This study aims to investigate the ameliorating effect of Corni Fructus(CF) on the myocardial ischemic injury and the pharmacokinetic properties of characteristic components of CF. The mouse model of isoproterenol-induced myocardial ischemia was established and administrated with the aqueous extract of CF. The general efficacy of CF in ameliorating the myocardial ischemic injury was evaluated based on the cardiac histopathology and the levels of myocardial injury markers: creatine kinase isoenzyme(CK-MB) and cardiac troponin I(cTn-I). The metabolomics analysis was carried out for the heart and serum samples of mice to screen the biomarkers of CF in ameliorating the myocardial ischemic injury and then the predicted biomarkers were submitted to metabolic pathway enrichment. The pharmacokinetic analysis was performed for morroniside, loganin, and cornuside Ⅰ in mouse heart and serum samples to obtain the pharmacokinetic parameters of these components. The pharmacokinetic parameters were then integrated on the basis of self-defined weighting coefficients to simulate an integrated pharmacokinetic profile of CF iridoid glycosides in the heart and serum of the mouse model of myocardial ischemia. The results indicated that CF reduced the pathological damage to cardiac cells and tissue(hematoxylin-eosin staining) and lowered the levels of CK-MB and cTn-I in the serum of the mouse model of myocardial ischemia(P<0.01). Metabolomics analysis screed out 31 endogenous metabolites in the heart and 35 in the serum as biomarkers of CF in ameliorating the myocardial ischemic injury. These biomarkers were altered by modeling and restored by CF. Six metabolic pathways in the heart and 5 in the serum were enriched based on these metabolic markers. The main integrated pharmacokinetic parameters of CF iridoid glycosides were T_(max)=1 h, t_(1/2)=(1.52±0.05) h in the heart and T_(max)=1 h, t_(1/2)=(1.56±0.50) h in the serum. Both concentration-time curves showed a double-peak phenomenon. In conclusion, CF demonstrated the cardioprotective effect by regulating metabolic pathways such as taurine and hypotaurine metabolism, and pantothenic acid and coenzyme A biosynthesis. The integrated pharmacokinetics reflect the general pharmacokinetic properties of characteristic components in CF.
Animals ; Cornus/chemistry* ; Mice ; Metabolomics ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Myocardial Ischemia/metabolism* ; Humans ; Troponin I/metabolism* ; Myocardium/pathology* ; Disease Models, Animal ; Biomarkers/metabolism* ; Creatine Kinase, MB Form/metabolism*

Objective: To investigate the clinicopathological features and differential diagnosis of olfactory carcinoma (OC). Methods: Twenty-one cases of sinonasal tumors, including those initially diagnosed as olfactory neuroblastoma (ONB) and those with uncertain diagnosis, were collected from the Department of Pathology, the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) from January 2016 to August 2022, among which 3 cases were reclassified as OC. The clinicopathological features were investigated, and the remaining 18 cases were used as control. Results: Of the three OC patients, 2 were male and 1 was female, with an average age of 57 years ranging from 35 to 74 years. Microscopically, the tumor cells were arranged in solid, nested or lobulated patterns with occasional palisading around the solid nests. The stroma was highly vascular with focal neurofibrillary areas. There were prominent rosettes or pseudorosettes formation. The tumor cells were mainly ovoid to spindly with scant to moderate amount of cytoplasm, one or several small nucleoli, and fine chromatin content. Brisk mitotic figures were seen. In all 3 cases of OC, there were scanty atypical glands and some were ciliated. Immunohistochemically, at least one epithelial marker and neuroendocrine marker were diffusely expressed in the tumor. Some of the tumor cells were positive for p40 and p63, and the sustentacular cells showed the expression of S-100 protein. All cases tested were negative for NUT, CD99 and desmin, with intact expression of SMARCA4 (BRG1) and SMARCB1 (INI-1). Ki-67 proliferation index varied from 20% to 80%. Follow-up after 16-18 months showed no mortality with tumor recurrence from 1 patient after 16 months. Conclusion: OC is a rare sinonasal tumor with neuroepithelial differentiation, its histomorphology is diverse, and the combination of immunohistochemical markers is essential for appropriate diagnosis.
Humans ; Male ; Female ; Middle Aged ; Paranasal Sinus Neoplasms/chemistry* ; Biomarkers, Tumor/metabolism* ; Carcinoma/chemistry* ; Diagnosis, Differential ; S100 Proteins ; DNA Helicases/metabolism* ; Nuclear Proteins/metabolism* ; Transcription Factors/metabolism*

