CAR immunotherapy in autoimmune diseases: promises and challenges.

In recent years, the use of chimeric antigen receptor (CAR)-T cells has emerged as a promising immunotherapy in multiple diseases. CAR-T cells are T cells genetically modified to express a surface receptor, known as CAR, for the targeting of cognate antigens on specific cells. The effectiveness of CAR-T cell therapy in hematologic malignancies including leukemia, myeloma, and non-Hodgkin's lymphoma has led to consider its use as a potential avenue of treatment for autoimmune diseases. However, broadening the use of CAR-T cell therapy to a large spectrum of autoimmune conditions is challenging particularly because of the possible development of side effects including cytokine release syndrome and neurotoxicity. The design of CAR therapy that include additional immune cells such as double-negative T cells, γδ T cells, T regulatory cells and natural killer cells has shown promising results in preclinical studies and clinical trials in oncology, suggesting a similar potential utility in the treatment of autoimmune diseases. This review examines the mechanisms, efficacy, and safety of CAR approaches with a focus on their use in autoimmune diseases including systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, multiple sclerosis, myasthenia gravis, lupus nephritis and other autoimmune diseases. Advantages and disadvantages as compared to CAR-T cell therapy will also be discussed.

Sparse-Laplace hybrid graph manifold method for fluorescence molecular tomography.

Objective.Fluorescence molecular tomography (FMT) holds promise for early tumor detection by mapping fluorescent agents in three dimensions non-invasively with low cost. However, since ill-posedness and ill-condition due to strong scattering effects in biotissues and limited measurable data, current FMT reconstruction is still up against unsatisfactory accuracy, including location prediction and morphological preservation.Approach.To strike the above challenges, we propose a novel Sparse-Laplace hybrid graph manifold (SLHGM) model. This model integrates a hybrid Laplace norm-based graph manifold learning term, facilitating a trade-off between sparsity and preservation of morphological features. To address the non-convexity of the hybrid objective function, a fixed-point equation is designed, which employs two successive resolvent operators and a forward operator to find a converged solution.Main results.Through numerical simulations andin vivoexperiments, we demonstrate that the SLHGM model achieves an improved performance in providing accurate spatial localization while preserving morphological details.Significance.Our findings suggest that the SLHGM model has the potential to advance the application of FMT in biological research, not only in simulation but also inin vivostudies.

Improving physical and mental health in women with breast cancer undergoing anthracycline-based chemotherapy through wearable device-based aerobic exercise: a randomized controlled trial.

Purpose: Aimed to assess the impact of wearable device-based aerobic exercise on the physical and mental well-being of women with breast cancer (BC) undergoing chemotherapy. Methods: Forty adult women with BC who underwent anthracycline-based chemotherapy were randomly allocated to the exercise group (n = 21) or the control group (n = 19). Both groups received standard health education and oncology care. In addition, the exercise group wore wearable devices to engage in moderate to high-intensity (50-90% HRmax) aerobic exercise during chemotherapy, while the control group did not carry out exercise intervention. Health-related physical fitness level, physical activity energy expenditure (PAEE), anxiety and depression scores, sleep quality, cancer-related fatigue, and overall quality of life (QoL), were assessed both before (prior to the first chemotherapy session) and after (prior to the fifth chemotherapy session) the exercise intervention. Exercise-related adverse events, exercise compliance, number and severity of gastrointestinal reactions and myelosuppression occurred were recorded during the exercise intervention. Results: After the intervention, compared to the control group, the exercise group (1) had significantly higher relative VO2peak (p = 0.003) and handgrip strength (p < 0.001); (2) had significantly higher PAEE (p < 0.001); (3) had a significantly lower scores in anxiety (p = 0.007), depression (p = 0.028), sleep quality in domains of subjective sleep quality (p = 0.010), sleep disturbances (p = 0.004), daytime dysfunction (p = 0.007), cancer-related fatigue in domains of physical (p < 0.001) and affective (p < 0.001); and (4) had a significantly lower scores in QoL in domains of physical well-being (p < 0.001) and emotional well-being (p = 0.019), while a significantly higher scores in functional well-being (p < 0.001). Patients in the exercise group experienced less severe gastrointestinal reactions (p = 0.028) and myelosuppressive symptoms (p < 0.001) than that in the control group. Patients in the exercise group had no serious exercise-related adverse events, with a mean exercise adherence of 81.8%. Conclusion: Wearable device-based aerobic exercise during chemotherapy can be an effective adjunctive therapy to improve physical and mental health in BC patients. Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=200247, Identifier: ChiCTR2300073667.

