Simultaneous determination of five compounds of fried Radix Paeoniae Alba extract in beagle dogs plasma by Ultra Performance Liquid Chromatography Tandem Mass Spectrometry and its application in a pharmacokinetic study.

In this present study, we developed a reliable and simple ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay for the simultaneous quantification of paeoniflorin, albiflorin, oxypaeoniflorin, benzoylpaeoniflorin and isomaltopaeoniflorin in beagle dog plasma. We also analyzed the pharmacokinetics of those components after oral administration of fried Radix Paeoniae Alba (FRPA) in beagle dogs. Plasma samples were processed by protein precipitation with methanol. Chromatographic separation was performed with a Waters HSS-T3 C18 column (100 × 2.1 mm, 1.8 µm, kept at 40°C) using multiple reaction monitoring mode. A gradient elution procedure was used with solvent A (0.02% formic acid-water) and solvent B (0.02% formic acid-acetonitrile) as mobile phases. Method validation was performed as US Food and Drug Administration guidelines, and the results met the acceptance criteria. The method we establish in this experiment was successfully applied to the pharmacokinetic study after oral administration of FRPA extract to beagle dogs.

Change of Cerebral Hemodynamic Signals during the Process of Swallowing Water, Acetic Acid Solution and Salt Solution in Healthy Adults: An fNIRS Study.

BACKGROUND: The aim of this preliminary study was to investigate the similarities and differences in cortical activation patterns during the swallowing of water, acetic acid solution and salt solution in healthy adults using functional near-infrared spectroscopy (fNIRS). METHODS: Eighteen right-handed healthy adults were recruited and fNIRS was used to measure changes in concentrations of oxygenated hemoglobin (HbO2) and deoxygenated hemoglobin (HbR) in 35 channels during the swallowing of water, acetic acid solution and salt solution. The task-based experiment used a block-design in which participants alternated between resting blocks of 30 s and task blocks (swallowing water, acetic acid solution, or salt solution) of 30 s, repeated six times. Participants remained still during the resting blocks and performed a swallowing action every 6 s during the task blocks. Data preprocessing was conducted using NirSpark software and statistical analyses were performed using either one-sample or paired t-tests to compare differences in cortical activation in healthy participants between swallowing a water and acetic acid solution, as well as swallowing a water and salt solution. RESULTS: Compared to the resting state, nine brain regions, including primary somatosensory cortex (S1), primary motor cortex (M1), dorsolateral prefrontal cortex (DLPFC), Wernicke's area, premotor cortex (PMC), supplementary motor area (SMA), inferior frontal cortex (IFC), orbitofrontal cortex (OFC) and frontopolar area, were commonly activated during the process of swallowing water, acetic acid solution, and salt solution. The DLPFC, Broca's area, PMC and SMA showed higher activation levels during the swallowing of acetic acid solution when compared to swallowing water, with statistically significant differences (p < 0.05). The frontopolar area and OFC exhibited higher activation during the swallowing of salt solution when compared to water, also with statistically significant differences (p < 0.05). CONCLUSIONS: Multiple brain regions were activated during the swallowing of water, acetic acid solution and salt solution in healthy adults. Moreover, swallowing acetic acid solution leads to stronger activation of DLPFC, Broca's area, PMC and SMA, while swallowing salt solution leads to stronger activation of the frontopolar area and OFC.

[Determination of nine components of fried Ziziphi Spinosae Semen extract in beagle dog plasma by UPLC-MS/MS and its application in pharmacokinetic research].