The dry root and rhizome of Panax ginseng C. A. Mey has garnered much interest owing to its medicinal properties against diabetes and cardiovascular diseases. In this study, an ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS)-based metabolomics approach was used to illustrate the therapeutic mechanisms of ginseng extract on the serum and urinary metabolic profiles in streptozotocin-induced type 1 diabetes mellitus (T1DM) rats. Pharmacological and renal parameters in response to the administration of ginseng were also evaluated. In total, 16 serum endogenous metabolites and 14 urine endogenous metabolites, including pyruvic acid, indoleacetic acid, and phenylacetylglycine, were identified as potential biomarkers for diabetes. Pathway enrichment and network analysis revealed that the biomarkers modulated by ginseng were primarily involved in phenylalanine and pyruvate metabolism, as well as in arginine biosynthesis. Moreover, the levels of several renal injury-related biomarkers in T1DM rats were significantly restored following treatment with ginseng. The administration of the extract helped maintain tissue structure integrity and ameliorated renal injury. The findings suggest that the regulatory effect of ginseng extract on T1DM involves metabolic management of diabetic rats, which subsequently attenuates T1DM-induced early renal dysfunction.
Animals ; Biomarkers ; Chromatography, High Pressure Liquid/methods* ; Diabetes Mellitus, Experimental/metabolism* ; Diabetes Mellitus, Type 1/drug therapy* ; Kidney ; Metabolomics/methods* ; Panax/chemistry* ; Plant Extracts/pharmacology* ; Rats

Immune-based therapies have experienced a pronounced breakthrough in the past decades as they acquired multiple US Food and Drug Administration (FDA) approvals for various indications. To date, six chimeric antigen receptor T cell (CAR-T) therapies have been permitted for the treatment of certain patients with relapsed/refractory hematologic malignancies. However, several clinical trials of solid tumor CAR-T therapies were prematurely terminated, or they reported life-threatening treatment-related damages to healthy tissues. The simultaneous expression of target antigens by healthy organs and tumor cells is partly responsible for such toxicities. Alongside targeting tumor-specific antigens, targeting the aberrantly glycosylated glycoforms of tumor-associated antigens can also minimize the off-tumor effects of CAR-T therapies. Tn, T, and sialyl-Tn antigens have been reported to be involved in tumor progression and metastasis, and their expression results from the dysregulation of a series of glycosyltransferases and the endoplasmic reticulum protein chaperone, Cosmc. Moreover, these glycoforms have been associated with various types of cancers, including prostate, breast, colon, gastric, and lung cancers. Here, we discuss how underglycosylated antigens emerge and then detail the latest advances in the development of CAR-T-based immunotherapies that target some of such antigens.
Antigens, Neoplasm/chemistry* ; Biomarkers, Tumor/metabolism* ; Glycosylation ; Hematologic Neoplasms/drug therapy* ; Humans ; Immunotherapy, Adoptive/methods* ; Male ; Neoplasm Recurrence, Local/metabolism* ; Receptors, Chimeric Antigen ; T-Lymphocytes ; United States

Ginseng has been used to treat Qi-deficiency syndrome up to now, while the therapeutic mechanism is still unclear. In order to explore the mechanism of ginseng in the treatment of Qi-deficiency constitution, the untargeted metabonomics with blood was studied based on rapid resolution high performance liquid chromatography-quadrupole time-of-flight mass spectrometry(RRLC-Q-TOF-MS). In the results, 13 potential biomarkers were found and identified, which mainly involved in the body's antioxidant and immune functions and energy, glycerol, fatty acid, sugar metabolism and bile acid metabolism. The results of blood biochemical analysis also indicated that ginseng could regulate the body's energy metabolism, immune functions and antioxidant capacity in spleen-Qi deficiency constitution. This study revealed the mechanism of ginseng in the treatment of spleen-Qi deficiency using the blood metabonomics, which could provide technological support and scientific basis for further research on ginseng treatment of Qi-deficiency.
Antioxidants ; Biomarkers/blood* ; Chromatography, High Pressure Liquid ; Drugs, Chinese Herbal/therapeutic use* ; Energy Metabolism ; Humans ; Immune System ; Medicine, Chinese Traditional ; Metabolomics ; Panax/chemistry* ; Qi ; Spleen