Metabolite Measurement in Index Substrate Drug Interaction Studies: A Review of the Literature and Recent New Drug Application Reviews.

BACKGROUND/OBJECTIVES: Index substrates are used to understand the processes involved in pharmacokinetic (PK) drug-drug interactions (DDIs). The aim of this analysis is to review metabolite measurement in clinical DDI studies, focusing on index substrates for cytochrome P450 (CYP) enzymes, including CYP1A2 (caffeine), CYP2B6 (bupropion), CYP2C8 (repaglinide), CYP2C9 ((S)-warfarin, flurbiprofen), CYP2C19 (omeprazole), CYP2D6 (desipramine, dextromethorphan, nebivolol), and CYP3A (midazolam, triazolam). METHODS: All data used in this evaluation were obtained from the Certara Drug Interaction Database. Clinical index substrate DDI studies with PK data for at least one metabolite, available from literature and recent new drug application reviews, were reviewed. Further, for positive DDI studies, a correlation analysis was performed between changes in plasma exposure of index substrates and their marker metabolites. RESULTS: A total of 3261 individual index DDI studies were available, with 45% measuring at least one metabolite. The occurrence of metabolite measurement in clinical DDI studies varied widely between index substrates and enzymes. DISCUSSION AND CONCLUSIONS: For substrates such as caffeine, bupropion, omeprazole, and dextromethorphan, the use of the metabolite/parent area under the curve ratio can provide greater sensitivity to DDI or reduce intrasubject variability. In some cases (e.g., omeprazole, repaglinide), the inclusion of metabolite measurement can provide mechanistic insights to understand complex interactions.

Selective Copolymerization from Mixed Monomers of Phthalic Anhydride, Propylene Oxide and Lactide Using Nano-Sized Zinc Glutarate.

Selective polymerization with heterogeneous catalysts from mixed monomers remains a challenge in polymer synthesis. Herein, we describe that nano-sized zinc glutarate (ZnGA) can serve as a catalyst for the selective copolymerization of phthalic anhydride (PA), propylene oxide (PO) and lactide (LA). It was found that the ring-opening copolymerization (ROCOP) of PA with PO occurs firstly in the multicomponent polymerization. After the complete consumption of PA, the ring-opening polymerization (ROP) of LA turns into the formation of block polyester. In the process, the formation of zinc-alkoxide bonds on the surface of ZnGA accounts for the selective copolymerization from ROCOP to ROP. These results facilitate the understanding of the heterogeneous catalytic process and offer a new platform for selective polymerization from monomer mixtures.

Yap methylation-induced FGL1 expression suppresses anti-tumor immunity and promotes tumor progression in KRAS-driven lung adenocarcinoma.

BACKGROUND: Despite significant strides in lung cancer immunotherapy, the response rates for Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven lung adenocarcinoma (LUAD) patients remain limited. Fibrinogen-like protein 1 (FGL1) is a newly identified immune checkpoint target, and the study of related resistance mechanisms is crucial for improving the treatment outcomes of LUAD patients. This study aimed to elucidate the potential mechanism by which FGL1 regulates the tumor microenvironment in KRAS-mutated cancer. METHODS: The expression levels of FGL1 and SET1 histone methyltransferase (SET1A) in lung cancer were assessed using public databases and clinical samples. Lentiviruses were constructed for transduction to overexpress or silence FGL1 in lung cancer cells and mouse models. The effects of FGL1 and Yes-associated protein (Yap) on the immunoreactivity of cytotoxic T cells in tumor tissues were evaluated using immunofluorescence staining and flow cytometry. Chromatin immunoprecipitation and dual luciferase reporter assays were used to study the SET1A-directed transcriptional program. RESULTS: Upregulation of FGL1 expression in KRAS-mutated cancer was inversely correlated with the infiltration of CD8+ T cells. Mechanistically, KRAS activated extracellular signal-regulated kinase 1/2 (ERK1/2), which subsequently phosphorylated SET1A and increased its stability and nuclear localization. SET1A-mediated methylation of Yap led to Yap sequestration in the nucleus, thereby promoting Yap-induced transcription of FGL1 and immune evasion in KRAS-driven LUAD. Notably, dual blockade of programmed cell death-1 (PD-1) and FGL1 further increased the therapeutic efficacy of anti-PD-1 immunotherapy in LUAD patients. CONCLUSION: FGL1 could be used as a diagnostic biomarker of KRAS-mutated lung cancer, and targeting the Yap-FGL1 axis could increase the efficacy of anti-PD-1 immunotherapy.

