea nitrogen (BUN) and lower risk of cardiovascular and bleeding events, with significant statistical difference when compared with patients treated with HD (albumin: SMD = -1.22, 95%CI: -1.53, -0.91; total protein: SMD = -0.96, 95%CI: -1.16, -0.77; SBP: SMD = -0.35, 95%CI: -0.64, -0.06; urine volume: SMD = 0.68, 95%CI: 0.40, 0.96; creatinine: SMD = 0.49, 95%CI: 0.27, 0.72; BUN: SMD = 0.55, 95%CI: 0.25, 0.85; cardiovascular events: OR = 0.42, 95%CI: 0.28, 0.62; bleeding: OR = 0.41, 95%CI 0.27, 0.62). Conclusion: This meta-analysis summarized the advantages and disadvantages of PD and HD for treating diabetic kidney failure patients. Compared with HD, PD is more effective in preserving residual kidney function, reducing hemodynamic effect, and lowering the risk of bleeding and cardiovascular events in diabetic kidney failure patients, but it also predisposes to protein-energy malnutrition and increases the risk of infection.

SIRT4 protects against intestinal fibrosis by facilitating GLS1 degradation.

Intestinal fibrosis is a prevalent complication of Crohn's disease (CD), characterized by excessive deposition of extracellular matrix (ECM), and no approved drugs are currently available for its treatment. Sirtuin 4 (SIRT4), a potent anti-fibrosis factor in mitochondria, has an unclear role in intestinal fibrosis. In this study, fibroblasts isolated from biopsies of stenotic ileal mucosa in CD patients were analyzed to identify the most down-regulated protein among SIRT1-7, and SIRT4 was found to be the most affected. Moreover, in vivo and in vitro models of intestinal fibrosis, SIRT4 expression was significantly decreased in a TGF-ß dependent manner, and its decrease was negatively associated with disease severity. SIRT4 impeded ECM deposition by inhibiting glutaminolysis, but not glycolysis, and α-ketoglutarate (α-KG) was identified as the key metabolite. Specifically, SIRT4 hinders SIRT5's stabilizing interaction with glutaminase 1 (GLS1), thereby facilitating the degradation of GLS1. KDM6, rather than KDM4, is a potential mediator for α-KG-induced transcription of ECM components, and SIRT4 enhances the enrichment of H3K27me3 on their promotors and enhancers. These findings indicate that the activation of TGF-ß signals decreases the expression of SIRT4 in intestinal fibrosis, and SIRT4 can facilitate GLS1 degradation, thereby resisting glutaminolysis and alleviating intestinal fibrosis, providing a novel therapeutic target for intestinal fibrosis.

Cholinergic dysfunction-induced insufficient activation of alpha7 nicotinic acetylcholine receptor drives the development of rheumatoid arthritis through promoting protein citrullination via the SP3/PAD4 pathway.

Both cholinergic dysfunction and protein citrullination are the hallmarks of rheumatoid arthritis (RA), but the relationship between the two phenomena remains unclear. We explored whether and how cholinergic dysfunction accelerates protein citrullination and consequently drives the development of RA. Cholinergic function and protein citrullination levels in patients with RA and collagen-induced arthritis (CIA) mice were collected. In both neuron-macrophage coculture system and CIA mice, the effect of cholinergic dysfunction on protein citrullination and expression of peptidylarginine deiminases (PADs) was assessed by immunofluorescence. The key transcription factors for PAD4 expression were predicted and validated. Cholinergic dysfunction in the patients with RA and CIA mice negatively correlated with the degree of protein citrullination in synovial tissues. The cholinergic or alpha7 nicotinic acetylcholine receptor (α7nAChR) deactivation and activation resulted in the promotion and reduction of protein citrullination in vitro and in vivo, respectively. Especially, the activation deficiency of α7nAChR induced the earlier onset and aggravation of CIA. Furthermore, deactivation of α7nAChR increased the expression of PAD4 and specificity protein-3 (SP3) in vitro and in vivo. Our results suggest that cholinergic dysfunction-induced deficient α7nAChR activation, which induces the expression of SP3 and its downstream molecule PAD4, accelerating protein citrullination and the development of RA.