This study established a convenient, rapid, and sensitive ultra-performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS) method for simultaneous determination of magnoflorine,(R)-coclaurine, vicenin Ⅱ, isospinosin, spinosin, swertisin, N-nornuciferine, 6-feruloylspinosin, and jujuboside B in beagle dog plasma after oral administration of fried Ziziphi Spinosae Semen(FZSS) extract. The Waters HSS-T3 C_(18) column(2.1 mm×100 mm, 1.8 µm) was used. The methanol-aqueous solution(containing 0.01% formic acid) was adopted as the mobile phase for gradient elution. The nine components and two internal standards were completely separated within 8 min. The mass spectrometry detection was performed in multiple reaction monitoring(MRM) mode by positive and negative ion switching of electrospray ionization. The analytical method was validated in terms of specificity, selectivity, linear range, accuracy, precision, recovery, matrix effect, and stability. It could meet the requirement of pharmacokinetic research after oral administration of FZSS extract to beagle dogs. The results showed that the time to reach the peak concentration(T_(max)) of magnoflorine,(R)-coclaurine, vicenin Ⅱ, isospinosin, spinosin, 6-feruloylspinosin, and jujuboside B was 2.40-3.20 h, and the elimination halflife(t_(1/2)) was 2.08-6.79 h after a single-dose oral administration of FZSS to beagle dogs. The exposure of magnoflorine and spinosin was high, with a peak concentration(C_(max)) of 76.7 and 31.5 ng·mL~(-1) and an area under the curve(AUC_(0-∞)) of 581 and 315 ng·h·mL~(-1), respectively. The exposure of the remaining five compounds was lower, with a C_(max) of 0.81-13.0 ng·mL~(-1) and an AUC_(0-∞) of 6.00-106 ng·h·mL~(-1). This study provides a reference for the follow-up research of FZSS.

Correlation between gut microbiome and cognitive impairment in patients undergoing peritoneal dialysis.

BACKGROUND: Growing evidence has demonstrated that patients undergoing peritoneal dialysis (PD) are more likely to experience cognitive impairment than patients with non-dialysis end-stage renal disease (ESRD); however, the underlying mechanisms remain unclear. This study aimed to identify the role and predictive significance of gut microbiome alterations in PD-associated cognitive impairment. METHODS: A total of 29 non-dialysis ESRD patients and 28 PD patients were enrolled in this study and divided into subgroups according to the Montreal Cognitive Assessment (MoCA). Faecal samples were analyzed using 16 S rRNA. Mini-Mental State Examination (MMSE) and MoCA scores were used to assess the degree of cognitive impairment in patients. RESULTS: The 16 S rRNA analysis demonstrated differences in gut microbiome abundance and structure between PD and non-dialysis ESRD patients and between PD patients with cognitive impairment (PCI) and PD patients with normal cognition (PNCI). At family and genus levels, Prevotellaceae exhibited the greatest structure difference, while Lactobacillus exhibited the greatest abundance difference between PCI and PNCI. Altered microbiota abundance significantly correlated with cognitive function and serum indicators in PD. In addition, different modules related to fatty acid, lipid, pantothenate, and coenzyme A biosynthesis, and tyrosine and tryptophan metabolism were inferred from 16 S rRNA data between PCI and PNCI. Both groups could be distinguished using models based on the abundance of Lactobacillaceae (Area under curve [AUC] = 0.83), Actinomycetaceae (AUC = 0.798), and Prevotellaceae (AUC = 0.778) families and Lactobacillus (AUC = 0.848) and Actinomyces (AUC = 0.798) genera. CONCLUSION: Gut microbiome evaluation could aid early cognitive impairment diagnosis in patients undergoing PD.

Low-Temperature 3D Printing Technology of Poly (Vinyl Alcohol) Matrix Conductive Hydrogel Sensors with Diversified Path Structures and Good Electric Sensing Properties.

Novel and practical low-temperature 3D printing technology composed of a low-temperature 3D printing machine and optimized low-temperature 3D printing parameters was successfully developed. Under a low-temperature environment of 0--20 °C, poly (vinyl alcohol) (PVA) matrix hydrogels including PVA-sodium lignosulphonate (PVA-LS) hydrogel and PVA-sodium carboxymethylcellulose (PVA-CMC) hydrogel exhibited specific low-temperature rheology properties, building theoretical low-temperature 3D printable bases. The self-made low-temperature 3D printing machine realized a machinery foundation for low-temperature 3D printing technology. Combined with ancillary path and strut members, simple and complicated structures were constructed with high precision. Based on self-compiling G-codes of path structures, layered variable-angle structures with high structure strength were also realized. After low-temperature 3D printing of path structures, excellent electrical sensing functions can be constructed on PVA matrix hydrogel surfaces via monoplasmatic silver particles which can be obtained from reduced reactions. Under the premise of maintaining original material function attributes, low-temperature 3D printing technology realized functionalization of path structures. Based on "3D printing first and then functionalization" logic, low-temperature 3D printing technology innovatively combined structure-strength design, 3D printable ability and electrical sensing functions of PVA matrix hydrogels.

