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Osseointegration commences with foreign body inflammation upon implant placement, where macrophages play a crucial role in the immune response. Subsequently, during the intermediate and late stages of osseointegration, mesenchymal stem cells (MSCs) migrate and initiate their osteogenic functions, while macrophages support MSCs in osteogenesis. The utilization of ferroelectric P(VDF-TrFE) covered ITO planar microelectrodes facilitated the simulation of various surface charge to investigate their effects on MSCs' osteogenic differentiation and macrophage polarization and the results indicated a parabolic increase in the promotional effect of both with the rise in piezoelectric coefficient. Furthermore, the surface charge with a piezoelectric coefficient of -18 exhibited the strongest influence on the promotion of M1 polarization of macrophages and the promotion of MSCs' osteogenic differentiation. The impact of macrophage polarization and MSC osteogenesis following the interaction of macrophages affected by surface charge and MSC was ultimately investigated. It was observed that macrophages affected by the surface charge of -18 piezoelectric coefficient still exerted the most profound induced osteogenic effect, validating the essential role of M1-type macrophages in the osteogenic differentiation of MSCs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Xu, Huang, Chen, Cheng, Wang and Chen.)

Purpose: To develop and validate a nomogram for assessing the risk of developing hypercapnic respiratory failure (HRF) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD)., Patients and Methods: From January 2019 to August 2023, a total of 334 AECOPD patients were enrolled in this research. We employed the Least Absolute Shrinkage and Selection Operator (LASSO) regression and multivariate logistic regression to determine independent predictors and develop a nomogram. This nomogram was appraised by the area under the receiver operating characteristic curve (AUC), calibration curve, Hosmer-Lemeshow goodness-of-fit test (HL test), decision curve analysis (DCA), and clinical impact curve (CIC). The enhanced bootstrap method was used for internal validation., Results: Sex, prognostic nutritional index (PNI), hematocrit (HCT), and activities of daily living (ADL) were independent predictors of HRF in AECOPD patients. The developed nomogram based on the above predictors showed good performance. The AUCs for the training, internal, and external validation cohorts were 0.841, 0.884, and 0.852, respectively. The calibration curves and HL test showed excellent concordance. The DCA and CIC showed excellent clinical usefulness. Finally, a dynamic nomogram was developed (https://a18895635453.shinyapps.io/dynnomapp/)., Conclusion: This nomogram based on sex, PNI, HCT, and ADL demonstrated high accuracy and clinical value in predicting HRF. It is a less expensive and more accessible approach to assess the risk of developing HRF in AECOPD patients, which is more suitable for primary hospitals, especially in developing countries with high COPD-related morbidity and mortality., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Zhou et al.)

Ethnopharmacological Relevance: With the emergence of endocrine resistance, the survival and good prognosis of HR-positive breast cancer (HR + BC) patients are threatened. As a common complementary and alternative therapy in cancer treatment, traditional Chinese medicine (TCM) has been widely used, and its internal mechanisms have been increasingly explored., Aim of the Review: In this review, the development status and achievements in understanding of the mechanisms related to the anti-invasion and anti-metastasis effects of TCM against HR + BC and the reversal of endocrine drug resistance by TCM in recent years have been summarized to provide ideas for antitumour research on the active components of TCM/natural medicine., Methods: We searched the electronic databases PubMed, Web of Science, and China National Knowledge Infrastructure database (CNKI) (from inception to July 2023) with the key words "HR-positive breast cancer" or "HR-positive breast carcinoma", "HR + BC" and "traditional Chinese medicine", "TCM", or "natural plant", "herb", etc., with the aim of elucidating the intrinsic mechanisms of traditional Chinese medicine and natural medicine in the treatment of HR + BC., Results: TCM/natural medicine monomers and formulas can regulate the expression of related genes and proteins through the PI3K/AKT, JAK2/STAT3, MAPK, Wnt and other signalling pathways, inhibit the proliferation and metastasis of HR + BC tumours, play a synergistic role in combination with endocrine drugs, and reverse endocrine drug resistance., Conclusion: The wide variety of TCM/natural medicine components makes the research and development of new methods of TCM for BC treatments more selective and innovative. Although progress has been made on research on TCM/natural medicine, there are still many problems in clinical and basic experimental designs, and more in-depth scientific explorations and research are still needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This experiment investigates how the miR-99b/let-7e/miR-125a cluster regulates the mechanism of NR6A1 involved in the invasive and metastatic effects of pancreatic cancer (PCa). Bioinformatics prediction and dual luciferase reporter gene assay were applied to verify the targeted relationship between miR-99b/let-7e/miR-125a and NR6A1. ASPC1 cells underwent transfection with lentiviruses to overexpress miR-99b/let-7e/miR-125a (individual or together) to explore functions of miR-99b/let-7e/miR-125a cluster governing NR6A1 in PCa. The detection of tumorigenesis was verified by tumor formation assay in nude mice in vivo, and mouse models of liver metastasis of PCa observed cell metastasis of PCa. MiR-99b/let-7e/miR-125a cluster was screened for differential expression in PCa. NR6A1 was confirmed as a target gene of the miR-99b/let-7e/miR-125a cluster. Findings demonstrated that overexpression of the miR-99b/let-7e/miR-125a cluster inhibited cell invasion, metastasis, proliferation, and tumorigenesis in PCa. Conversely, overexpressed NR6A1, a crucial gene in the miR-99b/let-7e/miR-125a cluster, promoted cell invasion, migration, and proliferation in PCa. Moreover, the overexpression of the miR-99b/let-7e/miR-125a cluster inhibited liver metastases and tumor formation. Thus, the study concludes that the miR-99b/let-7e/miR-125a cluster impedes the invasion and metastasis of PCa cells via targeting the NR6A1 gene., Competing Interests: None., (AJCR Copyright © 2024.)