3, 3'-diindolylmethane enhances macrophage efferocytosis and subsequently relieves visceral pain via the AhR/Nrf2/Arg-1-mediated arginine metabolism pathway.

BACKGROUND: 3, 3'-diindolylmethane (DIM), a classical aryl hydrocarbon receptor (AhR) agonist, has been shown to relieve neuropathic pain, but few studies have reported the efficacy of DIM in visceral pain under colitis condition. PURPOSE: This study aimed to investigate the effect and mechanism of DIM on visceral pain under colitis condition. METHODS: Cytotoxicity was performed using the MTT assay. RT-qPCR and ELISA assays were applied to determine the expression and release of algogenic substance P (SP), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Flow cytometry was used to examine the apoptosis and efferocytosis. The expression of Arg-1-arginine metabolism-related enzymes was detected using western blotting assays. ChIP assays were used to examine the binding of Nrf2 to Arg-1. Mouse models of dextran sulfate sodium (DSS) were established to illustrate the effect of DIM and validate the mechanism in vivo. RESULTS: DIM did not directly affect expressions and release of algogenic SP, NGF and BDNF in enteric glial cells (EGCs). However, when co-cultured with DIM-pre-treated RAW264.7 cells, the release of SP and NGF was decreased in lipopolysaccharides-stimulated EGCs. Furthermore, DIM increased the number of PKH67+ F4/80+ cells in the co-culture system of EGCs and RAW264.7 cells in vitro and alleviated visceral pain under colitis condition by regulating levels of SP and NGF as well as values of electromyogram (EMG), abdominal withdrawal reflex (AWR) and tail-flick latency (TFL) in vivo, which was significantly inhibited by efferocytosis inhibitor. Subsequently, DIM was found to down-regulate levels of intracellular arginine, up-regulate levels of ornithine, putrescine and Arg-1 but not extracellular arginine or other metabolic enzymes, and polyamine scavengers reversed the effect of DIM on efferocytosis and release of SP and NGF. Moving forward, Nrf2 transcription and the binding of Nrf2 to Arg-1-0.7 kb was enhanced by DIM, AhR antagonist CH223191 abolished the promotion of DIM on Arg-1 and efferocytosis. Finally, nor-NOHA validated the importance of Arg-1-dependent arginine metabolism in DIM-alleviated visceral pain. CONCLUSION: DIM enhances macrophage efferocytosis in an arginine metabolism-dependent manner via "AhR-Nrf2/Arg-1" signals and inhibits the release of SP and NGF to relieve visceral pain under colitis condition. These findings provide a potential therapeutic strategy for the treatment of visceral pain in patients with colitis.

Galangin Targets HSP90ß to Alleviate Ulcerative Colitis by Controlling Fatty Acid Synthesis and Subsequent NLRP3 Inflammasome Activation.

SCOPE: The purpose of this research is to investigate the specific role of HSP90 paralogs in ulcerative colitis (UC), and to explore the mechanisms behind the inhibitory effects of galangin (Gal) on UC by inhibiting HSP90ß in vivo. METHODS AND RESULTS: In order to achieve this, publicly available gene expression data and molecular biology techniques are used. The results show that the expression of HSP90ß is significantly increased in the mucosal biopsies of UC patients and in the colons of colitis mice, and that there is a significant correlation between HSP90ß levels and disease severity. Then, Gal is found to bind directly to HSP90ß and downregulates the level of p-AKT, as well as the stability and oligomerization of HSP90ß, indicating Gal as an HSP90ß inhibitor. Moreover, the findings reveal that HSP90ß plays a critical role in controlling UC, and that Gal can alleviate colitis by inhibiting HSP90ß and perturbing fatty acid synthesis-mediated NLRP3 inflammasome activation. CONCLUSION: These results not only provide insight into the potential therapeutic use of Gal in the treatment of UC, but also offer new perspectives on the role of HSP90ß in this disease.