The role of reactive oxygen species in gastric cancer.

Gastric cancer (GC) ranks fifth in cancer incidence and fourth in cancer-related mortality worldwide. Reactive oxygen species (ROS) are highly oxidative oxygen-derived products that have crucial roles in cell signaling regulation and maintaining internal balance. ROS are closely associated with the occurrence, development, and treatment of GC. This review summarizes recent findings on the sources of ROS and the bidirectional regulatory effects on GC and discusses various treatment modalities for GC that are related to ROS induction. In addition, the regulation of ROS by natural small molecule compounds with the highest potential for development and applications in anti-GC research is summarized. The aim of the review is to accelerate the clinical application of modulating ROS levels as a therapeutic strategy for GC.

Metabolome analysis revealed the critical role of betaine for arsenobetaine biosynthesis in the marine medaka (Oryzias melastigma).

Arsenobetaine (AsB), a non-toxic arsenic (As) compound found in marine fish, structurally resembles betaine (GB), a common methyl donor in organisms. This study investigates the potential role of GB in AsB synthesis in marine medaka (Oryzias melastigma) using metabolomic analysis. Dietary exposure to arsenate (As(V)) and varying GB concentrations (0.05% and 0.1% in diets) increased total As and AsB bioaccumulation, particularly in marine medaka muscle. Metabolomic analysis revealed that GB played a crucial role in promoting up-regulation in methylthioadenosine (MTA) by modulating the methionine cycle and down-regulation in glutathione (GSH) by modulating the glutathione cycle. Methionine metabolism and GSH, potentially binding again to exogenous GB, could synchronously produce more non-toxic AsB. Combining verification experiments of differential metabolites of Escherichia coli in vitro, GB, GSH, S-adenosylmethionine (SAM), and arsenocholine (AsC) entered methionine and glutathione metabolism pathways to generate more AsB. These findings underscore the GB's crucial regulatory role in modulating the synthesis of AsB. This study provides vital insights into the interplay between the structural analogs GB and AsB, offering specific strategies to enhance the detoxification mechanisms of marine fish in As-contaminated environments.

Development and validation of a deep learning model for predicting gastric cancer recurrence based on CT Imaging: a multicenter study.

INTRODUCTION: The postoperative recurrence of gastric cancer has a significant impact on the overall prognosis of patients. Therefore, accurately predicting the postoperative recurrence of gastric cancer is crucial. METHODS: This retrospective study gathered data from 2,813 gastric cancer patients who underwent radical surgery between 2011 and 2017 at two medical centers. Follow-up was extended until May 2023, and cases were categorized as recurrent or non-recurrent based on postoperative outcomes. Clinical pathological information and imaging data were collected for all patients. A new deep learning signature (DLS) was generated using pretreatment CT images, based on a pre-trained baseline (a customized Resnet50), for predicting postoperative recurrence. The deep learning fusion signature (DLFS) was created by combining the score of DLS with the weighted values of identified clinical features. The predictive performance of the model was evaluated based on discrimination, calibration, and clinical usefulness. Survival curves were plotted to investigate the differences between DLFS and prognosis. RESULTS: In this study, 2813 patients with gastric cancer (GC) were recruited and allocated into training, internal validation, and external validation cohorts. The DLFS was developed and assessed for its capability in predicting the risk of postoperative recurrence. The DLFS exhibited excellent performance with AUCs of 0.833 (95% CI, 0.809-0.858) in the training set, 0.831 (95% CI, 0.792-0.871) in the internal validation set, and 0.859 (95% CI, 0.806-0.912) in the external validation set, along with satisfactory calibration across all cohorts (P>0.05). Furthermore, the DLFS model significantly outperformed both the clinical model and DLS (P<0.05). High-risk recurrent patients exhibit a significantly poorer prognosis compared to low-risk recurrent patients (P<0.05). CONCLUSIONS: The integrated model developed in this study, focusing on GC patients undergoing radical surgery, accurately identifies cases at high risk of postoperative recurrence and highlights the potential of DLFS as a prognostic factor for GC patients.

Photosensitive pro-drug nanoassemblies harboring a chemotherapeutic dormancy function potentiates cancer immunotherapy.