Mentorship of Junior Surgical Faculty Across Academic Programs in Surgery.

Importance: Because mentorship is critical for professional development and career advancement, it is essential to examine the status of mentorship and identify challenges that junior surgical faculty (assistant and associate professors) face obtaining effective mentorship. Objective: To evaluate the mentorship experience for junior surgical faculty and highlight areas for improvement. Design, Setting, and Participants: This qualitative study was an explanatory sequential mixed-methods study including an anonymous survey on mentorship followed by semistructured interviews to expand on survey findings. Junior surgical faculty from 18 US academic surgery programs were included in the anonymous survey and interviews. Survey responses between "formal" (assigned by the department) vs "informal" (sought out by the faculty) mentors and male vs female junior faculty were compared using χ2 tests. Interview responses were analyzed for themes until thematic saturation was achieved. Survey responses were collected from November 2022 to August 2023, and interviews conducted from July to December 2023. Exposure: Mentorship from formal and/or informal mentors. Main Outcomes and Measures: Survey gauged the availability and satisfaction with formal and informal mentorship; interviews assessed broad themes regarding mentorship. Results: Of 825 survey recipients, 333 (40.4%) responded; 155 (51.7%) were male and 134 (44.6%) female. Nearly all respondents (319 [95.8%]) agreed or strongly agreed that mentorship is important to their surgical career, especially for professional networking (309 respondents [92.8%]), career advancement (301 [90.4%]), and research (294 [88.3%]). However, only 58 respondents (18.3%) had a formal mentor. More female than male faculty had informal mentors (123 [91.8%] vs 123 [79.4%]; P = .003). Overall satisfaction was higher with informal mentorship than formal mentorship (221 [85.0%] vs 40 [69.0%]; P = .01). Most male and female faculty reported no preferences in gender or race and ethnicity for their mentors. When asked if they had good mentor options if they wanted to change mentors, 141 (47.8%) responded no. From the interviews (n = 20), 6 themes were identified, including absence of mentorship infrastructure, preferred mentor characteristics, and optimizing mentorship. Conclusions and Relevance: Academic junior surgical faculty agree mentorship is vital to their careers. However, this study found that few had formal mentors and almost half need more satisfactory options if they want to change mentors. Academic surgical programs should adopt a framework for facilitating mentorship and optimize mentor-mentee relationships through alignment of mentor-mentee goals and needs.

Effects of Trimethylamine N-Oxide in Improving Exercise Performance in Mice: A 1H-NMR-Based Metabolomic Analysis Approach.

To improve exercise performance, the supplement of nutrients has become a common practice before prolonged exercise. Trimethylamine N-oxide (TMAO) has been shown to ameliorate oxidative stress damage, which may be beneficial in improving exercise capacity. Here, we assessed the effects of TMAO on mice with exhaustive swimming, analyzed the metabolic changes, and identified significantly altered metabolic pathways of skeletal muscle using a nuclear magnetic resonance-based (NMR-based) metabolomics approach to uncover the effects of TMAO improving exercise performance of mice. We found that TMAO pre-administration markedly prolonged the exhaustive time in mice. Further investigation showed that TMAO pre-administration increased levels of 3-hydroxybutyrate, isocitrate, anserine, TMA, taurine, glycine, and glutathione and disturbed the three metabolic pathways related to oxidative stress and protein synthesis in skeletal muscle. Our results provide a metabolic mechanistic understanding of the effects of TMAO supplements on the exercise performance of skeletal muscle in mice. This work may be beneficial in exploring the potential of TMAO to be applied in nutritional supplementation to improve exercise performance. This work will lay a scientific foundation and be beneficial to exploring the potential of TMAO to apply in nutritional supplementation.

