Faecalibacterium prausnitzii-derived extracellular vesicles alleviate chronic colitis-related intestinal fibrosis by macrophage metabolic reprogramming.

Faecalibacterium prausnitzii (F. prausnitzii) has been recognized for its various intestinal and extraintestinal benefits to human. And reduction of F. prausnitzii has been linked to an increased risk of intestinal fibrosis in patients of Crohn's disease (CD). In this study, oral administration of either live F. prausnitzii or its extracellular vesicles (FEVs) can markedly mitigate the severity of fibrosis in mice induced by repetitive administration of DSS. In vitro experiment revealed that FEVs were capable of directing the polarization of peripheral blood mononuclear cells (PBMCs) towards an M2b macrophage phenotype, which has been associated with anti-fibrotic activities. This effect of FEV was found to be stable under various conditions that promote the development of pro-fibrotic M1/M2a/M2c macrophages. Proteomics and RNA sequencing were performed to uncover the molecular modulation of macrophages by FEVs. Notably, we found that FEVs reprogramed every metabolism of macrophages by damaging the mitochondria, and inhibited oxidative phosphorylation and glycolysis. Moreover, FEV-treated macrophages showed a decreased expression of PPARγ and an altered lipid processing phenotype characterized by decreased cholesterol efflux, which may promote energy reprogramming. Taken together, these findings identify FEV as a driver of macrophage reprogramming, suggesting that triggering M2b macrophage polarization by oral admiration of FEV may serve as strategy to alleviate hyperfibrotic intestine conditions in CD.

Lithocholic acid promotes skeletal muscle regeneration through the TGR5 receptor.

Lithocholic acid (LCA) is a classical secondary bile acid formed by the metabolism of gut microbiota. The TGR5 receptor (also known as G protein-coupled receptor 1, GPBAR1) is an important bile acid membrane receptor that mediates a variety of metabolic processes in vivo. In recent years, most studies have focused on the role of bile acid receptors in the intestine and liver. However, there are few reports on its effect on skeletal muscle regeneration, and the specific mechanism remains unclear. Therefore, it is necessary to investigate the mechanism of the TGR5 receptor in the regulation of skeletal muscle regeneration. The results demonstrate that muscle injection with LCA significantly reduces the necrosis rate of injured muscle and improves muscle injury. Moreover, treatment of C2C12 cells with LCA significantly increases AKT/mTOR/FoxO3 phosphorylation through the TGR5 receptor, enhances MyoG transcription and reduces FBXO32 transcription. These findings indicate that LCA can activate the TGR5/AKT signaling pathway, inhibit protein degradation and promote protein synthesis to enhance the myogenic process and promote skeletal muscle regeneration.

Efficacy and Safety of Theta Burst vs Repetitive Transcranial Magnetic Stimulation for the Treatment of Depression: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: Theta burst stimulation (TBS) is more energy- and time-efficient than is standard repetitive transcranial magnetic stimulation (rTMS). However, further studies are needed to analyze TBS therapy for its efficacy and safety compared with standard rTMS in treating depression. The aim of this meta-analysis was to compare TBS therapy with standard rTMS treatment regarding their safety and therapeutic effect on individuals with depression. MATERIALS AND METHODS: Six data bases (Wanfang, the China National Knowledge Infrastructure, PubMed, Embase, Cochrane Library, and PsycINFO) were searched from inception till December 20, 2022. Two independent reviewers selected potentially relevant studies on the basis of the inclusion criteria, extracted data, and evaluated the methodologic quality of the eligible trials using the modified ten-item Physiotherapy Evidence Database scale per Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Finally, ten comparable pairs of nine randomized controlled trials (RCTs) were included for meta-analysis. Summary odds ratios (ORs) of the rates of response, remission, and adverse events were simultaneously calculated using quality-effects (QE) and random-effects (RE) models. Changes in depression scores associated with antidepressant effects were expressed using standardized mean differences simultaneously. This study was registered with the International Prospective Register of Systematic Reviews (CRD42022376790). RESULTS: Nine of the 602 RCTs, covering 1124 patients (616 who had TBS protocols applied vs 508 treated using standard rTMS), were included. Differences in response rates between the above two treatment modalities were not significant (OR = 1.01, 95% CI: 0.88-1.16, p = 0.44, I2 = 0%, RE model; OR = 1.07, 95% CI: 0.87-1.32, p = 0.44, I2 = 0%, QE model). Differences in adverse event rates between TBS and standard rTMS groups were not statistically significant. CONCLUSIONS: TBS has similar efficacy and safety to standard rTMS for treating depression. Considering the short duration of daily stimulation sessions, this meta-analysis supports the continued development of TBS for treating depression.