Safe Rice Production in Cd-Contaminated Paddy Soil: Strategy and Environmental Implications.

This field study explored safe rice production in Cd-contaminated red paddy soil by application of the combined Si-/Se- containing foliar inhibitors (Si or Se) and the mixture amendments of quicklime (Q), polyacrylamide (A), or/and sepiolite (S) at low (1) and high (2) application rates. The results showed that all treatments increased soil pH and decreased total P and soil organic matter (excluding QSe2). With the increasing application rates, QAS significantly decreased the available Cd because of the enhanced stabilization, while QSi and QSe significantly increased the available Cd because of the inhibited plant uptake. After remediation, QA1, QSi2, and QSe2 most effectively decreased the uptake Cd by rice to meet the threshold of National Food Safety Standard of China. The treatments excluding Q1, QA1, QSi1, and QSi2 did not dramatically change the bacterial community structure in soil. Collectively, QSe2 was recommended for remediating Cd-contaminated red paddy soil.

Simultaneous determination and pharmacokinetic study of six components in beagle dog plasma by UPLC-MS/MS after oral administration of Astragalus Membranaceus aqueous extract.

Astragalus Membranaceus (AM) is widely applied in Chinese herbal compound formulas for treating various kinds of diseases. However, relative pharmacokinetics data on AM in nonrodents is still lacking. Here, an UPLC-MS/MS method for determining the six main compounds of AM was developed. The chromatographic separation was carried out by a Waters Acquity UPLC HSS T3 column (100 × 2.1 mm, 1.8 µm) with gradient elution of water-formic acid (99.98:0.02, v/v) and acetonitrile-formic acid (99.98:0.02, v/v) at a flow rate of 0.3 ml/min within 11 min. Analyses of all compounds were conducted in multiple reaction monitoring mode with a positive/negative ion-switching mode of an electrospray ionization source in a single run. The analytical method was validated in terms of specificity, linearity, accuracy, precision, stability, etc. The method showed excellent linearity (r > 0.999) over certain concentration ranges. The intra-day and inter-day precisions were evaluated, and the RSD values were <12.4%. Furthermore, the validated method was successfully applied to determine the six components in plasma after oral administration of AM aqueous extract to beagle dogs and the pharmacokinetic parameters were obtained. Together, this study provides a reference for medication in the clinical practice of AM.

Simultaneous determination of periplocin, periplocymarin, periplogenin, periplocoside M and periplocoside N of Cortex Periplocae in rat plasma and its application to a pharmacokinetic study.

A sensitive and specific ultra-performance liquid chromatographic-tandem mass spectrometric method was developed and validated to simultaneously determine periplocin, periplocymarin (PM), periplogenin (PG), periplocoside M (PSM) and periplocoside N (PSN) in rat plasma. Acetonitrile was employed to precipitate plasma with appropriate sensitivity and acceptable matrix effects. Chromatographic separation was performed using a Waters HSS T3 column with a gradient elution using water and acetonitrile both containing 0.1% formic acid and 0.1 mm ammonium formate within 8 min. Detection was performed in positive ionization mode using multiple reaction monitoring. The method was fully validated in terms of selectivity, linearity, accuracy, precision, recovery, matrix effects and stability. Using this method, the concentrations of periplocin, PM, PG, PSM and PSN were established after oral administration of Cortex Periplocae extract to rats, and the pharmacokinetic characteristics of periplocin, PM, PG, PSM and PSN were assessed. Generally, PM, PG, PSM and PSN were eliminated slowly and their half-lives were all >8 h. In addition, the systemic exposure of PSM showed significant differences between genders with more than 10 times higher area under the concentration-time curve in female rats than in male rats. The findings of this study provide useful information for further research on Cortex Periplocae.

Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking.

Glycogen metabolism commonly altered in cancer is just beginning to be understood. Phosphoglucomutase 1 (PGM1), the first enzyme in glycogenesis that catalyzes the reversible conversion between glucose 1-phosphate (G-1-P) and glucose 6-phosphate (G-6-P), participates in both the breakdown and synthesis of glycogen. Here, we show that PGM1 is down-regulated in hepatocellular carcinoma (HCC), which is associated with the malignancy and poor prognosis of HCC. Decreased PGM1 expression obstructed glycogenesis pathway, which leads to the increased flow of glucose into glycolysis, thereby promoting tumor cell proliferation and HCC development. The loss of forkhead box protein J2 (FOXJ2), at least partly due to low genomic copy number in HCC, releases cellular nucleic acid-binding protein (CNBP), a nucleic acid chaperon, to bind to and promote G-quadruplex formation in PGM1 promoter and therefore decreases PGM1 expression. In addition, integrated analyses of PGM1 and FOXJ2 expression provide a better prediction for the malignance and prognosis of HCC. This study establishes a tumor-suppressive role of PGM1 by regulating glucose trafficking and uncovers a novel regulatory mechanism of PGM1 expression.

[Pharmacokinetic characteristics of psoralen,isopsoralen,psoralenoside and isopsoralenoside in rats after oral administration of Psoraleae Fructus extract].

Coumarins are the main active components in Psoraleae Fructus. To study the multi-component pharmacokinetics of Psoraleae Fructus, this study established a sensitive and rapid ultra-pressure liquid chromatography coupled to tandem mass spectrometry(UPLC-MS/MS) method for simultaneous determination of psoralen, isopsoralen, psoralenoside, and isopsoralenoside in rat plasma. After validation, the method was applied to the investigation of pharmacokinetics of psoralen, isopsoralen, psoralenoside, and isopso-ralenoside in rats after single and multiple administration of Psoraleae Fructus extract. The results revealed that the exposure of psoralen and isopsoralen in rat plasma was high after a single intragastric administration of Psoraleae Fructus extract, with an AUC_(0-∞) of 443 619-582 680 and 167 314-276 903 ng·mL~(-1)·h~(-1), respectively. Compared with these two compounds, the exposure of psoralenoside and isopsoralenoside was lower with marked gender difference. After 7-day administration of Psoraleae Fructus extract to rats, the AUC_(0-∞) of psoralen and isopsoralen was 29 701-81 783 and 39 234-89 914 ng·mL~(-1)·h~(-1), respectively, which was significantly lower than that at the first day(P<0.05), and that of psoralenoside and isopsoralenoside was 7 360-19 342 and 8 823-45 501 ng·mL~(-1)·h~(-1), respectively. There was no significant gender difference in exposure of psoralenoside and isopsoralenoside in male and female rats. However, the exposure of psoralenoside and isopsoralenoside in male rats was reduced(P<0.05), and the t_(1/2) and mean residence time(MRT) were shortened, suggesting that the removal of these two compounds from the body was accelerated.

[Rapid and simultaneous determination of 10 active components of Psoraleae Fructus in beagle dog plasma using UPLC-MS/MS and its application in pharmacokinetic study].