Efficient Strategy to Discover DNA Aptamers Against Low Abundance Cell Surface Proteins in Scarce Samples.

Molecular recognition probes targeting cell surface proteins such as aptamers play crucial roles in precise diagnostics and therapy. However, the selection of aptamers against low-abundance proteins in situ on the cell surface, especially in scarce samples, remains an unmet challenge. In this study, we present a single-round, single-cell aptamer selection method by employing a digital DNA sequencing strategy, termed DiDS selection, to address this dilemma. This approach incorporates a molecular identification card for each DNA template, thereby mitigating biases introduced by multiple PCR amplifications and ensuring the accurate identification of aptamer candidates. Through DiDS selection, we successfully obtained a series of high-quality aptamers against cell lines, clinical specimens, and neurons. Subsequent analyses for target identification revealed that aptamers derived from DiDS selection exhibit recognition capabilities for proteins with varying abundance levels. In contrast, multiple rounds of selection resulted in the enrichment of only one aptamer targeting a high-abundance target. Moreover, the comprehensive profiling of cell surfaces at the single-cell level, utilizing an enriched aptamer pool, revealed unique molecular patterns for each cell line. This streamlined approach holds promise for the rapid generation of specific recognition molecules targeting cell surface proteins across a broad range of expression levels and expands its applications in cell profiling, specific probe identification, biomarker discovery, etc.

Cordyceps polysaccharide improves polycystic ovary syndrome by inhibiting gut-derived LPS/TLR4 pathway to attenuates insulin resistance.

Polycystic ovary syndrome (PCOS) is an endocrine disorder marked by aberrant glucose metabolism and reproductive dysfunction. It is characterized by polycystic ovaries, ovulatory dysfunction, and hyperandrogenemia. PCOS patients often experience a persistent, mild inflammation linked to various metabolic issues and insulin resistance (IR). Cordyceps polysaccharide (CP), extracted from the asexual form of the fungus Cordyceps gunnii, Hirsutella sinensis, is a bioactive crude polysaccharide with triple helix structure. CP was a spherical molecular polymer composed of rhamnose, arabinose, aminoglucose hydrochloride, galactose, glucose, and mannose, and has two molecular weights, 156.511 and 27.298 kDa. Our results corroborated that CP improve polycystic lesions in ovarian tissue and regulates hormone levels and the estrous cycle in rats with PCOS. However, the mechanism of action of this therapy in the treatment of polycystic ovary syndrome is not clear. In the present study, CP was found to modulates disturbances in glucose-lipid metabolism in model rats. In addition, it modulated gut microbiota by decreasing abundance of Gram-negative bacteria (norank_f__Desulfovibrionaceae, Helicobacter), hereby inhibiting the production and transfer of LPS into the systemic circulation. This suppressed the TLR4/MyD88/NF-κB inflammatory pathway in the liver and adipose tissue and restored insulin signaling, which improved IR in PCOS rats. Our findings demonstrate that based on the regulation of gut microbiota disorders and the repair of intestinal barrier damage, CP inhibited the gut-derived LPS/TLR4 inflammatory pathway in liver to attenuated IR, which led to the improvement of ovarian polycystic lesions. In addition, this study tapped into the role of Cordyceps polysaccharides in improving female reproductive function, expanding its clinical application in women with PCOS, which is innovative and offers valuable insights into the therapeutic potential of CP for treating PCOS.

Development of Oleogel-in-Water High Internal Phase Emulsions with Improved Physicochemical Stability and Their Application in Mayonnaise.