Immunotherapy combined with effective therapeutics such as chemotherapy and photodynamic therapy have been shown to be a successful strategy to activate anti-tumor immune responses for improved anticancer treatment. However, developing multifunctional biodegradable, biocompatible, low-toxic but highly efficient, and clinically available transformed nano-immunostimulants remains a challenge and is in great demand. Herein, we report and design of a novel carrier-free photo-chemotherapeutic nano-prodrug COS-BA/Ce6 NPs by combining three multifunctional components-a self-assembled natural small molecule betulinic acid (BA), a water-soluble chitosan oligosaccharide (COS), and a low toxic photosensitizer chlorin e6 (Ce6)-to augment the antitumor efficacy of the immune adjuvant anti-PD-L1-mediated cancer immunotherapy. We show that the designed nanodrugs harbored a smart and distinctive "dormancy" characteristic in chemotherapeutic effect with desired lower cytotoxicity, and multiple favorable therapeutic features including improved 1O2 generation induced by the reduced energy gap of Ce6, pH-responsiveness, good biodegradability, and biocompatibility, ensuring a highly efficient, synergistic photochemotherapy. Moreover, when combined with anti-PD-L1 therapy, both nano-coassembly based chemotherapy and chemotherapy/photodynamic therapy (PDT) could effectively activate antitumor immunity when treating primary or distant tumors, opening up potentially attractive possibilities for clinical immunotherapy.

Biodegradation of arsenobetaine to inorganic arsenic regulated by specific microorganisms and metabolites in mice.

Arsenobetaine (AsB) is a primary arsenic (As) compound found in marine organisms. However, in mammals, the metabolic mechanism of AsB remains indistinct. Therefore, in this study, we investigated the biotransformation and regulatory mechanism of AsB, particularly the biodegradation process, in a mouse model to assess the underlying health hazards of AsB. We studied the biotransformation process of AsB in mice through the food chain [AsB feed-marine fish (Epinephelus fuscoguttatus)-mice (Mus musculus)]. Our results showed the significant bioaccumulation of total As, AsB, and, in particular, arsenate [As(V)] through biodegradation in mice tissues. As the abundance of Staphylococcus and Blautia (phylum, Firmicutes) increased, the expression of aqp7 (absorption) and methyltransferase (as3mt) (methylation) was upregulated. In contrast, the expression of S-adenosyl methionine (sam) (methylation) was downregulated. These findings suggest that demethylation and methylation occurred simultaneously in the intestines, with demethylation capacity being greater than that of methylation. Furthermore, Firmicutes such as Staphylococcus and Blautia showed a significant inverse relationship with arachidonic acid, choline, and sphingosine. Gene, microbiome, and metabolomics analyses indicated that Staphylococcus and Blautia and arachidonic acid, choline, and sphingosine participated in the degradation of AsB to As(V) in mouse intestines. Therefore, long-term AsB ingestion through marine fish consumption could cause potential health hazards in humans.

Effect of autoinduction and food on the pharmacokinetics of furmonertinib and its active metabolite characterized by a population pharmacokinetic model.

Furmonertinib (AST2818) is a novel third-generation irreversible EGFR TKI and recently has been approved in China for the treatment of non-small cell lung cancer (NSCLC) with EGFR-sensitizing and T790M resistance mutations. In the current study, we developed a semi-mechanistic population pharmacokinetic model to characterize the nonstationary pharmacokinetics (PK) of the furmonertinib and its active metabolite AST5902 simultaneously. The PK data of furmonertinib and AST5902 were obtained from 38 NSCLC patients and 16 healthy volunteers receiving 20-240 mg furmonertinib in three clinical trials. A nonlinear mixed-effects modeling approach was used to describe the PK data. The absorption process of furmonertinib was described by a transit compartment model. The disposition of both furmonertinib and AST5902 was described by a two-compartment model. An indirect response model accounted for the autoinduction of furmonertinib metabolism mediated by CYP3A4. The model-based simulation suggested that furmonertinib clearance was increased in one cycle of treatment (orally once daily for 21 days) compared to baseline, ranging from 1.1 to 1.8 fold corresponding to the dose range of 20-240 mg. The concentration of furmonertinib was decreased over time whereas that of AST5902 was increased. Interestingly, the concentration of the total active compounds (furmonertinib and AST5902) appeared to be stable. The food intake, serum alkaline phosphatase and body weight were identified as statistically significant covariates. The mechanism of food effect on PK was investigated, where the food intake might increase the bioavailability of furmonertinib via increasing the splanchnic blood flow. Overall, a population PK model was successfully developed to characterize the nonstationary PK of furmonertinib and AST5902 simultaneously. The concentrations of total active compounds were less affected by the autoinduction of furmonertinib metabolism.

