Establishment of a Magnetically Controlled Scalable Nerve Injury Model.

Animal models of peripheral nerve injury (PNI) serve as the fundamental basis for the investigations of nerve injury, regeneration, and neuropathic pain. The injury properties of such models, including the intensity and duration, significantly influence the subsequent pathological changes, pain development, and therapeutic efficacy. However, precise control over the intensity and duration of nerve injury remains challenging within existing animal models, thereby impeding accurate and comparative assessments of relevant cases. Here, a new model that provides quantitative and off-body controllable injury properties via a magnetically controlled clamp, is presented. The clamp can be implanted onto the rat sciatic nerve and exert varying degrees of compression under the control of an external magnetic field. It is demonstrated that this model can accurately simulate various degrees of pathology of human patients by adjusting the magnetic control and reveal specific pathological changes resulting from intensity heterogeneity that are challenging to detect previously. The controllability and quantifiability of this model may significantly reduce the uncertainty of central response and inter-experimenter variability, facilitating precise investigations into nerve injury, regeneration, and pain mechanisms.

Noninvasive Raman spectroscopy for the detection of rice bacterial leaf blight and bacterial leaf streak.

Plant diseases pose significant threats to agricultural yields and are responsible for nearly 20 % of losses in total food production. Therefore, the rapid detection of plant pathogens is critically important for preventing the rapid development of plant diseases and minimizing crop damage. Raman spectroscopy (RS) has been shown to be effective for detecting living biological samples. Compared with traditional detection methods, RS is fast, sensitive, and non-destructive; it also does not require sample labeling. In this study, we used Laser tweezers Raman spectroscopy combined with convolutional neural networks to detect two closely related strains of bacteria, Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas oryzae pv. oryzicola (Xoc), exuded from bacteria-infected rice leaves. The accuracy of this technique was 97.5 %. For the application of RS in the field, we used the portable Raman spectrometer to detect mock-inoculated as well as Xoo- and Xoc-infected rice leaves at different disease courses. The identification accuracy via this technique was 87.02 % in the early stage, in which no obvious symptoms were apparent. This method also revealed spectral differences in rice leaves caused by the two bacteria, which could be leveraged for subsequent analysis of the molecular mechanism of infection. Our results indicate that RS is a promising approach for the early detection of bacterial diseases in rice in the field, as well as for in-depth single-cell analysis in laboratory settings.

Pirfenidone inhibits CCL2-mediated Treg chemotaxis induced by palbociclib and fulvestrant in HR+/HER2- breast cancer.

In human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer, the most prevalent subtype, the pathological complete response (pCR) rate after neoadjuvant chemotherapy is less than 18 %, and the survival of patients with advanced-stage disease is approximately 34 %, highlighting the critical demand for more potent therapies. Recent research has underscored the substantial therapeutic benefits of the combination of CDK4/6 inhibitors and fulvestrant (Ful) in managing HR+/HER2- breast cancer. These therapeutics not only curtail tumor proliferation but also alter the tumor immune microenvironment, suggesting novel avenues for immunotherapy for this breast cancer subtype. Flow cytometry, PCR, WB, and RNA-seq experiments revealed that the combination of the CDK4/6 inhibitor palbociclib (Pal) with Ful upregulated CCL2 in tumor cells by inducing the SASP and activating the MAPK signaling pathway. CCL2 attracts Tregs to the tumor microenvironment, where it exerts an immunosuppressive effect. By administering the CCL2 inhibitor pirfenidone, we inhibited these effects and enhanced the antitumor efficacy of Pal + Ful. Our research revealed an immunosuppressive effect of CDK4/6 inhibitors and fulvestrant and suggested that CCL2 inhibitors may be a viable approach for treating patients with advanced HR+/HER2- breast cancer.

Selectively Extending the Curved Side of N-Doped Hexa-peri-hexabenzocoronene.

A curved nanographene, conceptually by insertion of nitrogen into a trapezoidal planar nanographene at the edge was synthesized by π-extension of the nitrogen-doped hexa-peri-hexabenzocoronene. This aza-doped nanographene exhibited a π-electronic concave face containing a nonaromatic azepine ring in the middle with a size of 14.0 Å length and 4.0 Å depth, which represents an unprecedented half-side concave geometry of curved nanographene. The bent π-extension exhibited a low degree of conjugation suggested by calculation results. Due to the unique 3D structure and electron-rich property, this nanographene showed pronounced intermolecular charge transfer with C60.