Wogonin improves colitis by activating the AhR pathway to regulate the plasticity of ILC3/ILC1.

BACKGROUND: Intestinal barrier dysfunction caused by the disrupted balance of group 3 innate lymphoid cells (ILC3)/group 1 innate lymphoid cells (ILC1) is a significant feature in the pathogenesis of inflammatory bowel disease (IBD). Activation of aryl hydrocarbon receptor (AhR) signaling contributes to the maintenance of ILC3/ILC1 balance. Wogonin, a natural flavonoid from Scutellaria baicalensis Georgi, can repair intestinal mucosal damage of IBD. However, it remains unclear if wogonin can exert a therapeutic effect by activating the AhR pathway to regulate the plasticity of ILC3/ILC1. PURPOSE: In this study, we investigated the immunomodulatory effects of wogonin on IBD and its potential mechanisms in vitro and in vivo. STUDY DESIGN AND METHODS: Chronic colitis was induced by four cycles of 2 % DSS treatment in mice. 20 mg kg-1/day wogonin was administrated by oral gavage and mice were treated intraperitoneally with 10 mg kg-1/2 days CH223191 to block the AhR pathway. Colon tissues were processed for histopathological examination and evaluation of the epithelial barrier function by immunohistochemistry. The activation of the AhR pathway and the plasticity of ILC3/ILC1 were determined by western blot and flow cytometry. Then, we also detected the intestinal microflora and their metabolites by 16 s sequencing and non-targeted Metabolomics analysis. Furthermore, an in vitro culture system consisting of MNK3 cells and NCM460 cells, and a CETSA assay were performed to confirm the molecular mechanism. RESULTS: Wogonin ameliorated histological severity of the colon, decreased the secretion of inflammatory factors, and increased tight junction proteins in colitis mice. These effects are associated with the tendency of conversion from ILC3 to ILC1 prevented by wogonin, which was offset by AhR antagonist CH223191. In addition, wogonin exerted the curative effect by altering gut microbiota to produce metabolites such as Kynurenic acid, and 1H-Indole-3-carboxaldehyde as AhR endogenous ligands. In vitro data further verified that wogonin as an exogenous ligand directly binds to the structural domain of AhR by CETSA. Also, the supernatant of MNK-3 cells stimulated with wogonin enhanced expression of Occludin and Claudin1 in NCM460 cells induced by LPS. CONCLUSION: Cumulatively, our study illustrated that wogonin improved the outcomes of DSS-induced chronic colitis via regulating the plasticity of ILC3/ILC1. Its specific mechanism is to binding to AhR directly, and to activate the AhR pathway indirectly by altering the tryptophan metabolisms of gut microbiota.

Individualized prediction of cognitive test scores from functional brain connectome in patients with first-episode late-life depression.

BACKGROUND: In the realm of cognitive screening, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are widely utilized for detecting cognitive deficits in patients with late-life depression (LLD), However, the interindividual variability in neuroimaging biomarkers contributing to individual-specific symptom severity remains poorly understood. In this study, we used a connectome-based predictive model (CPM) approach on resting-state functional magnetic resonance imaging data from patients with LLD to establish individualized prediction models for the MoCA and the MMSE scores. METHODS: We recruited 135 individuals diagnosed with first-episode LLD for this research. Participants underwent the MMSE and MoCA tests, along with resting-state functional magnetic resonance imaging scans. Functional connectivity matrices derived from these scans were utilized in CPM models to predict MMSE or MoCA scores. Predictive precision was assessed by correlating predicted and observed scores, with the significance of prediction performance evaluated through a permutation test. RESULTS: The negative model of the CPM procedure demonstrated a significant capacity to predict MoCA scores (r = -0.309, p = 0.002). Similarly, the CPM procedure could predict MMSE scores (r = -0.236, p = 0.016). The predictive models for cognitive test scores in LLD primarily involved the visual network, somatomotor network, dorsal attention network, and ventral attention network. CONCLUSIONS: Brain functional connectivity emerges as a promising predictor of personalized cognitive test scores in LLD, suggesting that functional connectomes are potential neurobiological markers for cognitive performance in patients with LLD.

Mannan Oligosaccharides Promoted Skeletal Muscle Hypertrophy through the Gut Microbiome and Microbial Metabolites in Mice.