Proteases are important molecules that are involved in many physiological and pathological processes of the human body, such as growth, apoptosis and metastasis cancer cells. They are potential targets in cancer diagnosis and biotherapy. In this study, we analyzed the salivary protease spectrum of patients with oral squamous cell carcinoma (OSCC), oral benign masses and chronic periodontitis, as well as that of health, using human protease array kits, enzyme-linked immunosorbent assay, western blot and immunofluorescence. The salivary protease spectrum was found to be associated with oral diseases. For example, the saliva of patients with OSCC contained increased numbers of proteases than those of other oral diseases and health. The levels of matrix metalloproteinase (MMP)-1, MMP-2, MMP-10, MMP-12, A disintegrin and metalloprotease (ADAM)9, A disintegrin and metalloprotease with thrombospondin type 13 motifs (ADAMST13), cathepsin V and kallikrein 5 in the saliva of patients with OSCC were significantly increased compared with those of other groups. Taking MMP-1, cathepsin V, kallikrein 5 and ADAM9 as biomarkers of OSCC, cutoff values were199, 11.34, 9.29 and 202.55 pg·mL, respectively. From the area under the curve, sensitivity and specificity, the combination of cathepsin V/kallikrein5/ADAM9 was an optimal biomarker for diagnosing OSCC. Thus, analysis of the salivary protease spectrum may be an innovative and cost-efficient approach to evaluating the health status of the oral cavity. Specifically, increases in cathepsin V, kallikrein 5 and ADAM9 may be useful biomarkers in the screening and diagnosis of OSCC.
ADAM Proteins ; Biomarkers, Tumor ; analysis ; Carcinoma, Squamous Cell ; diagnosis ; metabolism ; Humans ; Matrix Metalloproteinase 9 ; analysis ; Membrane Proteins ; Mouth Neoplasms ; diagnosis ; metabolism ; Saliva ; chemistry

OBJECTIVE: To evaluate the effects of Celastrus Orbiculatus extracts (COE) on metastasis in hypoxia-induced hepatocellular carcinoma cells (HepG2) and to explore the underlying molecular mechanisms. METHODS: The effect of COE (160, 200 and 240 µ g/mL) on cell viability, scratch-wound, invasion and migration were studied by 3-4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2-H-tetrazolium bromide (MTT), scratch-wound and transwell assays, respectively. CoCl was used to establish a hypoxia model in vitro. Effects of COE on the expressions of E-cadherin, vimentin and N-cadherin were investigated with Western blot and immunofluorescence analysis, respectively. RESULTS: COE inhibited proliferation and metastasis of hypoxia-induced hepatocellular carcinoma cells in a dose-dependent manner (P<0.01). Furthermore, the expression of epithelial-mesenchymal transition (EMT) related markers were also remarkably suppressed in a dose-dependent manner (P<0.01). In addition, the upstream signaling pathways, including the hypoxia-inducible factor 1 α (Hif-1 α) and Twist1 were suppressed by COE. Additionally, the Hif-1 α inhibitor 3-5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), potently suppressed cell invasion and migration as well as expression of EMT in hypoxia-induced HepG2 cells. Similarly, the combined treatment with COE and YC-1 showed a synergistic effect (P<0.01) compared with the treatment with COE or YC-1 alone in hypoxia-induced HepG2 cells. CONCLUSIONS COE significantly inhibited the tumor metastasis and EMT by suppressing Hif-1 α/Twist1 signaling pathway in hypoxia-induced HepG2 cell. Thus, COE might have potential effect to inhibit the progression of HepG2 in the context of tumor hypoxia.
Biomarkers, Tumor ; metabolism ; Carcinoma, Hepatocellular ; drug therapy ; pathology ; Celastrus ; chemistry ; Cell Hypoxia ; drug effects ; Cell Proliferation ; drug effects ; Cell Shape ; drug effects ; Cobalt ; Down-Regulation ; drug effects ; Epithelial-Mesenchymal Transition ; drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms ; drug therapy ; pathology ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Neoplasm Proteins ; metabolism ; Plant Extracts ; pharmacology ; therapeutic use ; Signal Transduction ; drug effects