Treatment of tumor-associated macrophages with PD-1 monoclonal antibodies affects vascular generation in cervical cancer via the PD-1/IRE1α/SHP2/HIF1α signaling pathway.

OBJECTIVE: To investigate the effect of PD-1 monoclonal antibodies in tumor-associated macrophages on angiogenesis in cervical cancer and its mechanism of action. METHODS: The effect of PD-1 monoclonal antibodies on the progression of cervical cancer was assessed using the nude mouse xenograft model and HE staining; the impact of PD-1 monoclonal antibodies on cervical cancer cell migration was evaluated using wound healing assay and Transwell assay; the effect on vascular formation in cervical cancer cells was examined using an angiogenesis assay; the impact on the expression of related proteins was tested using Western blotting. RESULTS: PD-1 monoclonal antibodies in tumor-associated macrophages can regulate and thus inhibit the progression of cervical cancer while promoting the expression of SHP2. Additionally, Sindilizumab inhibited the expression of tissue-type fibrinogen activator K and HIF1α through the PD-1/IRE1α/SHP2 signaling pathway, which inhibited the migration and neovascularization of cervical cancer cells. CONCLUSIONS: This study discovered that PD-1 monoclonal antibodies in tumor-associated macrophages inhibit vascular generation inside cervical cancer by affecting the PD-1/IRE1α/SHP2/HIF1α signaling pathway, providing a new therapeutic target for the treatment of cervical cancer.

Integrating musculoskeletal simulation and machine learning: a hybrid approach for personalized ankle-foot exoskeleton assistance strategies.

Introduction: Lower limb exoskeletons have shown considerable potential in assisting human walking, particularly by reducing metabolic cost (MC), leading to a surge of interest in this field in recent years. However, owing to significant individual differences and the uncertainty of movements, challenges still exist in the personalized design and control of exoskeletons in human-robot interactions. Methods: In this study, we propose a hybrid data-driven approach that integrates musculoskeletal simulation with machine learning technology to customize personalized assistance strategies efficiently and adaptively for ankle-foot exoskeletons. First, optimal assistance strategies that can theoretically minimize MC, were derived from forward muscle-driven simulations on an open-source dataset. Then, a neural network was utilized to explore the relationships among different individuals, movements, and optimal strategies, thus developing a predictive model. Results: With respect to transfer learning, our approach exhibited effectiveness and adaptability when faced with new individuals and movements. The simulation results further indicated that our approach successfully reduced the MC of calf muscles by approximately 20% compared to normal walking conditions. Discussion: This hybrid approach offers an alternative for personalizing assistance strategy that may further guide exoskeleton design.

Developing mapping algorithms to predict EQ-5D health utility values from Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index among patients with Ankylosing Spondylitis.

BACKGROUND: Preference-based measures of health-related quality of life (HRQoL), such as the EQ-5D or the SF-6D, are essential for health economic evaluation. However, they are rarely included in clinical trials of ankylosing spondylitis (AS). This study aims to develop mapping algorithms to predict EQ-5D-3L and EQ-5D-5L health utility scores from the Bath Ankylosing Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI). METHODS: Patients with AS were recruited from the largest tertiary hospital in Shandong province, China, between December 2019 and October 2020. Patients were selected by convenience sampling method according to the following criteria: (1) diagnosed with AS according to the New York criteria; (2) aged 18 years and above; and (3) without mental disorders; (4) able to understand the questionnaires; (5) without serious complications. There were 243 patients who completed the face-to-face questionnaire survey, and 5 cases with missing values in key variables were excluded. Ordinary least squares, censored least absolute deviations, Tobit, adjusted limited dependent variable mixture model and beta-mixture model (BM) in the direct approach and ordered logit and multinomial logit (Mlogit) model in the response approach were used to develop mapping algorithms. Mean absolute error, root mean square error, Spearman's correlation coefficient and concordance correlation coefficient were used to access predictive performance. RESULTS: The 238 patients with AS had a mean age of 35.19 (SD = 9.59) years, and the majority (74.47%) were male. The observed EQ-5D-3L and EQ-5D-5L health utility values were 0.88 (SD = 0.12) and 0.74 (SD = 0.27), respectively. The EQ-5D-5L had higher conceptual overlap with the BASDAI and BASFI than the EQ-5D-3L did. The Mlogit was the best-performing model for the EQ-5D-3L, and the BM showed better performance in predicting EQ-5D-5L than other direct and indirect mapping models did. CONCLUSION: This study demonstrates that the EQ-5D-5L, rather than EQ-5D-3L, should be selected as the target outcome measure of HRQoL in patients with AS in China, and the BM mapping algorithm could be used to predict EQ-5D-5L values from BASDAI and BASFI for health economic evaluation.