Mannan oligosaccharides (MOSs) have been implicated in the animal growth rate, health indices, and lipid oxidative stability. MOSs have been indicated to maintain intestinal health and anti-inflammatory effects via modulation of gut microbiota. Furthermore, the role of MOSs in modulating skeletal muscle function is largely unknown. Here, this study aimed to investigate the effects of MOS supplementation on muscle function and muscle mass in mice. Additionally, the possible underlying mechanisms, including the contributions of gut microbiota and microbial metabolites, were explored. In our study, 3-week-old C57BL/6J male mice (body weight of approximately 10.7 ± 1.1 g) were given pure water or pure water with 1% MOS. To study the effect of MOSs on gut-microbiota-derived metabolites, serum metabolic profiles were analyzed through untargeted metabolomic profiling. Moreover, we detected the downstream signals of differential metabolites, and decanoic acid (DA) was selected as our target spot. Then, DA was used to treat C2C12 cells, and we found that DA promotes C2C12 cell differentiation via the GPR84 and PI3K/AKT signaling pathways. In conclusion, these results showed that MOS supplementation improves muscle function and muscle mass. Additionally, gut microbiome and microbial metabolites were regulated by MOSs, and DA may be one of the most important links between the gut microbiome and skeletal muscle function regulation.

Efficacy and tolerability of escitalopram in treatment of major depressive disorder with anxiety symptoms: a 24-week, open-label, prospective study in Chinese population.

BACKGROUND: Significant anxiety symptoms are associated with poor clinical course and outcome in major depressive disorder (MDD). This single-arm, open-label study aimed to evaluate the efficacy and tolerability of escitalopram treatment in patients with MDD and anxiety symptoms. METHODS: Adult patients with MDD and anxiety symptoms (Montgomery-Asberg Depression Rating Scale [MADRS] ≥22 and Hamilton Anxiety Rating Scale [HAM-A] ≥14) were enrolled and received escitalopram (10-20 mg/day) treatment for 24 weeks. Symptom status was assessed by MADRS, 17-item-Hamilton Depression Rating Scale, HAM-A, and Clinical Global Impression Scale at baseline and the following visits. Quality of life was assessed by Short Form-12, and safety was evaluated by adverse events, laboratory investigations, vital signs, and physical findings. RESULTS: Overall, 200 of 318 (66.2%) enrolled patients completed the 24-week treatment. The remission (MADRS ≤10 and HAM-A ≤7) rate in the full analysis set (N=285) was 73.3% (95% confidence interval: 67.80, 78.38) at week 24. Mean (± standard deviation) MADRS total score was 33.4 (±7.13) and HAM-A score was 27.6 (±7.26) at baseline, which reduced to 6.6 (±10.18) and 6.0 (±8.39), respectively, at week 24. Patients with higher baseline depression and anxiety level took longer to achieve similar remission rates. Overall, 80 of the 302 (26.5%) patients included in the safety set reported at least 1 treatment-emergent adverse event (TEAE). Most frequently reported TEAEs (>2%) were headache (4.0%), nasopharyngitis (3.6%), nausea (3.0%), and dizziness (2.6%). Serious TEAEs were reported by 1.3% patients; no deaths were reported. CONCLUSION: Escitalopram 10-20 mg/day was effective and well-tolerated in the long-term treatment of MDD with anxiety symptoms in adult Chinese population.

The MARCOPOLO Study of Ustekinumab Utilization and Efficacy in a Real-World Setting: Treatment of Patients with Plaque Psoriasis in Asia-Pacific Countries.

BACKGROUND: Ustekinumab is a fully human monoclonal antibody approved for the treatment of chronic moderate-to-severe plaque psoriasis in adults. However, factors including efficacy, tolerability, ease of use, and cost burden may affect ustekinumab utilization. Noncompliance may, in turn, affect treatment response. OBJECTIVE: To evaluate ustekinumab utilization in the real-world setting in Asia-Pacific countries. METHODS: In this phase 4 observational study conducted in Indonesia, Malaysia, Singapore, Korea, and Taiwan, adults with plaque psoriasis receiving ustekinumab were followed for up to 52 weeks. Study endpoints were the proportion of all patients using ustekinumab according to label-recommended intervals and the proportion of Korean patients who achieved a psoriasis area severity index 75 response at week 16. Safety was assessed by monitoring adverse events. RESULTS: Overall, 169 patients received ustekinumab (Korea, n=102; other countries, n=67). Just over half (56.2%) of patients used ustekinumab with the label-recommended interval from baseline to week 40; the proportion was higher in Korea (73.5%) than in other countries (29.9%), probably because ustekinumab was provided without charge for Korean patients up to week 40. Noncompliance increased after week 40 in Korea and from week 28 in other Asia-Pacific countries, with cost cited as the most common reason. At week 16, 56.9% of Korean patients achieved a Psoriasis Area Severity Index 75 response. Safety results were in line with those seen in previous studies. CONCLUSION: More than half of all patients in Asia-Pacific countries used ustekinumab as per the label-recommended dose interval, but reimbursement variations between countries may have confounded overall results.