Background: Malignant pleural effusion is mostly a complication of advanced malignant tumors. However, the cancer markers such as carbohydrate antigen 125 (CA 125), carbohydrate antigen 15-3 (CA 15-3), carbohydrate antigen 19-9 (CA 19-9), and cytokeratin fragment 21-1 (CYFRA 21-1) have low sensitivity and organ specificity for detecting malignant pleural effusion., Research Question: Is IR808@MnO nano-near infrared fluorescent dye worthy for the diagnosis in differentiating benign and malignant pleural effusions., Study Design and Methods: This experiment was carried out to design and characterize the materials for in vitro validation of the new dye in malignant tumor cells in the A549 cell line and in patients with adenocarcinoma pleural effusion. The dye was verified to possess tumor- specific targeting capabilities. Subsequently, a prospective hospital-based observational study was conducted, enrolling 106 patients and excluding 28 patients with unknown diagnoses. All patients underwent histopathological analysis of thoracoscopic biopsies, exfoliative cytological analysis of pleural fluid, and analysis involving the new dye. Statistical analyses were performed using Microsoft Excel, GraphPad Prism, and the R language., Results: The size of IR808@MnO was 136.8 ± 2.9 nm, with peak emission at 808 nm, and it has near-infrared fluorescence properties. Notably, there was a significant difference in fluorescence values between benign and malignant cell lines (p < 0.0001). The malignant cell lines tested comprised CL1-5, A549, MDA-MB-468, U-87MG, MKN-7, and Hela, while benign cell lines were BEAS-2B, HUVEC, HSF, and VE. The most effective duration of action was identified as 30 min at a concentration of 5 μl. This optimal duration of action and concentration were consistent in patients with lung adenocarcinoma accompanied by pleural effusion and 5 μl. Of the 106 patients examined, 28 remained undiagnosed, 39 were diagnosed with malignant pleural effusions, and the remaining 39 with benign pleural effusions. Employing the new IR808@MnO staining method, the sensitivity stood at 74.4%, specificity at 79.5%, a positive predictive value of 69.2%, and a negative predictive value of 82.1%. The area under the ROC curve was recorded as 0.762 (95% CI: 0.652-0.872). The confusion matrix revealed a positive predictive value of 75.7%, a negative predictive value of 75.6%, a false positive rate of 22.5%, and a false negative rate of 26.3%., Interpretation: The IR808@MnO fluorescent probe represents an efficient, sensitive, and user-friendly diagnostic tool for detecting malignant pleural fluid, underscoring its significant potential for clinical adoption., (© 2024. The Author(s).)

Structural parameters of the implants such as shape, size, and porosity of the pores have been extensively investigated to promote bone tissue repair, however, it is unknown how the pore interconnectivity affects the bone growth behaviors in the scaffolds. Herein we systematically evaluated the effect of biodegradable bioceramics as a secondary phase filler in the macroporous networks on the mechanical and osteogenic behaviors in sparingly dissolvable bioceramic scaffolds. The pure hardystonite (HT) scaffolds with ∼550 & 800 μm in pore sizes were prepared by digital light processing, and then the Sr-doped calcium silicate (SrCSi) bioceramic slurry without and with 30 % organic porogens were intruded into the HT scaffolds with 800 μm pore size and sintered at 1150 °C. It indicated that the organic porogens could endow spherical micropores in the SrCSi filler, and the invasion of the SrCSi component could not only significantly enhance the compressive strength and modulus of the HT-based scaffolds, but also induce osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). The pure HT scaffolds showed extremely slow bio-dissolution in Tris buffer after immersion for 8 weeks (∼1 % mass decay); in contrast, the SrCSi filler would readily dissolve into the aqueous medium and produced a steady mass decay (>6 % mass loss). In vivo experiments in rabbit femoral bone defect models showed that the pure HT scaffolds showed bone tissue ingrowth but the bone growth was impeded in the SrCSi-intruded scaffolds within 4 weeks; however, the group with higher porosity of SrCSi filler showed appreciable osteogenesis after 8 weeks of implantation and the whole scaffold was uniformly covered by new bone tissues after 16 weeks. These findings provide some new insights that the pore interconnectivity is not inevitable to impede bone ingrowth with the prolongation of implantation time, and such a highly biodegradable and bioactive filler intrusion strategy may be beneficial for optimizing the performances of scaffolds in bone regenerative medicine applications., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

In recent years, there has been a significant increase in the incidence of Breast cancer (BC), making it the most common cancer among women and a major threat to women's health. Consequently, there is an urgent need to discover new and effective strategies for treating BC. Ferroptosis, a novel form of cell death characterized by the accumulation of iron-dependent lipid reactive oxygen species, has emerged as a distinct regulatory pathway separate from necrosis, apoptosis, and autophagy. It is widely recognized as a crucial factor in the development and progression of cancer, offering a promising avenue for BC treatment. While significant progress has been made in understanding the mechanisms of ferroptosis in BC, drug development is still in its early stages. Numerous compounds, including phytochemicals derived from dietary sources and medicinal plants, as well as synthetic drugs (both clinically approved medications and laboratory reagents), have shown the ability to induce ferroptosis in BC cells, effectively inhibiting tumor growth. This comprehensive review aims to examine in detail the compounds that target ferroptosis in BC and elucidate their potential mechanisms of action. Additionally, the challenges associated with the clinical application of ferroptosis-inducing drugs are discussed, offering valuable insights for the development of novel treatment strategies for BC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xu, Chen, Yu, Song, Jin and Gao.)

Colorectal cancer has a poor prognosis and is prone to recurrence and metastasis. DPP7, a prolyl peptidase, is reported to regulate lymphocyte quiescence. However, the correlation of DPP7 with prognosis in CRC remains unclear. With publicly available cohorts, the Wilcoxon rank-sum test and logistic regression were employed to analyze the relationship between DPP7 expression and the clinicopathological features of CRC patients. Specific pathways of differentially expressed genes were determined through biofunctional analysis and gene set enrichment analysis (GSEA). qPCR and immunohistochemical staining were used to determine DPP7 expression levels in surgical specimens. The public dataset and analysis of the biospecimens of CRC patients revealed that DPP7, in the CRC samples, was expressed significantly higher than in non-tumor tissues. Moreover, increased DPP7 was significantly associated with a higher N stage, lymphatic invasion, and shorter overall survival. Functionally, DPP7 is involved in neuroactive ligand-receptor interaction and olfactory transduction signaling. We identified a series of targeted drugs and small-molecule drugs with responses to DPP7. To conclude, DPP7 is a valuable diagnostic and prognostic biomarker for CRC and considered as a new therapeutic target.