Liraglutide, a glucagon-like peptide-1 receptor agonist, ameliorates inflammation and apoptosis via inhibition of receptor for advanced glycation end products signaling in AGEs induced chondrocytes.

BACKGROUND: This study aimed to investigate functions of GLP-1R agonist by liraglutide (LIRA) and revealing the mechanism related to AGEs/RAGE in chondrocytes. METHODS: To illustrate potential effect of GLP-1R agonist on AGEs induced chondrocytes, chondrocytes were administrated by AGEs with LIRA and GLP-1R inhibitor exendin. Inflammatory factors were assessed using ELISA. Real-time PCR was used to evaluate the catabolic activity MMPs and ADAMTS mRNA level, as well as anabolic activity (aggrecan and collagen II). RAGE expression was investigated by Western blotting. TUNEL, caspase3 activity and immunofluorescence were performed to test the apoptotic activity. RESULTS: Our results showed that treatment with LIRA at > 100 nM attenuated the AGE-induced chondrocyte viability. Western bolt demonstrated that GLP-1R activation by LIRA treatment reduced RAGE protein expression compared with the AGEs groups. ELISA showed that LIRA hindered the AGEs-induced production of inflammatory cytokines (IL-6, IL-12 and TNF-α) in primary chondrocytes. AGEs induced catabolism levels (MMP-1, -3, -13 and ADAMTS-4, 5) are also attenuated by LIRA, causing the retention of more extracellular matrix (Aggrecan and Collagen II). TUNEL, caspase3 activity and immunofluorescence results indicated that LIRA inhibited the AGEs-induced production of inflammatory cytokines in primary chondrocytes and attenuated the caspase 3 level, leading to the reduced apoptotic activity. All the protective effects are reversed by exendin (GLP-1R blockers). CONCLUSIONS: The present study demonstrates for the first time that LIRA, an agonist for GLP-1R which is commonly used in type 2 diabetes reverses AGEs induced chondrocyte inflammation and apoptosis through suppressing RAGE signaling, contributing to reduced catabolism and retention of more extracellular matrix. The above results indicate the possible effect of GLP-1R agonist on treating OA.

The relationship between inflammatory bowel disease and sarcopenia-related traits: a bidirectional two-sample mendelian randomization study.

Objective: Observational studies have revealed a link between inflammatory bowel disease (IBD) and sarcopenia. However, it remains unclear whether this correlation between IBD and sarcopenia is causal. Methods: The genetic instrumental variables (IVs) associated with IBD and sarcopenia-related traits were derived from publicly available genome-wide association studies. We employed a two-sample bidirectional Mendelian randomization (MR) method. we obtained genetic IVs for five phenotypes from 34,652 cases in IBD, 27,432 cases in ulcerative colitis (UC), 212356 cases in crohn's disease (CD), 9336415 cases in low hand grip strength (LHGS), and 450243 cases in appendicular lean mass (ALM), respectively. The inverse variance weighting and other MR methods were used to explore the bidirectional causal relationship. Furthermore, we performed heterogeneity test, pleiotropy test, leave-one-out sensitivity test, and multivariate MR to evaluate the robustness of the results. Results: The forward MR results showed that the UC (OR=0.994, 95% CI: 0.9876-0.9998, P = 0.044) and CD (OR=0.993, 95% CI: 0.988-0.998, P = 0.006) was negatively correlated with ALM. In the reverse MR analysis, we also found that LHGS was negatively correlated with the IBD (OR=0.76, 95% CI: 0.61-0.94, P = 0.012) and CD (OR=0.53, 95% CI: 0.40-0.70, P <0.001). Besides, genetically predicted higher ALM reduced IBD (OR=0.87, 95% CI: 0.79-0.95, P = 0.002), UC (OR=0.84, 95% CI: 0.76-0.93, P = 0.001), and CD (OR=0.87, 95% CI: 0.77-0.99, P = 0.029). However, the results of other MR Analyses were not statistically different. Conclusions: We found genetically predicted UC and CD are causally associated with reduced ALM, and higher hand grip strength reduced IBD and CD risk, and higher ALM reduced IBDs risk. This MR study provides moderate evidence for a bidirectional causal relationship between IBD and sarcopenia.