Egg-free mayonnaise is receiving greater attention due to its potential health benefits. This study used whey protein isolate (WPI) as an emulsifier to develop high internal phase emulsions (HIPEs) based on beeswax (BW) oleogels through a simple one-step method. The effects of WPI, NaCl and sucrose on the physicochemical properties of HIPEs were investigated. A novel simulated mayonnaise was then prepared and characterized. Microstructural observation revealed that WPI enveloped oil droplets at the interface, forming a typical O/W emulsion. Increase in WPI content led to significantly enhanced stability of HIPEs, and HIPEs with 5% WPI had the smallest particle size (11.9 ± 0.18 µm). With the increase in NaCl concentration, particle size was increased and ζ-potential was decreased. Higher sucrose content led to reduced particle size and ζ-potential, and slightly improved stability. Rheological tests indicated solid-like properties and shear-thinning behaviors in all HIPEs. The addition of WPI and sucrose improved the structures and viscosity of HIPEs. Simulated mayonnaises (WE-0.3%, WE-1% and YE) were then prepared based on the above HIPEs. Compared to commercial mayonnaises, the mayonnaises based on HIPEs exhibited higher viscoelastic modulus and similar tribological characteristics, indicating the potential application feasibility of oleogel-based HIPEs in mayonnaise. These findings provided insights into the development of novel and healthier mayonnaise alternatives.

Association between BMI and health-related physical fitness in adolescents with hearing impairment in China: a cross-sectional study.

Background: This cross-sectional study aimed to address a critical gap in the understanding of the association between body mass index (BMI) and physical fitness levels in adolescents with hearing impairment (HI) in China. This study investigated how different BMI levels impact the physical fitness index (PFI) of HI adolescents. Methods: This study employed a physical fitness test for HI adolescents attending special education schools. The test included eight components: height, weight, 50-m sprint, standing long jump, sit and reach, endurance run, bent-knee sit-up (for girls), and pull-up (for boys). Test scores for each student were standardized by age and gender. Individual Z-scores were then calculated, and the sum of these Z-scores constituted the PFI. Logistic regression was used to analyze the relationship between BMI and PFI across different gender and age groups. Statistical significance was set at P < 0.05. Results: The linear regression model showed an inverted U-shaped relationship between BMI and PFI. At the same BMI level, boys exhibited superior physical fitness compared to girls with the same BMI (P < 0.05). Statistically significant differences in PFI levels were observed between normal-weight and obese males, as well as between underweight and obese boys (P < 0.05). In the 13-15 and 16-18 age groups, the increase in BMI has a greater impact on boys PFI than on girls. Conclusions: Adolescents with HI generally demonstrated good physical fitness. Compared to individuals with normal weight, those who were underweight, overweight, or obese exhibited lower levels of physical fitness. Future interventions should focus on adolescents with HI with abnormal BMI.

Bacteroides acidifaciens drives a liver detox program.

Alcohol-associated liver disease is a leading cause of chronic liver conditions, yet there are limited effective therapies. In this issue of Cell Host & Microbe, Shen et al. demonstrate that soluble dietary fiber enhances intestinal Bacteroides acidifaciens, which ameliorates alcohol-associated liver injury in mice by activating hepatic ornithine aminotransferase.

Polysaccharides, the active component of Dendrobiumofficinale flower, ameliorates chronic pharyngitis in rats via TLR4/NF-κb pathway regulation.

ETHNOPHARMACOLOGICAL RELEVANCE: Chronic pharyngitis persistently afflicts a large population and accounts for approximately one-third of otolaryngology patients. Currently, the treatment of CP remains controversial because of the poor outcomes. Dendrobium officinale is a well-used "Yin-nourishing" traditional Chinese medicinal and edible herb used for thousands of years in China. The flowers of D. officinale are often used in folk of China to make tea for voice protection on and throat clearing. AIM OF THE STUDY: This study was to evaluate beneficial effects of polysaccharides from D. officinale flower (DOFP) on CP and its potential mechanisms. METHODS: Chemical characterization of DOFP, including polysaccharide content and monosaccharide composition, structural characterization using Fourier transform infrared spectroscopy were performed. A CP model was established in rats by administering a mixture of Chinese Baijiu and chili pepper liquid, combined with low-concentration ammonia spraying. The general states, amount of oral secretion, and apparent state of the pharynx of CP rats were observed during the period of DOFP administration. Furthermore, hemorheological parameters were measured using an automatic hematology analyzer. The levels of tumor necrosis factor-α (TNF-α), interleukin 1ß (1L-1ß), lipopolysaccharide (LPS), and D-lactate (D-LA) in the serum were measured by enzyme-linked immunosorbent assay. Morphological changes in the pharynx and colon were observed by hematoxylin-eosin staining. The expression of nuclear factor-κB p65 (NF-κB p65), p-NF-κB p65, cyclooxygenase-2 (COX-2), interleukin 1ß（IL-1ß）and mucin 5AC (MUC5AC) in the pharynx,Claudin-1, Occludin, and interleukin 6 (IL-6) in the colon was detected by immunohistochemistry and Western Blot. The mRNA expression of TLR4, COX-2, and IL-1ß in the pharynx were determined using reverse transcription quantitative real-time PCR. RESULTS: In this study, DOFP with a total polysaccharide content of 71.44% and a composition of D-mannose, galacturonic acid, glucose, galactose, and arabinose in a molar ratio of 3.95:2.19:1.00:0.74:1.30, was isolated from the flowers of D. officinale. DOFP improved the general state and exhibited significant effects on reducing oral secretion, alleviating pharyngeal injury, suppressing inflammatory cell infiltration in the pharynx, decreasing the serum levels of TNF-α and IL-1ß, and reducing the number of white blood cells and lymphocytes in the model rats. Moreover, the expressions of TLR4, p-NF-κB p65, COX-2, IL-1ß and MUC5AC in the pharynx of model rats were obviously inhibited. In addition, the levels of LPS, D-LA in the serum and the protein expression of IL-6 in the colon were downregulated when the protein expression of Occludin and Claudin-1 in the colon were upregulated. CONCLUSIONS: DOFP exerts significant ameliorating effects on CP and it likely acts by inhibiting LPS/TLR4-associated inflammatory mediator activation and reducing excessive secretion of mucus by repairing the intestinal barrier in CP rats.