Purpose: This study aims to evaluate the value of tissue inhibitors of MMPs-2 (TIMP-2) to indicate 5-Fluorouracil (5-Fu) resistance status in colorectal cancer., Methods: The 5-Fu resistance of colorectal cancer cell lines was detected using Cell-Counting Kit-8 (CCK-8) and calculated using IC 50 . Enzyme-linked immunosorbent assay (ELISA) and real time-quantitative polymerase chain reaction (RT-qPCR) were used to detect TIMP-2 expression level in the culture supernatant and serum. Twenty-two colorectal cancer patients' TIMP-2 levels and clinical characteristics were analyzed before and after chemotherapy. Additionally, the patient-derived xenograft (PDX) model of 5-Fu resistance was used to evaluate the feasibility of TIMP-2 as a predictive biomarker of 5-Fu resistance., Results: Our experimental results display that TIMP-2 expression is elevated in colorectal cancer drug-resistant cell lines, and its expression level is closely related to 5-Fu resistance. Moreover, TIMP-2 in colorectal cancer patient serum undergoing 5-Fu-based chemotherapy could indicate their drug resistance status, and its efficacy is higher than CEA and CA19-9. Finally, PDX model animal experiments reveal that TIMP-2 can detect 5-Fu resistance in colorectal cancer earlier than tumor volume., Conclusion: TIMP-2 is a good indicator of 5-Fu resistance in colorectal cancer. Monitoring the serum TIMP-2 level can help the clinician identify 5-Fu resistance in colorectal cancer patients earlier during chemotherapy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Tamoxifen is an effective anti-tumor medicine, but evidence has been provided on tamoxifen-related inflammation as well as its impact on gut microbiota. In this study, we aimed to investigate tamoxifen-induced gut microbiota and inflammation alteration., Methods: We established a BC xenograft mouse model using the MCF-7 cell line. 16S rRNA gene sequencing was used to investigate gut microbiota. qRT-PCR, western blotting, and cytometric bead array were used to investigate inflammation-related biomarkers. Various bioinformatic approaches were used to analyze the data., Results: Significant differences in gut microbial composition, characteristic taxa, and microbiome phenotype prediction were observed between control, model, and tamoxifen-treated mice. Furthermore, protein expression of IL-6 and TLR5 was up-regulated in tamoxifen-treated mice, while the mRNA of Tlr5 and Il-6, as well as protein expression of IL-6 and TLR5 in the model group, were down-regulated in the colon. The concentration of IFN-γ, IL-6, and IL12P70 in serum was up-regulated in tamoxifen-treated mice. Moreover, correlation-based clustering analysis demonstrated that inflammation-negatively correlated taxa, including Lachnospiraceae-UCG-006 and Anaerotruncus , were enriched in the model group, while inflammation-positively correlated taxa, including Prevotellaceae&#95;UCG&#95;001 and Akkermansia , were enriched in the tamoxifen-treated group. Finally, colon histologic damage was observed in tamoxifen-treated mice., Conclusion: Tamoxifen treatment significantly altered gut microbiota and increased inflammation in the breast cancer xenograft mice model. This may be related to tamoxifen-induced intestinal epithelial barrier damage and TLR5 up-regulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Gao, Chen, Wang, Xu, Yu, Jin, Song and Zhu.)

Introduction: Pentraxin 3 (PTX3) is involved in inflammation regulation and has a certain association with infectious diseases. However, its specific correlation with infectious diseases remains controversial. This study aimed to analyze the association between them and explore the possible role of PTX3 in the prognosis of coronavirus disease 2019 (COVID-19)., Methods: Five databases (PubMed, Cochrane Library, Embase, Clinicaltrials.gov, and gray literature) were searched. Outcomes were expressed as a standardized mean difference (SMD) and 95% confidence intervals (CI). The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of included articles. Stata 12 and Meta-DiSc were applied to analyze the pooled data. Receiver operating characteristic (ROC) curves were conducted to determine the prognostic value of PTX3 for mortality., Results: Six articles met the inclusion criteria. Circulating PTX3 levels had a nonsignificant difference between intensive care unit (ICU) and non-ICU patients with COVID-19 [SMD 1.37 (-0.08, 2.81); I 2  = 93.9%, P < 0.01], while the PTX3 levels in nonsurvival COVID-19 patients was significantly lower than those in survival patients [SMD -1.41 (-1.92, -0.91); I 2  = 66.4%, P = 0.051]. Circulating PTX3 had good mortality prediction ability (area under ROC curve, AUC = 0.829) in COVID-19. Funnel plots and Egger's tests showed low probabilities of publication bias. Through sensitivity analysis, the results of this study were robust., Conclusion: This study found that PTX3 was differentially expressed between survival and nonsurvival patients with COVID-19, while there was no significant difference between ICU and non-ICU patients. Meanwhile, circulating PTX3 may be a good biomarker for monitoring the prognosis of COVID-19, which may provide new ideas and directions for clinical and scientific research., (© 2022. The Author(s).)