An UPLC-MS/MS method for rapid and simultaneous determination of psoralen, isopsoralen, apigenin, genistein, bavaisoflavone, neobavaisoflavone, bavachin, bavachinin, psoralenoside, and isopsoralenoside of Psoraleae Fructus in beagle dog plasma was established, and then the method was applied in the pharmacokinetic study after oral administration of Psoraleae Fructus extract to beagle dogs. The pharmacokinetic parameters were calculated by the software of WinNonlin. A Waters HSS-T3 column(2.1 mm×100 mm,1.8 µm)was used for liquid chromatography separation with acetonitrile-water(containing 0.004% formic acid) as the mobile phase for gradient elution.The mass spectrometry was detected using electrospray ion source(ESI) under multi-reaction monitoring mode(MRM), as well as positive ion mode. Analysis time only takes 8.5 min. The methodological study in terms of specificity, accuracy, precision, linear range, recovery, matrix effect, and stability, was validated. The LC-MS analysis method established in this experiment was simple, specific, accurate, reliable, and meet the requirement of pharmacokinetic study in plasma after administration of Psoraleae Fructus extract to beagle dogs. Six beagle dogs received intragastric administration of Psoraleae Fructus extract, T_(max) of 10 chemical components is 1.92-5.67 h; among them, C_(max) of psoralen, isopsoralen, psoralenoside and isopsoralenoside is 383-3 613 ng·mL~(-1), and AUC_(0-∞) is 3 556-18 949 ng·h·mL~(-1), t_(1/2) is 2.45-4.83 h. C_(max) of the remaining six compounds is 0.81-19.9 ng·mL~(-1), AUC_(0-∞ )is 6.54-178 ng·h·mL~(-1), t_(1/2) is 2.95-7.29 h. The UPLC-MS/MS analysis method established in this study was proved to be accurate and sensitive that it can be applied to the pharmacokinetic study of beagle dogs after oral administration of Psoraleae Fructus extract.

Exploring and characterizing a novel combination of paeoniflorin and talatizidine for the treatment of rheumatoid arthritis.

Wutou Decoction (WTD) achieves favorable therapeutic response in treating rheumatoid arthritis (RA), especially for wind-cold-dampness stimulating RA. However, its material basis and molecular mechanisms remain unclear. To address this problem, the main bioactive compounds (BACs) of WTD against RA and the candidate targets were identified in the current study via transcriptional regulatory network analysis, computational structure-based methods, as well as in vivo and in vitro experimental validations. As a result, we successfully established a RA rat model named AIA-S, which simulated the clinical manifestations and pathological changes of wind-cold-dampness stimulating RA, and also displayed the distinctive characteristics and biological basis of inflammatory-immune system imbalance and abnormal energy metabolism changes. In addition, ALOX15B-PPAR-γ-PTGS2-FGF2-IL-1ß-c-JUN-MMP13-TGF-ß1 signal axis, involved into thermogenesis and energy metabolism, as well as maintaining the balance of inflammation-immune system, was identified as a candidate target of WTD against RA, according to the transcriptional regulatory network analysis on "RA-related gene-WTD-effective gene interaction network". Moreover, Paeoniflorin (PAE) and Talatizidine (TLT) were demonstrated to be the main BACs of WTD against RA for the following reasons: firstly, both PAE and TLT were the BACs of WTD according to ADME analysis in silico and the pharmacokinetics analysis in vivo. Secondly, both PAE and TLT were able to bind with PPAR-γ, c-JUN, MMP13 and TGF-ß1, which were the candidate targets of WTD against RA, with the strong binding affinity. Thirdly, the PAE and TLT combination exerted significant therapeutic effects on AIA-S rats through reversing the imbalance of inflammatory-immune system, and the disturbance of thermogenesis and energy metabolism, which were similar to WTD. More importantly, the administration of TLT or PAE alone didn't exert as prominently therapeutic effects as that of the two-BAC-combination did. Fourthly, the PAE and TLT combination promoted adipogenesis and lipogenesis by upregulating the PPAR-γ-induced lipogenic proteins. In conclusion, this study identified PAE and TLT as the main BACs of WTD in alleviating the severity of RA, and also developed a novel combination of PAE and TLT as a promising candidate drug for RA therapy.

Simultaneous determination of isochamaejasmin, neochamaejasmin A and aphnoretinin rat plasma by UPLC-MS/MS and its application to a pharmacokinetic study of Stellera chamaejasme L. extract.