The impact of aerobic exercise timing on BMAL1 protein expression and antioxidant responses in skeletal muscle of mice.

It is well known that the adaptations of muscular antioxidant system to aerobic exercise depend on the frequency, intensity, duration, type of the exercise. Nonetheless, the timing of aerobic exercise, related to circadian rhythms or biological clock, may also affect the antioxidant defense system, but its impact remains uncertain. Bain and muscle ARNT-like 1 (BMAL1) is the core orchestrator of molecular clock, which can maintain cellular redox homeostasis by directly controlling the transcriptional activity of nuclear factor erythroid 2-related factor 2 (NRF2). So, our research objective was to evaluate the impacts of aerobic exercise training at various time points of the day on BMAL1 and NRF2-mediated antioxidant system in skeletal muscle. C57BL/6J mice were assigned to the control group, the group exercising at Zeitgeber Time 12 (ZT12), and the group exercising at ZT24. Control mice were not intervened, while ZT12 and ZT24 mice were trained for four weeks at the early and late time point of their active phase, respectively. We observed that the skeletal muscle of ZT12 mice exhibited higher total antioxidant capacity and lower reactive oxygen species compared to ZT24 mice. Furthermore, ZT12 mice improved the colocalization of BMAL1 with nucleus, the protein expression of BMAL1, NRF2, NAD(P)H quinone oxidoreductase 1, heme oxygenase 1, glutamate-cysteine ligase modifier subunit and glutathione reductase in comparison to those of ZT24 mice. In conclusion, the 4-week aerobic training performed at ZT12 is more effective for enhancing NRF2-mediated antioxidant responses of skeletal muscle, which may be attributed to the specific activation of BMAL1.

[Effect of polymethoxylated flavonoids on glucose and lipid metabolism in rat model of obesity induced by a high-fat diet].