HLAIImaster: a deep learning method with adaptive domain knowledge predicts HLA II neoepitope immunogenic responses.

While significant strides have been made in predicting neoepitopes that trigger autologous CD4+ T cell responses, accurately identifying the antigen presentation by human leukocyte antigen (HLA) class II molecules remains a challenge. This identification is critical for developing vaccines and cancer immunotherapies. Current prediction methods are limited, primarily due to a lack of high-quality training epitope datasets and algorithmic constraints. To predict the exogenous HLA class II-restricted peptides across most of the human population, we utilized the mass spectrometry data to profile >223 000 eluted ligands over HLA-DR, -DQ, and -DP alleles. Here, by integrating these data with peptide processing and gene expression, we introduce HLAIImaster, an attention-based deep learning framework with adaptive domain knowledge for predicting neoepitope immunogenicity. Leveraging diverse biological characteristics and our enhanced deep learning framework, HLAIImaster is significantly improved against existing tools in terms of positive predictive value across various neoantigen studies. Robust domain knowledge learning accurately identifies neoepitope immunogenicity, bridging the gap between neoantigen biology and the clinical setting and paving the way for future neoantigen-based therapies to provide greater clinical benefit. In summary, we present a comprehensive exploitation of the immunogenic neoepitope repertoire of cancers, facilitating the effective development of "just-in-time" personalized vaccines.

Efficacy and Safety of Taletrectinib in Chinese Patients With ROS1+ Non-Small Cell Lung Cancer: The Phase II TRUST-I Study.

PURPOSE: Taletrectinib, a highly potent, CNS-active, ROS1 tyrosine kinase inhibitor (TKI), has demonstrated high and durable response rates, high intracranial objective response rate (ORR), prolonged progression-free survival (PFS), and activity against G2032R with a favorable safety profile. We report outcomes from the pivotal TRUST-I study (ClinicalTrials.gov identifier: NCT04395677) of taletrectinib for ROS1+ non-small cell lung cancer in China. METHODS: TRUST-I evaluated TKI-naїve and crizotinib-pretreated patients. The primary end point was confirmed ORR (cORR) by independent review committee; key secondary end points included duration of response (DOR), PFS, and safety. RESULTS: As of November 2023, 173 patients were enrolled (median age, 55 years; 58% female; 73% never smoked; TKI naїve: n = 106; crizotinib pretreated: n = 67). In TKI-naїve patients, cORR and intracranial cORR were 91% and 88%, respectively, and 52% and 73% in crizotinib-pretreated patients. In TKI-naїve patients, median DOR and median PFS were not reached (NR) with 22.1-month and 23.5-month follow-up, respectively. In crizotinib-pretreated patients, the median DOR was 10.6 months (95% CI, 6.3 months to NR; 8.4-month follow-up), and the median PFS was 7.6 months (95% CI, 5.5 to 12.0 months; 9.7-month follow-up). Eight of 12 patients (67%) with G2032R mutations responded. The most frequent treatment-emergent adverse events (TEAEs) were increased AST (76%), diarrhea (70%), and increased ALT (68%), most of which were grade 1-2. Incidences of neurologic TEAEs were low (dizziness: 23%; dysgeusia: 10%) and mostly grade 1. Discontinuations (5%) and dose reductions (19%) due to TEAEs were low. CONCLUSION: Taletrectinib continues to show high and durable overall responses, prolonged PFS, robust activity against intracranial lesions and acquired resistance mutations including G2032R, and a favorable safety profile with a low incidence of neurologic TEAEs.

Tofacitinib to prevent anti-drug antibody formation against LMB-100 immunotoxin in patients with advanced mesothelin-expressing cancers.