Using High-Temporal-Resolution Ambient Data to Investigate Gas-Particle Partitioning of Ammonium over Different Seasons.

Ammonium is one of the dominant inorganic water-soluble ions in fine particulate matter (PM2.5). In this study, source apportionment and thermodynamic equilibrium models were used to analyze the relationship between pH and the partitioning of ammonium (ε(NH4+)) using hourly ambient samples collected from Tianjin, China. We found a "Reversed-S curve" between pH and ε(NH4+) from the ambient hourly aerosol dataset when the theoretical ε(NO3-)* (an index identified in this work) was within specific ranges. A Boltzmann function was then used to fit the Reversed-S curve. For the summer data set, when ε(NO3-)* was between 0.7 and 0.8, the fitted R2 was 0.88. Through thermodynamic analysis, we found that the values of k[H+]2 (k = 3.08 × 104 L2 mol-2) and ε(NO3-)* can influence the pH-ε(NH4+) curve. Under certain situations, the values of k[H+]2 and ε(NO3-)* are similar to each other, and ε(NH4+) is sensitive to pH, suggesting that ε(NO3-)* plays an important role in affecting the ε(NH4+). During summer, winter, and spring seasons, when the relative humidity was greater than 0.36 and ε(NO3-)* was between 0.8 and 0.95, there was an obvious Reversed-S curve, with R2 = 0.60. The theoretical k[H+]2 and ε(NO3-)* developed in this work can be used to analyze the gas-particle partitioning of ammonia-ammonium and nitrate-nitric acid in the ambient atmosphere. Also, it is the first time that we created the joint source-NH3/HNO3 maps to integrate sources, aerosol pH and liquid water content, and ions (altogether in one map), which can provide useful information for designing effective strategies to control particulate matter pollution.

Functional characterization of a low-frequency V1937I variant in FASN associated with susceptibility to esophageal squamous cell carcinoma.

Metabolic reprogramming has been regarded as one of the core hallmarks of cancer and increased de novo fatty acid synthesis has been documented in multiple tumors including esophageal squamous cell carcinoma (ESCC). Our previous exome-wide analyses found a Val1937Ile variant (rs17848945) in the 34th exon of fatty acid synthase (FASN) that showed a strong association with the risk of ESCC. In this study, we performed a series of functional assays to investigate the biological functions underlying this variant in the development of ESCC. We demonstrated that FASN was upregulated in ESCC and both knockdown and knockout of FASN significantly inhibited ESCC cell proliferation, suggesting a tumor promoter role for this gene in ESCC. Furthermore, the results showed that overexpression of FASN[I] in the ESCC cells substantially enhanced cell proliferation, compared with overexpression of FASN[V], or the control vector. Intriguingly, we found that the FASN[I] variant can enhance the enzyme activity of FASN, and, thus, increase the amount of the FASN end-product, palmitate in the ESCC cells. We also observed elevated palmitate levels in the plasma of the FASN[I] genotype carriers among a total of 632 healthy Chinese adults. In conclusion, our results suggested that the FASN V1937I variant influenced ESCC cell proliferation and susceptibility by altering the catabolic activity of FASN on palmitate. These findings may highlight an important role of palmitate metabolism in the development of ESCC and may contribute to the personalized medicine of this disease.

Simultaneous determination of alflutinib and its active metabolite in human plasma using liquid chromatography-tandem mass spectrometry.