This study established a rat model of obesity by using a high-fat diet(HFD) to explore the effect of polymethoxylated flavonoids on glucose and lipid metabolism in the model rats and decipher the role and mechanism of polymethoxylated flavonoids in mitigating obesity. Thirty normal SD rats were selected and randomized into normal, model, ezetimibe(0.1 mg·kg~(-1)), and polymethoxylated flavonoids(62.5 mg·kg~(-1) and 125 mg·kg~(-1)) groups based on the body weight. Except the normal group receiving a conventional diet, the other groups received a HFD. Rats were administrated with corresponding doses of drugs by gavage. During the administration period, the body weight of each group of rats was regularly weighed, and the serum lipid and glucose levels were measured by a fully automated biochemical analyzer. Islet homeostasis and serum levels of obesity factors were measured by ELISA. The 16S rRNA high-throughput sequencing was employed to study the gut microbiota. Hematoxylin-eosin staining was employed to observe the histomorphology of white fat, brown fat, and pancreas. After the wet weights of white fat and brown fat were measured, the organ index was calculated. Immunohistochemistry and Western blot were employed to determine the protein levels. The results showed that polymethoxylated flavonoids reduced the body weight and Lee's index and improved blood lipid levels of the model rats. Polymethoxylated flavonoids reduced blood glucose and insulin secretion, increased insulin responsiveness, and alleviated insulin resistance. In addition, polymethoxylated flavonoids regulated the serum levels of obesity factors and reduced the weights and indexes of white fat and brown fat, the diameter of white adipocytes, and the number of fat vacuoles in brown fat and pancreatic islet cells. The intervention with polymethoxylated flavonoids increased the diversity of gut microbiota in the model rats, increasing the beneficial bacteria associated with glucose and lipid metabolism and reduced the harmful bacteria at the genus level. In addition, polymethoxylated flavonoids up-regulated the protein levels of glucose transporter 4(GLUT4), phosphorylated AMP-activated protein kinase(p-AMPK), peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α), and uncoupling protein 1(UCP1). In summary, polymethoxylated flavonoids may increase the body utilization of glucose and lipids by regulating the homeostasis of insulin, the serum levels of obesity factors, the diversity of gut microbiota, and the expression of mitochondrial metabolism-related proteins in brown adipocytes, thereby mitigating obesity in rats.

The effects of exergames for cognitive function in older adults with mild cognitive impairment: a systematic review and metaanalysis.

Purpose: Exergames are an innovative method that can promote neuroplasticity and improve the cognitive abilities of the elderly. This study aimed to compare the effects of single-task and multi-task exergames on the cognitive ability of the elderly with mild cognitive impairment (MCI). Methods: Computerized literature search was performed using PubMed, Web of Science, EBSCO, Elsevier, ProQuest, China National Knowledge Infrastructure (CNKI), Wanfang and VIP database to identify relevant articles from the establishment of the database from inception to April 1, 2024. The inclusion criteria were: (i) participants aged 60 or older diagnosed with mild cognitive impairment, regardless of gender; (ii) use of randomized controlled trials (RCTs); (iii) interventions involving exergames with physical activity or as the primary variable; and (iv) outcome measures using standardized neuropsychological instruments to assess cognitive function, including statistical data on sample size, mean, and standard deviation. Finally, the included study comprised a total of 526 participants. Mean difference (MD) and 95% confidence interval (CI) were used to synthesize the effect size in the data. Results: 11 studies were included. Due to the differences in the intervention methods, subgroup analysis was performed on the included research. Compared with the control group assessed by the Montreal Cognitive Assessment Scale, the single-task intervention improved the cognitive ability of the elderly with MCI (MD 3.40, 95% CI 2.43-4.37), the Mini-Mental State Examination Scale (MD 2.38, 95% CI -2.03 to 2.72), the Trail Making Test (MD -3.89, 95% CI -6.45 to -1.33), and the Digit Span Forward test (MD 1.16, 95% CI 0.73-1.60). Conclusion: This meta-analysis supports that exergames could be an effective cognitive rehabilitation method for MCI patients. Our study recommends that patients implement a customized exergames program and adhere to it for a long time. It is necessary to pay attention to the exercise guidelines and provide evidence from clinicians. Strengths and limitations of this study: (1) This meta-analysis supports that exergames could be an effective cognitive rehabilitation method for MCI patients. Our study recommends that patients implement a customized exergames program and adhere to it for a long time. It is necessary to pay attention to the exercise guidelines and provide evidence from clinicians. (2) This research provides preliminary evidence for the clinical utility of VR tasks developed for mild cognitive impairment. (3) In this paper, only relevant studies in Chinese and English were searched, and no studies in other languages were searched.

The mediating role of ego depletion in the relationship between state anxiety and academic procrastination among University students.