Background: LMB-100 is a mesothelin (MSLN)-targeting recombinant immunotoxin (iTox) carrying a Pseudomonas exotoxin A payload that has shown promise against solid tumors, however, efficacy is limited by the development of neutralizing anti-drug antibodies (ADAs). Tofacitinib is an oral Janus Kinase (JAK) inhibitor that prevented ADA formation against iTox in preclinical studies. Methods: A phase 1 trial testing LMB-100 and tofacitinib in patients with MSLN-expressing cancers (pancreatic adenocarcinoma, n=13; cholangiocarcinoma, n=1; appendiceal carcinoma, n=1; cystadenocarcinoma, n=1) was performed to assess safety and to determine if tofacitinib impacted ADA formation. Participants were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 µg/kg) while oral tofacitinib was administered for the first 10 days of the cycle (10 mg BID). Peripheral blood was collected for analysis of ADA levels, serum cytokines and circulating immune subsets. Results: The study was closed early due to occurrence of drug-induced pericarditis in 2 patients. Pericarditis with the combination was not reproducible in a transgenic murine model containing human MSLN. Two of 4 patients receiving all 3 cycles of treatment maintained effective LMB-100 levels, an unusual occurrence. Sustained increases in systemic IL-10 and TNF-α were seen, a phenomenon not observed in prior LMB-100 studies. A decrease in activated T cell subsets and an increase in circulating immunosuppressive myeloid populations occurred. No radiologic decreases in tumor volume were observed. Discussion: Further testing of tofacitinib to prevent ADA formation is recommended in applicable non-malignant disease settings. Clinical trial registration: https://www.clinicaltrials.gov/study/NCT04034238.

Wdr17 Regulates Cell Proliferation, Cell Cycle Progression and Apoptosis in Mouse Spermatocyte Cell Line.

We identified Wdr17 as a highly expressed gene in pachytene spermatocytes by transcriptomic analysis of mouse testis. Germ cell-deficient infertile mouse models had significantly reduced Wdr17 expression. We performed gene interference and overexpression in the mouse spermatocyte cell line GC-2spd(ts) and investigated how Wdr17 affects spermatocyte growth and development. Our results showed that Wdr17 suppression significantly decreased cell growth rate and increased cell apoptosis in GC-2spd(ts) cells. Wdr17 suppression also arrested the cell cycle at the G1 phase. On the contrary, Wdr17 overexpression significantly promoted cell proliferation and inhibited cell apoptosis in GC-2spd(ts) cells. More cells were enriched at the S stage with a concomitant reduction of cells at the G1 stage. Wdr17 promotes mouse spermatocyte proliferation by advancing cell cycle progression and inhibiting cell apoptosis, indicating its potential role in regulating spermatogenesis in the mouse.

Correlation between disease activity and patient-reported health-related quality of life in rheumatoid arthritis: a cross-sectional study.

OBJECTIVE: We aimed to provide a comprehensive assessment of health-related quality of life (HRQoL) in patients with rheumatoid arthritis (RA) of different activities and to evaluate the correlation between clinical activity measures and HRQoL instruments. This research also analysed the extent to which different aspects of HRQoL (physical, psychological and social) were affected. DESIGN: Cross-sectional, observational, non-interventional study. SETTING: The study was conducted at the Department of Rheumatology and Immunology, Qilu Hospital, Shandong University. METHODS: From December 2019 to October 2020, a total of 340 RA patients participated in the survey using convenient sampling. Three generic instruments, EQ-5D-5L,SF-12 and the AQoL-4D, as well as an RA-specific instrument,the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI), were administered to assess patients' HRQoL. The Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) was used by doctors to measure patients' clinical activity. Multivariable linear regression was used to compare patients' HRQoL across different levels of activity. Spearman's correlation was used to assess the correlation between doctor-reported clinical activity and HRQoL. RESULTS: A total of 314 patients with RA participated in this study. The mean score of HAQ-DI was 0.87 (SD: 0.91). Using patients in the clinical remission group as a reference, patients in the moderate and high disease activity groups showed significantly reduced health state utility values and HRQoL scores (all p<0.05). On the contrary, there was an increase in HAQ-DI scores, indicating more impairment (p<0.05). All instruments included in the study tended to differentiate disease activity based on multiple criteria, with scores showing a moderate to strong correlation with RA activity (|rs|=0.50 to 0.65). Among them, the disease-specific instrument had the highest correlation. CONCLUSIONS: RA can have considerable impairment on patients' HRQoL, both in terms of physical and psychosocial functioning. Given the strong correlation between clinical activity and HRQoL scores, and the fact that HRQoL can be an important clinical supplement. The EQ-5D-5L is probably the most appropriate generic measurement instrument for measuring HRQoL in RA patients.

DrugMGR: a deep bioactive molecule binding method to identify compounds targeting proteins.