Background: Androgen receptor (AR) is becoming an important factor in the pathogenesis of breast cancer. Traditional Chinese medicine (TCM) is widely used in treating breast cancer patients. Triple-negative breast cancer (TNBC) is a subtype of breast cancer, which has worse prognosis than other subtypes. Herein, through this retrospective study, we summarize the therapeutic implications of AR and TCM in TNBC., Methods: The clinical and pathological data of TNBC patients who had undergone surgery at The First Affiliated Hospital of Zhejiang Chinese Medical University from 2017 to 2019 were collected and examined. The t -test, chi-square test, logistic regression model, and Kaplan-Meier survival estimates were used to analyze the data., Results: We identified 823 early breast cancer patients from January 2017 to December 2019, of whom 92 (11.2%) were pathologically confirmed to have TNBC. We excluded 5 patients according to the inclusion and exclusion criteria. In relation to the remaining 87 patients, 33 (37.9%) were AR positive. In the TNBC patients, positive AR expression was correlated with an older age (P=0.006), a higher weight (P=0.006), and lower Ki-67 expression (P=0.031). After a median follow-up time of 37 months (range, 24-60 months), 13 cases of relapse and metastasis (14.9%) were observed. We found that relapse and metastasis were correlated with being unmarried [P=0.004; hazard ratio (HR) =0.105; 95% confidence interval (95% CI): 0.023-0.487], nonporous (P=0.046; HR =0.209; 95% CI: 0.045-0.971), and negative AR expression (P=0.042; HR =1.223; 95% CI: 0.049-1.012). The AR-positive TNBC patients had better disease-free survival (DFS) than the AR-negative TNBC patients 2-5 years after surgery (P<0.05). TCM was an effective treatment for TNBC (P<0.001; HR =51.682; 95% CI: 6.660-401.025). In the AR-negative group, patients who received the TCM treatment tended to have a better DFS than those who did not receive the TCM treatment (P<0.001; HR =34.832; 95% CI: 4.448-272.756); however, no such difference was found in the AR-positive group., Conclusions: The TNBC patients with positive AR tended to have a low expression of Ki-67 and a better prognosis than AR negative TNBC patients. TCM is an effective treatment and has slight side effects., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-22-508/coif). The authors have no conflicts of interest to declare., (2022 Gland Surgery. All rights reserved.)

Acute mastitis is one of the main reasons why breastfeeding women stop breastfeeding, and medication should be used with caution. Considering the uncertainty of mastitis infection and the indications of antibiotic use, as well as the problem of drug resistance and the safety of medication during lactation, probiotics have become an alternative treatment choice. However, a meta-analysis of the effects of probiotics in preventing and treating lactational mastitis is still lacking. Therefore, we searched six electronic databases and the sites of clinical trial registration, a total of six randomized controlled trials were included in this meta-analysis, which showed that oral probiotics during pregnancy can reduce the incidence of mastitis (RR: 0.49, 95% CI: 0.35 to 0.69; p<0.0001). After oral administration of probiotics, the counts of bacteria in the milk of healthy people and mastitis patients were both significantly reduced (in healthy people: MD: -0.19, 95% CI: -0.23 to -0.16, p<0.00001; in mastitis patients: MD: -0.89, 95% CI: -1.34 to -0.43, p = 0.0001). These indicate that to a certain extent, probiotics are beneficial in reducing the incidence rate of mastitis during lactation and some related mastitis symptoms. However, high-quality multicenter clinical trials are still needed to support this result., Competing Interests: The authors have declared that no competing interests exist.

Aim: We performed a systematic review and meta-analysis to evaluate the efficacy and safety of microwave ablation (MWA) for benign breast lesions., Material and Methods: PubMed, Embase, Web of Science, Cochrane Library databases, China National Knowledge Infrastructure, and Wanfang Data Knowledge Service Platform databases were searched., Results: A total of 10 studies were included, giving a sample size of 1241 patients and 2729 benign breast lesions. The first complete ablation success rate was 96%. The volume reduction ratio (VRR) after 3/6/12 months was 47.4%, 62.1%, and 85.8%, respectively. After 12 months, the lesion disappearance rate was 53.6%, and the efficiency rate was 99%. The rate of excellent cosmesis was 88% and the rate of good cosmesis was 10%. The complication rate was 2%., Conclusions: MWA is safe and effective for treating benign breast lesions. It can be a promising minimally invasive choice for benign breast lesions., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2022 Fundacja Videochirurgii.)

Ethnopharmacological Relevance: Amorphophalli Rhizoma (APR) is widely used as an adjuvant treatment for advanced and metastatic triple-negative breast cancer (TNBC), but its effects, potential active ingredients, and mechanism of action on estrogen receptor-positive (ER+) and human epidermal growth factor receptor-positive (HER2+) breast cancer cells were not reported., Aim of the Study: The present study investigated the effects and mechanism of APR on ER+ and HER2+ breast cancer cells., Materials and Methods: Rotary evaporation was used to prepare different extracts of APR. Cell activity was assessed using the cell counting kit-8 (CCK-8) method. Wound healing assays were used to assess cell migration, and a cell invasion assay was performed using a Transwell chamber with Matrigel matrix. A xenograft model was used to analyze the inhibitory effects of APR on tumor growth. Bioinformatics analyses were used to explore the potential mechanism of APR in breast cancer. RT-qPCR and Western blotting were performed to reveal the molecular mechanism., Results: The ethyl acetate extract of APR showed the strongest tumor inhibitory effect on ER+ and HER2+ breast cancer cells compared to petroleum ether or N-butanol extracts. APR inhibited ER+ and HER2+ breast cancer cell growth, proliferation, migration, and invasion via the phosphatidylinositol-3 kinase (PI3K)/AKT pathway., Conclusions: APR had a significant inhibitory effect on ER+ and HER2+ breast cancer cells via the PI3K/AKT signaling pathway. Therefore, APR may be useful for preventing ER+ and HER2+ breast tumor growth, proliferation, migration, and invasion., (Copyright © 2021. Published by Elsevier B.V.)