Alflutinib, or known as AST2818, is an irreversible tyrosine kinase inhibitor that selectively inhibits EGFR mutations, especially T790M. At present, alflutinib has undergone phase II/III clinical trials for non-small cell lung cancer (NSCLC) treatment in China. The present study aimed to analye the pharmacokinetics of alflutinib and its active metabolite AST5902 in a plasma sample of NSCLC patient. A sensitive and highly selective method was optimized and validated for the detection of alflutinib and AST5902 using a liquid chromatography-tandem mass spectrometry. After precipitating proteins with acetonitrile, alflutinib, AST5902 and AST2818-d3 (internal standard) were analyzed with a Waters BEH C18 column. The mobile phase was optimized with acetonitrile: ammonium acetate (2 mmol/L) containing 0.2% formic acid using gradient elution. Separation was achieved within a total chromatographic running time of 2.1 min. Quantification was carried out using positive ion multiple reaction monitoring mode at ion transitions m/z 569.3→441.2, 555.1→498.2 and 572.3→441.2 for alflutinib, AST5902 and AST2818-d3, respectively. An excellent linearity was observed for alflutinib and AST5902 within concentration ranges of 0.20-100 and 0.050-25.0 ng·mL-1, respectively. Notably, the lower limit of quantification for alflutinib and AST5902 were 0.20 and 0.050 ng/mL, respectively. The intra- and inter-day accuracy of alflutinib were 0.7-2.9%, while its intra- and inter-assay precision were ≤9.1% and ≤10.5%, respectively. The accuracy of AST5902 was within -0.2-3.9%, while the intra- and inter-assay precision were ≤8.0% and ≤8.6%, respectively. The recoveries of the analysts remained constant and could be reproduced at different concentrations. Furthermore, this analytical method could be applied to determine the pharmacokinetic analysis of alflutinib and AST5902 in human plasma.

High-Resolution Data Sets Unravel the Effects of Sources and Meteorological Conditions on Nitrate and Its Gas-Particle Partitioning.

Nitrate is one of the most abundant inorganic water-soluble ions in fine particulate matter (PM2.5). However, the formation mechanism of nitrate in the ambient atmosphere, especially the impacts of its semivolatility and the various existing forms of nitrogen, remain under-investigated. In this study, hourly ambient observations of speciated PM2.5 components (NO3-, SO42-, etc.) were collected in Tianjin, China. Source contributions were analyzed by PMF/ME2 (Positive Matrix Factorization using the Multilinear Engine 2) program, and pH were estimated by ISORROPIA-II, to investigate the relationship between pH and nitrate. Five sources (factors) were resolved: secondary sulfate (SS), secondary nitrate (SN), dust, vehicle and coal combustion. SN and pH showed a triangle-shaped relationship. When SS was high, the fraction of nitrate partitioning into the aerosol phase exhibits a characteristic "S-curve" relationship with pH for different seasons. An index ( ITL) is developed and combined with pH to explore the sensitive regions of "S-curve". Controlling the emissions of anions (SO42-, Cl-), cations (Ca2+, Mg2+, etc.) and gases (NO x, NH3, SO2, etc.) will change pH, potentially reducing or increasing SN. The findings of this work provide an effective approach for exploring the formation mechanisms of nitrate under different influencing factors (sources, pH, and IRL).

Amido surface-functionalized magnetic molecularly imprinted polymers for the efficient extraction of Sibiskoside from Sibiraea angustata.

A general method for efficient and selective extraction of a target compound from complex natural products remains elusive, despite decades of research. By introducing a functional amido group on the surface of dispersity-enhanced magnetic nanoparticles, a nanoparticle receptor to selectively recognize Sibiskoside (a monoterpene) from the aerial portion of Sibiraea angustata by hydrogen bond interaction was synthesized. The superparamagnetic Fe3O4 nanoparticles were successively modified with tetraethyl orthosilicate (TEOS), amino and amido functional groups, and 4-vinylbenzoic acid (VBZA) was used as the functional monomer. A thin layer of poly (VBZA) imprinted with Sibiskoside was immobilized on the surface of magnetic carriers. Attributing to the amido group introduced into the magnetic particles, the template could attract and bind to the surface and promote the formation of a hydrogen bond system between the carrier, template molecules and functional monomer. High-density molecular recognition sites grew on the surface of magnetic substrate. The adsorption reached equilibrium at approximately 150 min, while fast adsorption occurred during the first 60 min. The maximum adsorption capacity has been found to be 13.75 mg g-1 according to calculation with the Langmuir isotherm. The selectivity coefficients of Molecular imprinting polypers (MIPs) for Sibiskoside with respect to Andrographolide, Loganin, Gastrodin, geraniol-1-O-[α-l-rhamnopyranosyl-(1 → 6)-1-ß-d-glucopyranoside] (GRG), Sibiscolacton and Sibiraic acid were 2.26, 1.43, 1.701.56, 1.05, 0.73 and, respectively. The results indicated that the MIPs possessed good specific adsorption capacity and selectivity toward Sibiskoside and had the potential to be a candidate for the separation and purification of monoterpenes from Sibiraea angustata, which is of great significance to obesity management.