Isochamaejasmin, neochamaejasmin A and daphnoretin derived from Stellera chamaejasme L. are important because of their reported anticancer properties. In this study, a sensitive UPLC-MS/MS method for the determination of isochamaejasmin, neochamaejasmin A and daphnoretin in rat plasma was developed. The analyte and IS were separated on an Acquity UPLC HSS T3 column (100 × 2.1 mm, 1.8 µm) using gradient elution with the mobile phase of aqueous solution (methanol-water, 1:99, v/v, containing 1 mm formic acid) and organic solution (methanol-water, 99:1, v/v, containing 1 mm formic acid) at a flow rate of 0.3 mL/min. Multiple reaction monitoring mode with negative electrospray ionization interface was carried out to detect the components. The method was validated in terms of specificity, linearity, accuracy, precision, stability, etc. Excellent linear behavior was observed over the certain concentration ranges with the correlation coefficient values >0.99. Intra- and inter-day precisions (RSD) were <6.7% and accuracy (RE) ranged from -7.0 to 12.0%. The validated method was successfully applied to investigate the pharmacokinetics of three chemical ingredients after oral administration of S. chamaejasme L. extract to rats.

[Qualitative characterization of flavonoids in Scutellariae Radix by using PREC-IDA-EPI].

Flavonoids are the most abundant constituents and induce these the rapeutic effects against inflammation, gastrointestinal infections, cardiovascular diseases, and respiratory. Most of these flavonoids have low content in Scutellarie Radix. It was difficult to detect some minor compounds by using LC-MS method with full scan. Based on the review of flavonoids that had been extracted from Scutellariae Radix, a method with PREC-IDA-EPI technique was developed and applied to Scutellariae Radix by using UPLC-MS/MS. A total of 97 flavonoids were identified, including 29 aglycones and 68 O-glycosides. This study laid the foundation for pharmacodynamicss of Scutellariae Radix.It is believed that an individual detection scheme based on the PREC-IDA-EPI technique could be used to identify unknown compounds.

[Analysis of clinical characteristics and risk factors of obstructive sleep apnea hypopnea syndrome with hypertension].

OBJECTIVE: To study the risk factors contributing to the development of hypertension in patients with obstructive sleep apnoea hypopnea syndrome (OSAHS), and the clinical characteristics of OSAHS with hypertension. METHODS: A total of 2397 OSAHS patients aged above 30 years old and diagnosed by the sleep-disordered breathing center of Guangxi between July 2012 and August 2015 were recruited. OSAHS patients with new-onset hypertension (OSAHS with hypertension group) and those without hypertension (simple OSAHS group) were identified and their clinical data, including general status, family history of hypertension or snoring, Epworth Sleepiness Scale (ESS) score for daytime sleepiness, physical examination findings, and polysomnography monitoring data were collected. OSAHS patients with new-onset hypertension (n=101) and OSAHS patients without hypertension (n=202) matched by age and body mass index (BMI) (age difference, 2 years; BMI difference, 1.5 kg/m(2)) were recruited in the OSAHS with hypertension group and the simple OSAHS group. A case-control study was used to compare the clinical characteristics of these two groups, and univariate and multivariate Logistic regression were used to analyze all the factors contributing to hypertension development besides age and BMI. RESULTS: The average age and BMI of the OSAHS with hypertension group and the simple OSAHS group were respectively (46.2±9.3), (46.2±9.2) years old and (28.2±2.8), (28.2±2.8) kg/m(2). Patients in the two groups were well-matched with respect to age and BMI (P>0.05). The systolic blood pressure (SBP) and diastolic blood pressure (DBP) in the OSAHS with hypertension group were significantly higher than those in the simple OSAHS group at the first admission to the clinic and before and after the PSG examination. ESS values in the OSAHS with hypertension group and the simple OSAHS group were respectively 10.0±6.4 and 9.2±6.3 (P>0.05). There was no significant intergroup difference in neck circumference, waist circumference, duration of snoring, family history of snoring, and family history of hypertension (P>0.05) either. The apnea-hypopnea index (AHI) and apnea index (AI) in the OSAHS with hypertension group were higher than those in the simple OSAHS group (P<0.05); the longest apnea duration (LAD), mean apnea duration (MAD), and the total time spent with oxygen saturation below 90% (T90%) in the OSAHS with hypertension group were significantly longer than those in the simple OSAHS group (P<0.05). The minimal pulse oxygen saturation (MinSpO2) in the OSAHS with hypertension group was significantly lower than that in the simple OSAHS group (P<0.05). Six factors were identified to be associated with OSAHS with hypertension through univariate analysis: AHI (OR=0.985, P=0.001), AI (OR=0.983, P<0.001), LAD (OR=0.955, P=0.013), MAD (OR=0.874, P=0.015), MinSpO2 (OR=0.874, P=0.015), T90% (OR=0.997, P=0.036). Only MinSpO2 (P<0.001, OR=0.894) was closely related to OSAHS hypertension development in the multivariate Logistic regression model. CONCLUSIONS: OSAHS patients with hypertension may show lower MinSpO2, higher AHI and AI, and longer LAD, MAD, and T90% than OSAHS patients without hypertension. MinSpO2 is probably closely related to OSAHS hypertension development.