Background: An elevated level of olfactomedin-like-2A ( OLFML2A ) is unfavorable for female breast cancer patients. Patients with a high mRNA level of OLFML2A receive a poor prognosis. Therefore, we speculate that inhibiting the expression of this gene may be beneficial to breast cancer patients. We previously found that silencing the OLFML2A gene by using mRNA interference significantly inhibited proliferation and migration in triple-negative breast cancer (TNBC) cells., Methods: Cell activity and proliferation were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Celigo analyses. Cell migration and invasion were determined by wound-healing and transwell invasion assays. The mechanism of the inhibition of a small hairpin RNA that targets OLFML2A (sh OLFML2A ) was determined by using a GeneChip array, real-time quantitative PCR (RT-qPCR), and western blot analysis., Results: Gene silencing by sh OLFML2A induces apoptosis by promoting S phase arrest in TNBC cells. In addition, sh OLFML2A decreased the progression of epithelial-mesenchymal transition (EMT). Additionally, microarray analysis showed that sh OLFML2A significantly upregulated 428 genes and downregulated 712 genes. These significantly changed genes regulated DNA synthesis, chromosome alignment, microtubules and the cytoskeleton, cell movement, the cell cycle, cell necrosis, and apoptosis because they promoted G2/M DNA damage checkpoint regulation and p53 signaling, and because they inhibited integrin, hepatocyte growth factor (HGF), nerve growth Factor (NGF), and other tumor-promoting signaling pathways., Conclusions: sh OLFML2A reduces cell proliferation, migration, and invasion and promotes cell apoptosis. Therefore, the results of the present study suggest that OLFML2A is a potential therapeutic target for TNBC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-757/coif). All authors report that this work was supported by The National Natural Science Foundation of China (No. 82074438), the Natural Science Foundation of Zhejiang Province (No. LY18H270006), and the Zhejiang Province Traditional Chinese Medicine Scientific Research Foundation (No. 2016ZQ015). The authors have no other conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Introduction: Intestinal metaplasia (IM) is an independent risk factor for gastric cancer (GC). However, the subtypes of IM as a risk factor for GC remain controversial. We performed a systematic review and meta-analysis to evaluate the relationship between IM subtypes and GC risk., Methods: Systematic searches were conducted in PubMed, EMBASE, and the Cochrane Library for published cohort studies of patients with complete IM (type I) or incomplete IM (type II or type III) from inception to May 15, 2021. We extracted relevant data and calculated pooled risk ratios (RRs) and 95% confidence intervals (CIs) comparing the GC risk with IM subtypes., Results: Twelve cohort studies comprising 6,498 individuals were included in the study. Compared with complete IM, the pooled relative risk of GC risk of patients with incomplete IM was 5.16 (95% CI, 3.28-8.12), and the GC risk of type III IM was the highest, with a pooled relative risk of 2.88 (95% CI, 1.37-6.04) compared with that of type II. Compared with complete IM, the pooled relative risk of dysplasia risk in patients with incomplete IM was 3.72 (95% CI, 1.42-9.72), and the dysplasia risk of type III IM was 11.73 (95% CI, 2.08-66.08) compared with that of type I., Discussion: Patients with incomplete IM, especially type III, were at a higher risk of GC and dysplasia than those with complete IM. The current evidence indicates a potential correlation between IM subtypes and GC risk, which may support the use of IM subtypes in GC surveillance., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background and Objective: The application of curcumin is limited by its instability. Mono-carbonyl analogues of curcumin (MCACs) are structurally stable, yet the intermediate bridging ketones in their skeletons account for increased toxicity. This study aimed to synthesize and screen MCACs that exhibit low cytotoxicity and high antioxidant ability, and the effects of MCACs on experimental periodontitis were also investigated., Materials and Methods: The cytotoxicity of MCACs on MC3 T3-E1 was determined by MTT assay. The antioxidant capacity was investigated by the cell viability against H 2 O 2 -induced damage and the level of reactive oxygen species (ROS) and malondialdehyde (MDA). The localization and protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was detected by immunofluorescence and western blot, respectively. In addition, MCAC was intragastrically administrated in rats with ligature-induced experimental periodontitis. The effects were assessed by bone resorption, as well as the immunohistology staining of inflammatory and oxidative stress markers., Results: MCACs with cyclopentanone and containing pyrone showed lower toxicity than natural curcumin were synthesized (1A-10A, 1H-10H), among which, 1A exhibited the most potent cytoprotective effect against H 2 O 2 -induced damage. Such effects could be explained by the reduced MDA and ROS level, possibly through the nucleus translocation of Nrf2 and the induction of HO-1. Micro-CT results further indicated that 1A significantly reduced bone loss, along with an increased level of Nrf2 and HO-1, and decreased TNF-α and IL-1β., Conclusion: The present study has synthesized a novel antioxidant MCAC 1A with good biosafety and stability. MCAC 1A could serve as a host response modulator with preventive and protective effects on periodontitis., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Tracking and quantifying hypochlorite (ClO - ) in biological systems and environments remain challenging tasks, and many efforts have been made to improve ClO - recognition performance by modifying the sensor structure. In this study, a pre-designed coumarin/furanohydrazide-based sensor (CMFH) with the coumarin moiety as the building block (fluorogen) was rationally prepared as a ratiometric and colorimetric chemosensor for ClO - recognition. As expected, CMFH demonstrated excellent sensitivity and selectivity for ClO - detection. The fluorescence signal ratio (F 466 /F 556 ) showed strong ClO - dependency, and the sensor exhibited ultrafast detection (within 60 s) and a low detection limit of 563 nM. Due to its low cytotoxicity and good tissue permeability, CMFH was demonstrated as a dual-channel sensor for ClO - bioimaging and visualization in cells, zebrafish, and even bacteria. Furthermore, CMFH-loaded paper strips were successfully applied to the colorimetric and fluorescent visualization of ClO - . The results demonstrate that CMFH has potential application value for tracking ClO - in various biosystems and environments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Periodontitis is a chronic infection initiated by oral bacterial and their virulence factors, yet the severity of periodontitis is largely determined by the dysregulated host immuno-inflammatory response. Baicalein is a flavonoid extracted from Scutellaria baicalensis with promising anti-inflammatory properties. This study aims to clarify the anti-inflammatory and osteogenic effects of baicalein in periodontal ligament cells (PDLCs) treated with lipopolysaccharides (LPS)., Methods: Human PDLCs were incubated with baicalein (0-100 μM) for 2 h prior to LPS challenge for 24 h. MTT analysis was adopted to assess the cytoxicity of baicalein. The mRNA and protein expression of inflammatory and osteogenic markers were measured by real-time polymerase chain reaction (PCR), western blot and enzyme-linked immunosorbent assay (ELISA) as appropriate. Alkaline phosphatase (ALP) and Alizarin red S (ARS) staining were performed to evaluate the osteogenic differentiation of PDLCs. The expression of Wnt/β-catenin and mitogen-activated protein kinase (MAPK) signaling related proteins was assessed by western blot., Results: MTT results showed that baicalein up to 100 μM had no cytotoxicity on PDLCs. Baicalein significantly attenuated the inflammatory factors induced by LPS, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), matrix metalloprotein-1 (MMP-1), MMP-2 and monocyte chemoattractant protein 1 (MCP-1) at both mRNA and protein level. Moreover, MAPK signaling (ERK, JNK and p38) was significantly inhibited by baicalein, which may account for the mitigated inflammatory response. Next, we found that baicalein effectively restored the osteogenic differentiation of LPS-treated PDLCs, as shown by the increased ALP and ARS staining. Accordingly, the protein and gene expression of osteogenic markers, namely runt-related transcription factor 2 (RUNX2), collagen-I, and osterix were markedly upregulated. Importantly, baicalein could function as the Wnt/β-catenin signaling activator, which may lead to the increased osteoblastic differentiation of PDLCs., Conclusions: With the limitation of the study, we provide in vitro evidence that baicalein ameliorates inflammatory response and restores osteogenesis in PDLCs challenged with LPS, indicating its potential use as the host response modulator for the management of periodontitis.