Calcium­sensing receptors in human peripheral T lymphocytes and AMI: Cause and effect.

Acute myocardial infarction (AMI) is a disease associated with inflammation. T lymphocytes are involved by secreting cytokines and inflammatory factors. In our previous study, it was found that the T lymphocytes exhibited certain functional changes, the onset of which was induced by modulating calcium­sensing receptor (CaSR) in AMI. In the present study, western blotting was used to verified the expression of T lymphocyte CaSR and pathway proteins, including phosphorylated extracellular signal­regulated kinase (P­ERK)1/2 and phosphorylated c­Jun N­terminal kinase (P­JNK), and used cytometric bead array to detect the secretion of interleukin (IL)­4, IL­6, IL­10 and tumor necrosis factor (TNF)­α in AMI onset, the results demonstrated that they were all increased. In addition, the expression of T lymphocyte pathway proteins, including P­ERK1/2 and P­JNK, and the secretion of IL­4, IL­6, IL­10 and TNF­α decreased after T lymphocytes being transfected by CaSR small interfering RNA. By contrast, the neonatal mouse cardiomyocytes under hypoxia and hypoxia/re­oxygenation exhibited ultrastructural damage, increased apoptosis, increased production of lactate dehydrogenase (LDH) and malondialdehyde, and reduced superoxide dismutase; these indicators changed extensively when cardiomyocytes were co­cultured with T lymphocytes. However, the effects were reversed when the cardiomyocytes were co­cultured with CaSR­silenced T lymphocytes. These results indicated that CaSR may modulate T lymphocytes to release cytokines through mitogen­activated protein kinase pathways and affect cardiomyocyte injury. The relationship between AMI and T lymphocyte CaSR is reciprocal.

Dietary Fiber Intake and Endometrial Cancer Risk: A Systematic Review and Meta-Analysis.

Epidemiological studies are inconclusive regarding the association between dietary fiber intake and endometrial cancer risk. Thus, we aimed to conduct a meta-analysis to clarify the association between dietary fiber and endometrial cancer risk. We searched the PubMed and ISI Web databases for relevant studies through March 2018. The association between dietary fiber and endometrial cancer risk was evaluated by conducting a meta-analysis including 3 cohort and 12 case⁻control studies. A significant negative association was observed between total dietary fiber intake and endometrial cancer risk in 11 case⁻control studies (odds ratios (OR) 0.76, 95% confidence interval (CI): 0.64⁻0.89, I² = 35.2%, p = 0.117), but a marginal positive association was observed in three cohort studies (relative risk (RR) 1.22, 95% CI: 1.00⁻1.49, I² = 0.0%, p = 0.995). Particularly, a negative association was observed in North America (OR = 0.70, 95% CI: 0.59⁻0.83, I² = 8.9%, p = 0.362). In addition, a positive association was observed in cereal fiber (RR = 1.26, 95% CI: 1.03⁻1.52, I² = 0.0%, p = 0.530, 3 cohort studies) and a negative association was observed in vegetable fiber (OR = 0.74, 95% CI: 0.58⁻0.94, I² = 0.0%, p = 0.445, 3 case⁻control studies). In conclusion, negative associations with endometrial cancer risk were observed for higher total dietary fiber intake and higher vegetable fiber intake in the case⁻control studies. However, results from the cohort studies suggested positive relationships of higher total fiber intake and higher cereal fiber intake with endometrial cancer risk.