MOTIVATION: Understanding the intermolecular interactions of ligand-target pairs is key to guiding the optimization of drug research on cancers, which can greatly mitigate overburden workloads for wet labs. Several improved computational methods have been introduced and exhibit promising performance for these identification tasks, but some pitfalls restrict their practical applications: (i) first, existing methods do not sufficiently consider how multigranular molecule representations influence interaction patterns between proteins and compounds; and (ii) second, existing methods seldom explicitly model the binding sites when an interaction occurs to enable better prediction and interpretation, which may lead to unexpected obstacles to biological researchers. RESULTS: To address these issues, we here present DrugMGR, a deep multigranular drug representation model capable of predicting binding affinities and regions for each ligand-target pair. We conduct consistent experiments on three benchmark datasets using existing methods and introduce a new specific dataset to better validate the prediction of binding sites. For practical application, target-specific compound identification tasks are also carried out to validate the capability of real-world compound screen. Moreover, the visualization of some practical interaction scenarios provides interpretable insights from the results of the predictions. The proposed DrugMGR achieves excellent overall performance in these datasets, exhibiting its advantages and merits against state-of-the-art methods. Thus, the downstream task of DrugMGR can be fine-tuned for identifying the potential compounds that target proteins for clinical treatment. AVAILABILITY AND IMPLEMENTATION: https://github.com/lixiaokun2020/DrugMGR.

RNA atlas and competing endogenous RNA regulation in tissue-derived exosomes from luminal B and triple-negative breast cancer patients.

Background: Luminal B and triple-negative breast cancer (TNBC) are malignant subtypes of breast cancer (BC), which can be attributed to the multifaceted roles of tissue-derived exosomes (T-exos). Competing endogenous RNA (ceRNA) networks can regulate gene expression post-transcriptionally. Methods: RNAs in T-exos from luminal B BC (n=8) and TNBC (n=8) patients were compared with those from persons with benign breast disease (n=8). The differentially expressed (DE) mRNA, microRNA (miRNA), and long noncoding RNA (lncRNA) target genes were annotated using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to reveal the relevant biological processes.The ceRNA networks were constructed to show distinct regulation, and the mRNAs involved were annotated. The miRNAs involved in the ceRNA networks were screened with the Kaplan-Meier Plotter database to identify dysregulated ceRNAs with prognostic power. Results: In total, 802 DE mRNAs, 441 DE lncRNAs, and 104 DE miRNAs were identified in luminal B BC T-exos, while 1699 DE mRNAs, 590 DE lncRNAs, and 277 DE miRNAs were identified in TNBC T-exos. Gene annotation revealed that the RAS-MAPK pathway was the primary biological process in luminal B BC T-exos, while endocrine system development and growth were the main processes in TNBC T-exos. Survival analysis established seven survival-related lncRNA/miRNA/mRNA regulations in luminal B BC T-exos, and nineteen survival-related lncRNA/miRNA/mRNA regulations in TNBC T-exos. Conclusion: In addition to survival-related ceRNA regulations, ceRNA regulation of RAS-MAPK in luminal B and endocrine system development and growth regulation in TNBC might contribute to the tumorigenesis of BC.

Effects of various interventions on non-alcoholic fatty liver disease (NAFLD): A systematic review and network meta-analysis.

Background: With the increasing prevalence of obesity and metabolic syndrome, the incidence of non-alcoholic fatty liver disease (NAFLD) is also increasing. In the next decade, NAFLD may become the main cause of liver transplantation. Therefore, the choice of treatment plan is particularly important. The purpose of this study was to compare several interventions in the treatment of NAFLD to provide some reference for clinicians in selecting treatment methods. Methods: We searched Public Medicine (PubMed), Medline, Excerpta Medica Database (Embase), and Cochrane Library from January 2013 to January 2023 to identify randomized controlled trials (RCTs) published in English. The network meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Forty-three studies accounting for a total of 2,969 patients were included, and alanine aminotransferase (ALT), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL) were selected as outcome measures for analysis and comparison. Results: We evaluated the results of drug, diet, and lifestyle interventions between the intervention and control groups. Curcumin (CUN) and probiotics (PTC) were selected for medication, the Mediterranean diet (MDED) was selected for special diet (SPD), and various kinds of exercise and lifestyle advice were selected for lifestyle interventions (LFT). The SUCRA was used to rank interventions according to the effect on ALT indicators (SUCRA: PTC 80.3%, SPD 65.2%, LFT 61.4%, PLB 32.8%, CUN 10.2%), TC indicators (SUCRA: PTC 89.4%, SPD 64%, CUN 34%, LFT 36.6%, PLB 17%), and LDL indicators (SUCRA: PTC 84.2%, CUN 69.5%, LFT 51.7%, PLB 30.1%, SPD 14.5%). The pairwise meta-analysis results showed that MDED was significantly better than NT in improving ALT [SMD 1.99, 95% CI (0.38, 3.60)]. In terms of improving TC and LDL, ATS was significantly better than NT [SMD 0.19, 95% CI (0.03, 0.36)] [SMD 0.18, 95% CI (0.01, 0.35)]. Conclusion: Our study showed that PTC is most likely to be the most effective treatment for improving NAFLD indicators. Professional advice on diet or exercise was more effective in treating NAFLD than no intervention.