The issue of academic procrastination is highly prevalent among university students. It not only has a deterimental effect on students' academic performance but also poses a risk to their physical and mental well-being. Anxiety, as a negative emotion, has attracted researchers' attention in relation to academic procrastination. Research indicates a correlation between state anxiety and academic procrastination, but the underlying mechanisms that drive this association remain unclear. When individuals experience ego-depletion, it can lead to psychological exhaustion, subsequently leading to procrastination. Gender role conceptions, shaped by sociocultural and psychological mechanisms, have profound implications on individuals' cognition, emotions, and behaviors. This study primarily aims to explore the relationship between state anxiety and academic procrastination among university students, with a particularly focus on the mediating role of ego-depletion and the moderating role of gender. A survey using the State Anxiety Scale, Ego-Depletion Scale, and Irrational Procrastination Scale was administered to 3370 undergraduates. State anxiety shows positive correlations with ego depletion and academic procrastination (r = 0.665, p < 0.01; r = 0.491, p < 0.01), while ego depletion is also positively linked to academic procrastination (r = 0.500, p < 0.01). State anxiety serves as a positive predictor of academic procrastination, with a confidence interval of 95% [0.626, 0.696]; additionally, ego depletion partially mediates the relationship between state anxiety and academic procrastination, with a confidence interval of 95% [0.168, 0.251]. Gender acts as a moderator in directly predicting the impact of state anxiety on academic procrastination and in the latter stage of mediating the effect of ego depletion. State anxiety can significantly and positively predict academic procrastination among university students. Ego-depletion partially mediates the relationship between state anxiety and academic procrastination. The direct predictive effect of state anxiety on academic procrastination, as well as the mediating role of ego-depletion, is moderated by gender. This provides educators and university students themselves with reference for addressing the issue of academic procrastination.

Understanding gut dysbiosis for hepatocellular carcinoma diagnosis and treatment.

The gut microbiome can play a crucial role in hepatocellular carcinoma (HCC) progression through the enterohepatic circulation, primarily acting via metabolic reprogramming and alterations in the hepatic immune microenvironment triggered by microbe-associated molecular patterns (MAMPs), metabolites, and fungi. In addition, the gut microbiome shows potential as a biomarker for early HCC diagnosis and for assessing the efficacy of immunotherapy in unresectable HCC. This review examines how gut microbiota dysbiosis, with varied functional profiles, contributes to HCCs of different etiologies. We discuss therapeutic strategies to modulate the gut microbiome including diets, antibiotics, probiotics, fecal microbiota transplantation, and nano-delivery systems, and underscore their potential as an adjunctive treatment modality for HCC.

Helicobacter pylori CagA Promotes the Formation of Gallstones by Increasing the Permeability of Gallbladder Epithelial Cells.

BACKGROUND: The formation of gallstones is often accompanied by chronic inflammation, and the mechanisms underlying inflammation and stone formation are not fully understood. Our aim is to utilize single-cell transcriptomics, bulk transcriptomics, and microbiome data to explore key pathogenic bacteria that may contribute to chronic inflammation and gallstone formation, as well as their associated mechanisms. METHODS: scRNA-seq data from a gallstone mouse model were extracted from the Gene Expression Omnibus (GEO) database and analyzed using the FindCluster() package for cell clustering analysis. Bulk transcriptomics data from patients with gallstone were also extracted from the GEO database, and intergroup functional differences were assessed using GO and KEGG enrichment analysis. Additionally, 16S rRNA sequencing was performed on gallbladder mucosal samples from asymptomatic patients with gallstone (n = 6) and liver transplant donor gallbladder mucosal samples (n = 6) to identify key bacteria associated with stone formation and chronic inflammation. Animal models were constructed to investigate the mechanisms by which these key pathogenic bacterial genera promote gallstone formation. RESULTS: Analysis of scRNA-seq data from the gallstone mouse model (GSE179524) revealed seven distinct cell clusters, with a significant increase in neutrophil numbers in the gallstone group. Analysis of bulk transcriptomics data from patients with gallstone (GSE202479) identified chronic inflammation in the gallbladder, potentially associated with dysbiosis of the gallbladder microbiota. 16S rRNA sequencing identified Helicobacter pylori as a key bacterium associated with gallbladder chronic inflammation and stone formation. CONCLUSIONS: Dysbiosis of the gallbladder mucosal microbiota is implicated in gallstone disease and leads to chronic inflammation. This study identified H. pylori as a potential key mucosal resident bacterium contributing to gallstone formation and discovered its key pathogenic factor CagA, which causes damage to the gallbladder mucosal barrier. These findings provide important clues for the prevention and treatment of gallstones.