The C-X-C motif (CXC) chemokines play an important role in inflammatory processes and angiogenesis and are also associated with tumor development, progression and metastasis. They can be either promoting or inhibiting factors in colorectal cancers (CRC). The expression patterns and prognostic values of the CXC family still need further investigation. In this study, we investigated data related to transcription, translation, survival and tumor immune infiltration for CXC chemokines in patients with CRC from the ONCOMINE, GEPIA, cBioPortal, HPA and TIMER databases. We found that the expression levels of CXCL1-3, CXCL5, and CXCL8 were higher in CRC tissues than in colorectal tissues. Expression among stages significantly varied for CXCL1-3 and CXCL9-11. The survival analysis revealed that high transcriptional levels of CXCL4 and CXCL9-11 could serve as positive prognostic factors for patients with CRC. CXCL9-11 were highly associated with CD8+ T cells and natural killer (NK) cells in the tumor immune infiltration analysis, indicating their role in the antitumor immune response. This study implies that CXCL1-3, CXCL5, and CXCL8 are important factors during CRC oncogenesis and that CXCL9-11 could be new biomarkers for the prognosis of CRC., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Bioactive molecules play a vital role in the process of regulating the redox balance in the intracellular environment, especially in maintaining the function of organelles. To explore the association and function of bioactive molecules in organelles, it is essential to develop a chemosensor tool that uses multiresponse fluorescence signals to distinguish between and track two related bioactive molecules in organelles. However, the development of sensors with multiresponse functions is still a challenging task. Herein, we present a unique and practical single chemosensor ( Mito-CTC ) that can monitor HClO (as an oxidative substance) and H 2 S (as a reductive substance) in mitochondria (organelle targeting) with multiresponse fluorescence signals. The response of the sensor to HClO and H 2 S changes from red to green and blue channel emission simultaneously, respectively, thereby providing a specific signal response to reductive/oxidative substances in the mitochondria. Using a single chemosensor, we have realized multichannel bioimaging of the exogenous and endogenous HClO and H 2 S in cellular mitochondria. Additionally, the excellent properties of the sensor Mito-CTC can be used to reveal the relationship between HClO and H 2 S in mitochondria. Meanwhile, Mito-CTC has been endowed with the ability to image in bacteria and zebrafish attributed to the good permeability and low cytotoxicity. Expectantly, drug-induced liver injury (DILI) caused by fluoxetine (an antidepressant drug) and the degree of drug-induced toxicity to the liver were evaluated using Mito-CTC through discriminating and imaging HClO, indicating that Mito-CTC has the potential function of evaluating the toxicity of the drug to the liver.

In this work, a reaction-based ratiometric and colorimetric sensor was designed and synthesized for probing bisulfite (HSO 3 - ) by coupling coumarin ( CM ) with barbituric ( BA ) moiety. Further tests have shown that CM-BA has high selectivity and sensitivity for the recognition of HSO 3 - , which can be applied for the detection of HSO 3 - in environmental and biological systems very effectively. The fluorescence intensity ratios ( F 462 / F 568 ) exhibited an outstanding HSO 3 - -dependent response with ultrafast response time (within 20 s) and a lower detection limit (105 nM). Meanwhile, the color of the CM-BA solution changed from green to colorless during the recognition process, and its fluorescence changed from green to blue. The mechanism of response is confirmed by the density functional theory (DFT) model. In summary, CM-BA has demonstrated low toxicity and good permeability, which can be applied for imaging HSO 3 - in cells and zebrafish safely and effectively. Besides, this novel sensor CM-BA successfully realized the quantification of the concentration of HSO 3 - in paper strips and food samples.