Palmitate Induces Mitochondrial Energy Metabolism Disorder and Cellular Damage via the PPAR Signaling Pathway in Diabetic Cardiomyopathy.

Purpose: To establish an in vitro lipotoxicity model with mouse cardiomyocytes (MCMs) and investigate the molecular mechanism of the peroxisome proliferator-activated receptors (PPAR) signaling on mitochondrial energy metabolism disorder and cellular injury in diabetic cardiomyopathy (DCM). Methods: Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the differentially expressed genes (DEGs) of DCM. CCK-8 method was used to detect the proliferation inhibition effect of palmitate (PA) on MCMs. Oil red O staining and mRNA levels of CD36 were used to verify intracellular lipid accumulation. DCFH-DA method was used to determine the content of intracellular reactive oxygen species (ROS), and ATP levels were detected by the ATP Detection Kit. Transmission electron microscope (TEM) was used to observe the mitochondrial structure. Western blot was used to detect the expression levels of PPARα, PPARγ, P-mTOR, mTOR, PGC-1α, UCP2, and BNP. In addition, the expression of PPARγ was also detected by cellular immunofluorescence staining. BNP levels were detected by qRT-PCR and the ELISA Kit. Results: KEGG pathway analysis combined with GO analysis has shown that PPAR signaling played a significant regulatory role in mitochondrial biogenesis and fatty acid metabolism in DCM. Then, MCMs stimulated with PA for 24 h were selected as an in vitro lipotoxicity model. PA decreased cell viability, cell membrane shrinkage, and lipid accumulation. Meanwhile, PA-induced increase in cellular ROS led to ATP generation reduction and mitochondrial damage. Furthermore, the expression levels of p-mTOR- PPARα/γ were decreased, and the expressions of PGC-1α and UCP2 were increased. The levels of BNP were elevated, demonstrating PA impaired cardiomyocytes. Conclusion: Mitochondrial energy metabolism obstacle and cell injury appeared in cardiac lipotoxicity of DCM, associated with lipid accumulation and increased ROS, indicating a crosstalk with the PPAR pathway mediated mechanism.

DNA Methylation of Imprinted Genes KCNQ1, KCNQ1OT1, and PHLDA2 in Peripheral Blood Is Associated with the Risk of Breast Cancer.

Methylation alterations of imprinted genes lead to loss of imprinting (LOI). Although studies have explored the mechanism of LOI in breast cancer (BC) development, the association between imprinted gene methylation in peripheral blood and BC risk is largely unknown. We utilized HumanMethylation450 data from TCGA and GEO (n = 1461) to identify the CpG sites of imprinted genes associated with BC risk. Furthermore, we conducted an independent case-control study (n = 1048) to validate DNA methylation of these CpG sites in peripheral blood and BC susceptibility. cg26709929, cg08446215, cg25306939, and cg16057921, which are located at KCNQ1, KCNQ1OT1, and PHLDA2, were discovered to be associated with BC risk. Subsequently, the association between cg26709929, cg26057921, and cg25306939 methylation and BC risk was validated in our inhouse dataset. All 22 CpG sites in the KCNQ1OT1 region were associated with BC risk. Individuals with a hypermethylated KCNQ1OT1 region (>0.474) had a lower BC risk (OR: 0.553, 95% CI: 0.397−0.769). Additionally, the methylation of the KCNQ1OT1 region was not significantly different among B cells, monocytes, and T cells, which was also observed at CpG sites in PHLDA2. In summary, the methylation of KCNQ1, KCNQ1OT1, and PHLDA2 was associated with BC risk, and KCNQ1OT1 methylation could be a potential biomarker for BC risk assessment.