Seminal plasma is a rich source of proteins and serves as an ideal sample for proteomic analysis of male infertility. In varicocele-associated infertility, the contributory role of seminal plasma proteins specific to unilateral and bilateral varicocele is not clear. Furthermore, there is a lack of specific protein biomarker to differentiate bilateral from unilateral varicocele. The main objective is to identify the differentially regulated molecular and cellular pathways in bilateral varicocele. Furthermore, we intend to identify seminal plasma biomarkers to differentiate bilateral and unilateral varicocele patients in comparison with fertile healthy men. Global proteomic analysis of seminal plasma proteins has identified the functionality of differentially expressed proteins (DEPs) in varicocele patients. Bioinformatic analysis has revealed response to reactive oxygen species and oxidative stress, and tissue homeostasis as top process pathways that are affected in bilateral varicocele patients compared to fertile healthy men. In comparison with unilateral varicocele patients, inflammatory response pathways were dysregulated, especially interleukin 6 (IL-6) signaling and Janus kinase-signal transducer and activator of transcription (Jak-STAT) pathways, in bilateral varicocele patients, owing to the involvement of underexpressed DEPs. Key DEPs associated with oxidative stress (peroxiredoxin 2; PRDX2), DNA fragmentation (fatty acid synthase; FASN), and inflammatory response (fibronectin 1; FN1) validated by western blot analysis revealed differential expression of these proteins in unilateral and bilateral varicocele groups. Altered expression of DEPs and its association with key processes show that the seminal plasma homeostasis is compromised in bilateral varicocele patients. Furthermore, we propose PRDX2, FASN, and FN1 as potential noninvasive seminal plasma markers for the differentiation of unilateral and bilateral varicocele patients.
Biomarkers/analysis* ; Blotting, Western ; Humans ; Inflammation/metabolism* ; Male ; Metabolic Networks and Pathways ; Oxidative Stress ; Proteins/analysis* ; Proteomics ; Semen/chemistry* ; Varicocele/metabolism* ; Young Adult

Human seminal plasma is rich in potential biological markers for male infertility and male reproductive system diseases, which have an application value in the diagnosis and treatment of male infertility. The methods for the detection of semen biochemical markers have been developed from the manual, semi-automatic to the present automatic means. The automatic detection of semen biochemical markers is known for its advantages of simple reagent composition and small amount of reagents for each test, simple setting of parameters, whole automatic procedure with few errors, short detection time contributive to batch detection and reduction of manpower cost, simple calibration and quality control procedure to ensure accurate and reliable results, output of results in the order of the samples in favor of clinical diagnosis and treatment, and open reagents applicable to various automatic biochemistry analyzers. At present, the automatic method is applied in the detection of such semen biochemical markers as seminal plasma total and neutral alpha-glucosidase, acid phosphatase, fructose, γ-glutamyl transpeptidase, zinc, citric acid, uric acid, superoxide dismutase and carnitine, sperm acrosin and lactate dehydrogenase C4, and semen free elastase, which can be used to evaluate the secretory functions of the epididymis, seminal vesicle and prostate, sperm acrosome and energy metabolism function, seminal plasma antioxidative function, and infection or silent infection in the male genital tract.
Acid Phosphatase ; analysis ; Biomarkers ; analysis ; Carnitine ; analysis ; Citric Acid ; analysis ; Epididymis ; metabolism ; Fructose ; analysis ; Humans ; Infertility, Male ; diagnosis ; Isoenzymes ; L-Lactate Dehydrogenase ; Male ; Prostate ; metabolism ; Semen ; chemistry ; Seminal Vesicles ; Spermatozoa ; chemistry ; alpha-Glucosidases ; analysis ; gamma-Glutamyltransferase ; analysis

Tanreqing (TRQ), a traditional Chinese medicine (TCM) formula, can alleviate liver injury and improve liver function. Its pharmacological mechanisms of actions are still unclear due to its complex components and multi-target natures. Metabolomic study is an effective approach to investigating drug pharmacological actions, new diagnostic markers, and potential mechanisms of actions. In the present study, a new strategy was used to evaluate the protective effect of TRQ capsule against carbon tetrachloride (CCl)-induced hepatotoxicity in rats, by analyzing metabolic profiling of endogenous bile acids (BAs) along with biochemical and histological analyses. BAs concentrations were determined by ultra-performance liquid chromatography coupled with quadrupole mass spectrometry (UPLC-MS). Principal component analysis and partial least squares discriminant analysis were then employed to analyze the UPLC-MS results and compare the hepatoprotective effect of TRQ capsule in different groups at the doses of 0.36, 1.44, and 2.88 g·kg body weight, respectively. Moreover, our results suggested that taurocholic acid (TCA) and taurohyodesoxycholic acid (THDCA) were the most important biochemical markers, which were indicative of CCl-induced acute hepatic damage and hepatoprotective effect of TRQ capsule. Therefore, this new strategy would be an excellent alternative method for evaluating hepatoprotective effect and proposing potential mechanisms of action for other drugs as well.
Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Bile Acids and Salts ; blood ; metabolism ; Biomarkers ; blood ; Carbon Tetrachloride ; pharmacology ; Chemical and Drug Induced Liver Injury ; drug therapy ; metabolism ; pathology ; Chromatography, Liquid ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; therapeutic use ; Female ; Liver ; drug effects ; pathology ; Male ; Mass Spectrometry ; Metabolome ; drug effects ; Metabolomics ; Rats ; Rats, Wistar ; Taurocholic Acid ; blood ; Taurodeoxycholic Acid ; analogs & derivatives ; blood