Acid-alkaline balance plays a crucial role in all biological processes. Accordingly, monitoring pH changes will help us to understand the functional status of these physiological and pathological processes. Though fluorescent probes may be a useful tool for detecting pH changes, and there are many limitations to currently available probes, such as background interference, potential cytotoxicity, and poor cell permeability, which call for a solution urgently. In this work, a rhodamine-derived colorimetric and ratiometric sensor (Rh-HN) was fabricated for monitoring pH change via the mechanism of fluorescence resonance energy transfer (FRET). Rh-HN has been shown to possess several advantages over other probes, such as high sensitivity, outstanding permeability, and low toxicity. Besides, the fluorescence intensity ratio (F 526 /F 592 ) of Rh-HN displays a pH-sensitive response from 2.0 to 7.5 (pKa = 5.05) and linear response from pH 3.8 to 6.4, which was desirable for mapping pH change in the biological systems. Besides, the results indicated that Rh-HN generated a pH-dependent response regulated by switchable forms between closed and opened spirolactam ring. Overall, Rh-HN has accomplished sensing and mapping of pH in living cells, bacteria, and zebrafish. Those results demonstrated that the great potential of Rh-HN in sensing and visualizing pH in the living biosystem., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Hypochlorous acid (HOCl)/hypochlorite (ClO - ) was a biologically important component of reactive oxygen species (ROS) and plays a key role in human immune function systems. HOCl/ClO - can destroy invasive bacteria and pathogens, and mediate the physiological balance of the organism with low concentrations, and cause oxidation of the biomolecules such as proteins, cholesterol and nucleic acid in biological cells, leading to a series of diseases with over capacity. Therefore, quantifying the content of HOCl/ClO - in organisms are extremely urgent. In this work, coumarin-salicylic hydrazide Schiff base (CMSH), a ratiometric and colorimetric fluorescent probe for ClO- detection based on coumarin as the fluorophore unit was rationally designed and synthesized. The results indicated that CMSH exhibits high selectivity and sensitivity for ClO- identification. Additionally, the ratios (I 470 /I 532 ) displayed brilliant ClO - -dependent quick and sensitive performance within 40 s and limitation of 128 nM, respectively. As well as the color of the solution changes from green to colorless accompanied by the fluorescence form green turns into blue with addition of ClO - . Totally, CMSH has been successfully employed as ratiometric sensor to image in living cells, bacteria and zebrafish with low cytotoxicity and good permeability., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Objective: Bone remodeling during orthodontic treatment is achieved by the osteogenesis of human periodontal ligament cells (PDLCs) subjected to mechanical loadings. Transcriptional co-activator with PDZ-binding motif (TAZ) mediates bone remodeling in response to extracellular mechanical signals. This study aims to investigate the role of TAZ in osteogenesis of PDLCs under tensile strain., Materials and Methods: A uniaxial cyclic tensile stress (CTS) at 12% elongation and 6 cycles/min (5 s on and 5 s off) was applied to PDLCs. The osteogenic differentiation was determined by the protein and gene expressions of osteogenic markers using qRT-PCR and Western blot, respectively, and further by alkaline phosphatase (ALP) activity and Alizarin Red S staining. The interaction of TAZ with core-binding factor α1 (Cbfα1) was examined by co-immunoprecipitation. The immunofluorescence histochemistry was used to examine the nucleus aggregation of TAZ and the reorganization of actin filaments. Moreover, small interfering RNA-targeting TAZ (TAZsiRNA) was used for TAZ inhibition and Y-27632 was employed for Ras homologue-associated coiled-coil protein kinase (ROCK) signaling blockage., Results: CTS clearly stimulated the nucleus accumulation of TAZ and its interaction with Cbfα1. CTS-induced osteogenesis in PDLCs was significantly abrogated by the infection with TAZsiRNA, as shown by the decreased stained nodules and protein expressions of Cbfα1, collagen type I, osterix, and osteocalcin, along with the inhibition of β-catenin signaling. Moreover, ROCK inhibition by Y-27632 hindered TAZ nucleus aggregation and its binding with Cbfα1, which subsequently lead to the decreased osteoblastic differentiation of PDLCs., Conclusions: Taken together, we propose that TAZ nucleus localization and its interaction with Cbfα1 are essential for the CTS-induced osteogenic differentiation in PDLCs. And such TAZ activation by CTS could be mediated by ROCK signaling, indicating the pivot role of ROCK-TAZ pathway for PDLCs differentiation., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This work demonstrates a novel chemosensor, SPTPA, that exhibits fluorescence and colorimetric dual sensing of hypochlorite with an ICT ON strategy. Additionally, the chemosensor successfully detected and imaged endogenous hypochlorite in living cells, various types of bacteria, and zebrafish.

Salecan polysaccharide produced by Agrobacterium sp. ZX09 is an attractive biopolymer to construct hydrogel scaffolds for cell culture. However, some limitations such as poor mechanical performance, complicated fabrication process and slow gelation times still exist in the biomedical applications of microbial-based salecan polysaccharide hydrogels. Here, a series of polysaccharide hydrogels composed of salecan and agarose with adjustable structural properties are designed. The resultant hybrid salecan/agarose hydrogels exhibit controllable physical and chemical properties including thermal stability, water uptake, mechanical strength and microarchitecture, which can be readily realized with minimum change of the polysaccharide content. Furthermore, cytotoxicity assays reveal that the designed composite hydrogels are non-toxic. More importantly, these hydrogels support cell survival, proliferation, and migration. Together, this work opens up a new avenue to build polysaccharide hydrogel platforms for tissue engineering., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A bacilliform virus was isolated from yellow catfish in China. This virus can directly adapt in cultures of EPC cells. The virus particles, which were rod-shaped approximately 120 nm long and 20 nm wide, were visible in the cytoplasm of EPC cells. The full-length genome of this virus is 26,985 nt. The genome contains four open reading frames that encode polyprotein1ab, spike glycoprotein, M protein, and N protein. There was a putative slippery sequence 14861 UUUAAAC 14867 , which could be modeled into an RNA pseudoknot structure. The predicted amino acid sequence of pp1ab, S, M, and N genes shares 8.7%-40.2% homology with those of the two known Bafinivirus strains-WBV and FHMNV. Based on the viral morphology, genome organization, and sequence homology, this newly identified bacilliform virus appears to be Piscanivirus. To the best of our knowledge, this is the first report of Piscanivirus in yellow catfish and Piscanivirus in China., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Subclinical hypocalcaemia (SH) is an important metabolic disease in dairy cows that has a serious impact on production performance. The objective of this study was to investigate novel aspects of pathogenesis using proteomics technology to identify proteins that are differentially expressed in diseased and healthy animals. Dairy cows were divided into an SH group (T, n  = 10) and a control group (C, n  = 10) based on plasma calcium concentration. A total of 398 differentially expressed proteins were identified, of which 265 proteins were overlapped in the two parallel experiments. Of these, 24 differentially expressed proteins were statistically significant. Gene Ontology analysis yielded 74 annotations, including 7 cellular component, 55 biological process and 12 molecular function categories. Bioinformatics analysis indicated that calcium regulation, immune and inflammatory response, blood coagulation and complement pathway were all related to SH. Our iTRAQ/LC-MS/MS (isobaric tags for relative and absolute quantification/liquid chromatography-mass spectrometry/mass spectrometry) approach proved highly effective for plasma protein profiling of dairy cows with SH, and the results pave the way for further studies in this area.