The Noncanonical Functions of Metabolites in Tumor Progression.

Metabolic reprogramming has emerged as a prominent hallmark of cancer, characterized by substantial alterations in nutrient uptake and intracellular metabolic pathways. Consequently, intracellular metabolite concentrations undergo significant changes which can contribute to tumorigenesis through diverse mechanisms. Beyond their classical roles in regulating metabolic pathway flux, metabolites exhibit noncanonical functions that play a crucial role in tumor progression. In this review, we delve into the nonclassical functions of metabolites in the context of tumor progression, with a particular focus on their capacity to modulate gene expression and cell signaling. Furthermore, we discuss the potential exploitation of these nonclassical functions in the enhancement of cancer therapy.

LncRNA MEG3 suppresses hepatocellular carcinoma by stimulating macrophage M1 polarization and modulating immune system via inhibiting CSF-1 in vivo/vitro studies.

Hepatocellular carcinoma (HCC) is characterized by a complex tumor microenvironment (TME), and long non-coding RNAs (lncRNAs) MEG3 emerged as regulators of macrophage polarization with a negative relationship with colony-stimulating factor 1 (CSF-1). Few studies are on the interplay among MEG3, CSF-1, T helper cells (Th), and the programmed cell death protein 1 and its ligands (PD-1/PD-Ls) in TME of HCC.MEG3 expression in THP-1 macrophages, monitored polarization, and PD-1/PD-Ls expression were through flow cytometry, WB, and RT-qPCR. In co-cultures, the interaction of MEG3, macrophage, and HCC was assayed by ELISA. The invasive and migratory of HCC were assessed through experiments such as CCK-8, clonogenic assay, wound healing, and Transwell. A xenograft mouse model of HCC was established, administered with MEG3 overexpression (OE) or knockdown (KD) constructs, and monitored tumor growth. In vitro, MEG3 OE induced a robust M1 macrophage phenotype, evidenced by elevated expression of M1 markers and a significant increase in Th1 cytokines, with a concomitant decrease in Th2 cytokines. This was paralleled by reduced CSF-1 and PD-1/PD-Ls expression. In contrast, MEG3 KD promoted an M2 phenotype with increased CSF-1 and PD-1/PD-Ls expression, and an upregulation of Th2 cytokines. MEG3 OE inhibited the growth, invasion, and migration of HCC, while the opposite was observed when MEG3 was downregulated. In vivo, MEG3 OE resulted in significantly reduced tumor growth, with decreased PD-1/PD-Ls expression on macrophages and enhanced Th1 response. Conversely, MEG3 KD promoted tumor growth with increased PD-1/PD-Ls and a Th2-skewed immune response. MEG3 modulates the TME by affecting TAMs through CSF-1, thereby influencing the balance of Th1/Th2 cells and altering the expression of PD-1/PD-L1s. This study demonstrates that targeting MEG3 is an effective therapeutic strategy for HCC.

[Assessment and Source Analysis of Heavy Metal Pollution in Farmland Soil Around Tin Mine].