Endomorphin 1 effectively protects cadmium chloride-induced hepatic damage in mice.

The antioxidative capacity of endomorphin 1 (EM1), an endogenous mu-opioid receptor agonist, has been demonstrated by in vivo assays. The present study reports the effect of EM1 on hepatic damage induced by cadmium chloride (Cd(II)) in adult male mouse. Mouse were given intraperitoneally (i.p.) a single dose of Cd(II) (1mg/kg body weight per day) and the animals were co-administrated with a dose of EM1 (50 microM/kg body weight per day) for 6 days. Since hepatic damage induced by Cd(II) is related to oxidative stress, lipid peroxidation (LPO), protein carbonyl (PCO), superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH) were evaluated. The parameter indicating tissue damage such as liver histopathology was also determined. In addition, the concentrations of Cd and zinc (Zn) in the liver were analyzed. The intoxication of Cd(II) lead to the enhanced production of LPO and PCO, treatment with EM1 can effectively ameliorate the increase of LPO and PCO compared to the Cd(II) group. The increased activities of CAT, SOD and the elevated GSH induced by Cd(II) may relate to an adaptive-response to the oxidative damage, the effect of EM1 can restore the elevated antioxidant defense. Our results suggested that the structure features and the ability of chelating metal of EM1 may play a major role in the antioxidant effect of EM1 in vivo and opioid receptors may be involved in the protection of hepatic damage induced by Cd(II).

Protective effects of endomorphins, endogenous opioid peptides in the brain, on human low density lipoprotein oxidation.

Neurodegenerative disorders are associated with oxidative stress. Low density lipoprotein (LDL) exists in the brain and is especially sensitive to oxidative damage. Oxidative modification of LDL has been implicated in the pathogenesis of neurodegenerative diseases. Therefore, protecting LDL from oxidation may be essential in the brain. The antioxidative effects of endomorphin 1 (EM1) and endomorphin 2 (EM2), endogenous opioid peptides in the brain, on LDL oxidation has been investigated in vitro. The peroxidation was initiated by either copper ions or a water-soluble initiator 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH). Oxidation of the LDL lipid moiety was monitored by measuring conjugated dienes, thiobarbituric acid reactive substances, and the relative electrophoretic mobility. Low density lipoprotein oxidative modifications were assessed by evaluating apoB carbonylation and fragmentation. Endomorphins markedly and in a concentration-dependent manner inhibited Cu2+ and AAPH induced the oxidation of LDL, due to the free radical scavenging effects of endomorphins. In all assay systems, EM1 was more potent than EM2 and l-glutathione, a major intracellular water-soluble antioxidant. We propose that endomorphins provide protection against free radical-induced neurodegenerative disorders.

Endomorphins, endogenous opioid peptides, provide antioxidant defense in the brain against free radical-induced damage.

Oxidative stress has been considered to be a major cause of cellular injuries in a variety of chronic health problems, such as carcinogenesis and neurodegenerative disorders. The brain appears to be more susceptible to oxidative damage than other organs. Therefore, the existence of antioxidants may be essential in brain protective systems. The antioxidative and free radical scavenging effects of endomorphin 1 (EM1) and endomorphin 2 (EM2), endogenous opioid peptides in the brain, have been investigated in vitro. The oxidative damage was initiated by a water-soluble initiator 2,2'-azobis(2-amidinopropane hydrocholoride) (AAPH) and hydrogen peroxide (H2O2). The linoleic acid peroxidation, DNA and protein damage were monitored by formation of hydroperoxides, by plasmid pBR 322 DNA nicking assay and single-cell alkaline electrophoresis, and by SDS-polyacrylamide gel electrophoresis. Endomorphins can inhibit lipid peroxidation, DNA strand breakage, and protein fragmentation induced by free radical. Endomorphins also reacted with galvinoxyl radicals in homogeneous solution, and the pseudo-first-order rate constants were determined spectrophotometrically by following the disappearance of galvinoxyl radicals. In all assay systems, EM1 was more potent than EM2 and GSH, a major intracellular water-soluble antioxidant. We propose that endomorphins are one of the protective systems against free radical-induced damage in the brain.