To understand the differences in metabolic changes between cows with ovarian inactivity and estrus cows, we selected cows at 60-90 days postpartum from an intensive dairy farm. According to clinical manifestations, B-ultrasound scan, rectal examination, 10 cows were assigned to the estrus group (A) and 10 to the ovarian inactivity group (B). All plasma samples were analyzed by (1)H-nuclear magnetic resonance spectroscopy to compare plasma metabolomic profiles between the groups. We used multivariate pattern recognition to screen for different metabolites in plasma of anestrus cows. Compared with normal estrous cows, there were abnormalities in 12 kinds of metabolites in postpartum cows with ovarian inactivity (|r|> 0.602), including an increase in acetic acid (r = -0.817), citric acid (r = -0.767), and tyrosine (r = -0.714), and a decrease in low-density lipoprotein (r = 0.820), very low-density lipoprotein (r = 0.828), lipids (r = 0.769), alanine (r = 0.816), pyruvate (r = 0.721), creatine (r = 0.801), choline (r = 0.639), phosphorylcholine (r = 0.741), and glycerophosphorylcholine (r = 0.881). These metabolites were closely related to abnormality of glucose, amino acid, lipoprotein and choline metabolism, which may disturb the normal estrus. The decrease in plasma creatine and the increase in tyrosine were new changes for ovarian inactivity of postpartum cows. The decrease in plasma creatine and choline and the increase in tyrosine and p-hydroxyphenylalanine in cows with ovarian inactivity provide new directions for research on the mechanism of ovarian inactivity in cows., (Copyright © 2016 Elsevier Inc. All rights reserved.)

When abrin-a was combined with several polyclonal antibodies (PAb), the detection limit could be increased. In this way, a monoclonal antibody (capture) and polyclonal antibody (detection) sandwich enzyme-linked immunosorbent assay (ELISA) and a colloidal gold-PAb conjugate-based immunochromatographic assay for detection of abrin-a were developed. The ELISA had a detection limit of 3.9 ng/mL for abrin-a in standard solution and 7.8 ng/mL in soybean milk, and was more sensitive than polyclonal antibody (capture) and monoclonal antibody (detection) ELISA, which had a detection limit of 15.6 ng/mL. The test strip had a detection range of 50 to 500 ng/mL for abrin-a and a detection limit in standard solution or soybean milk samples of 50 ng/mL. However, the test strip had a reduced detection capability compared with a colloidal gold-monoclonal antibody conjugate-based immunochromatographic assay test strip, which had a lower detection limit of 10 ng/mL. The developed ELISAs and test strip show the specificity towards abrin-a and have no cross-reactivity towards abrin-b, -c, -d, ricin, or the agglutinins from either castor beans or rosary peas.

Background: Ketosis is an important metabolic disorder in dairy cows during the transition period. The urine proteomics of ketosis has not been investigated using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS)., Objective: The aim is to determine differences between urine proteomic profiles of healthy cows and those with clinical ketosis, and facilitate studies of the underlying physiological and biochemical mechanisms that lead to liver pathology in ketosis., Animals and Methods: We analyzed the urine samples of 20 cows with clinical ketosis (group 1) and 20 control cows (group 2) using SELDI-TOF-MS., Results: Thirty-nine peptide peaks differed between both groups. Polypeptides corresponding to 26 of these differential peptide peaks were identified using the SWISS-PROT protein database. We found that the peaks of 11 distinct polypeptides from the urine samples of the ketosis group were significantly reduced, compared with those of the control group as based on the Wilcoxon rank sum test. Among these were VGF (non-acronymic) protein, amyloid precursor protein, serum amyloid A (SAA), fibrinogen, C1INH, apolipoprotein C-III, cystatin C, transthyretin, hepcidin, human neutrophil peptides, and osteopontin., Conclusion: These proteins may represent novel biomarkers of the metabolic changes that occur in dairy cows with ketosis. Our results will help to better understand the physiological changes and pathogenesis observed in cows with ketosis., Clinical Importance: The SELDI-TOF-MS can be used to understand the physiological and biochemical mechanisms of ketosis and identify biomarkers of the disease.

Progesterone (P4) is a steroid gonadal hormone that is mainly produced from the corpus luteum and placenta and has various biological functions, especially reproductive regulation. It is important to establish a specific and sensitive P4 enzyme-linked immunosorbent assay (ELISA) for the study of ovary activity and reproductive disorders. Therefore, we prepared a monoclonal antibody (MAb) in a completed antigen (11α-OH-P4-HS-OVA). Based on the MAb and our previously prepared completed antigen, a highly specific and sensitive ELISA was developed. In the present study, a competitive ELISA for the determination of P4 was described in dairy cow milk. It was found that P4 concentration in milk samples from five pregnant cows was significantly higher than that from five estrus cows. The diagnosis rate for pregnancy and non-pregnancy in 54 dairy cows were 93.3% and 95.8%, respectively, at 19 to 23 days after pregnancy by detecting milk P4 concentration. In summary, the developed ELISA is a potential tool for P4 research and offers an alternative, simple, rapid technique for detecting P4, especially in future large clinical investigations on pregnancy identification and reproductive disorders in dairy farms in China.

Background: Milk fever (MF) is a common calcium metabolism disorder in perinatal cows. Currently, information regarding the detailed metabolism in cows suffering from MF is scant., Objective: The purpose was to study the metabolic profiling of serum samples from cows with MF in comparison to control cows, and thereby exploring other underlying pathological mechanisms of this disease., Animals and Methods: In the current study, we compared the serum metabolomic profile of dairy cows with MF (n = 8) to that of healthy dairy cows (n = 24) using a 500-MHz digital (1)H-nuclear magnetic resonance ((1)H-NMR) spectrometer. Based on their clinical presentation and serum calcium concentration, cows were assigned either to the control group (no MF symptoms and serum calcium concentration >2.5 mmol/L) or to the MF group (MF symptoms and serum calcium concentration <1.4 mmol/L). For statistical analysis, a one-way analysis of variance was performed., Results: We identified differences regarding nine metabolites between the two groups, among which glucose, alanine, glycerol, phosphocreatine, and gamma-aminobutyrate decreased, and β-hydroxybutyrate, acetone, pyruvate, and lysine increased in cows with MF. Most of these were carbohydrates and amino acids involved in various energy metabolism pathways., Conclusion: The different metabolites in cows with MF reflected the pathological features of negative energy balance and fat mobilization, suggesting that MF is associated with altered energy metabolism., Clinical Importance: The (1)H-NMR spectroscopy can be used to understand the pathogenesis of MF and identify biomarkers of the disease.