Studying the status and source analysis of heavy metal pollution in farmland in typical mining and processing areas is an important prerequisite for promoting farmland soil ecological restoration and farmland protection in concentrated mining areas. In this study, the heavy metal content of farmland soil around a mining area in southwest China was detected, and the pollution status, distribution law, health risks, and sources of heavy metals were studied by using the land accumulation index method, comprehensive pollution index method, kriging interpolation method, health risk assessment method, and PMF receptor model on the sampling data. The results showed that the mean values of eight heavy metals in farmland soil except Ni exceeded the local soil background values, and the results of the ground accumulation index evaluation showed that Cd and Hg were extremely polluted； Pb and As showed medium pollution-heavy pollution； and Cr, Zn, Ni, and Cu were lightly polluted. In the health risk assessment, oral ingestion was the main exposure route posing a health risk to the human body； the main element that constituted non-carcinogenic health risks was As, and the carcinogenic risks were from As and Cd. PMF model analysis showed that the contribution rate of weathering natural sources of iron-bearing ore was 28.02%, and the main factors were Ca and Fe. The contribution rate of agricultural sources was 3.02%, and the main factors were Pb and As. The contribution rate of industrial and atmospheric deposition composite sources was 33.09%, and the main factor was Hg. The contribution rate of the parent material source was 17.27%, and the main factor was Ca. The contribution rate of mining activities such as mining and smelting was 18.60%, and the main factors were Zn and Cd.

Elevated origin recognition complex subunit 6 expression promotes non-small cell lung cancer cell growth.

Exploring novel targets for non-small cell lung cancer (NSCLC) remains of utmost importance. This study focused on ORC6 (origin recognition complex subunit 6), investigating its expression and functional significance within NSCLC. Analysis of the TCGA-lung adenocarcinoma database revealed a notable increase in ORC6 expression in lung adenocarcinoma tissues, correlating with reduced overall survival, advanced disease stages, and other key clinical parameters. Additionally, in patients undergoing surgical resection of NSCLC at a local hospital, ORC6 mRNA and protein levels were elevated in NSCLC tissues while remaining low in adjacent normal tissues. Comprehensive bioinformatics analyses across various cancers suggested that ORC6 might play a significant role in crucial cellular processes, such as mitosis, DNA synthesis and repair, and cell cycle progression. Knocking down ORC6 using virus-delivered shRNA in different NSCLC cells, both primary and immortalized, resulted in a significant hindrance to cell proliferation, cell cycle progression, migration and invasion, accompanied by caspase-apoptosis activation. Similarly, employing CRISPR-sgRNA for ORC6 knockout (KO) exhibited significant anti-NSCLC cell activity. Conversely, increasing ORC6 levels using a viral construct augmented cell proliferation and migration. Silencing or knockout of ORC6 in primary NSCLC cells led to reduced expression of several key cyclins, including Cyclin A2, Cyclin B1, and Cyclin D1, whereas their levels increased in NSCLC cells overexpressing ORC6. In vivo experiments demonstrated that intratumoral injection of ORC6 shRNA adeno-associated virus markedly suppressed the growth of primary NSCLC cell xenografts. Reduced ORC6 levels, downregulated cyclins, and increased apoptosis were evident in ORC6-silenced NSCLC xenograft tissues. In summary, elevated ORC6 expression promotes NSCLC cell growth.

Number of denatured rigor cross-bridges determines the intracellular volume shrinkage in porcine muscle fibre under PSE-inducing condition.

Earlier onset of rigor mortis is a critical physiological progress occurring in the development of pale soft and exudative (PSE) meat. However, how rigor cross-bridges denature under different physiological conditions and their impacts on water-holding capacity remains unclear. To address this scientific question, we firstly established a method to quantify the extent of rigor cross-bridge denaturation using skinned fibres prepared from porcine longissimus thoracis et lumborum muscle. Effects of pH and temperature on the kinetics of rigor cross-bridge denaturation, actomyosin denaturation and shrinkage of muscle fibre were studied. We then manipulated the number of rigor cross-bridges before the denaturation condition was initiated (pH 5.5, 38 °C). Results suggested that the loss of water-holding capacity in PSE meat is determined by the number of denatured rigor cross-bridges. Physiochemical analysis on myofibrils demonstrated that increase in protein oxidation, surface hydrophobicity and loss of electrostatic repulsive force between myofibrils may be involved in the mechanism.