Association between priori and posteriori dietary patterns and gastric cancer risk: an updated systematic review and meta-analysis of observational studies.

An increasing number of epidemiological studies have explored the relationship between the risk of gastric cancer and specific dietary patterns, but the findings remain inconclusive. We, therefore, performed this comprehensive systematic review and meta-analysis to analyze the available evidence regarding the associations between a priori and a posteriori dietary patterns and the risk of gastric cancer. A systematic search of six electronic databases, including PubMed, Web of Science, EBSCO, Scopus, China National Knowledge Infrastructure (CNKI), and Wanfang Data, was carried out to retrieve the relevant articles published up to March 2024. Thirty-six studies (10 cohort and 26 case-control studies) with a total of 2 181 762 participants were included in the final analyses. Combining 15 effect sizes extracted from 12 articles, we observed a reduced risk of gastric cancer in the highest versus the lowest categories of the Mediterranean diet [relative risk (RR), 0.72; 95% confidence interval (CI), 0.61-0.85; P < 0.001]. Combining 11 effect sizes from 10 articles (involving 694 240 participants), we found that the highest Dietary Inflammatory Index scores were significantly associated with an increased risk of gastric cancer (RR, 1.32; 95% CI, 1.11-1.57; P < 0.001). A reduced risk of gastric cancer was shown for the highest compared with the lowest categories of healthy dietary pattern (RR, 0.78; 95% CI, 0.67-0.91; P = 0.002). Conversely, the highest adherence to the Western dietary pattern was associated with an increased risk of gastric cancer (RR, 1.33; 95% CI, 1.19-1.49; P < 0.001). Our study demonstrated that the Mediterranean diet and a healthy dietary pattern were associated with a decreased risk of gastric cancer. Conversely, the Dietary Inflammatory Index and Western dietary pattern were associated with an increased risk of gastric cancer.

Long-Term Accumulation of T Cytotoxic 1, T Cytotoxic 17, and T Cytotoxic 17/1 Cells in the Brain Contributes to Microglia-Mediated Chronic Neuroinflammation After Ischemic Stroke.

Post-stroke neuroinflammation affects the damage and recovery of neurological functions. T cells including CD8+ T cells were present in the ipsilateral hemisphere in the subacute and late phases of ischemic stroke. However, the potential roles of CD8+ T cell subsets in the progression of neuroinflammation have not been characterized. In the current mouse transient middle cerebral artery occlusion model, we investigated the existence of CD8+ T cell subsets in the ipsilateral hemisphere in the subacute and late phases of stroke. We found that ipsilateral CD8+ T cells were present on post-stroke day 3 and increased on post-stroke day 30. The day-3 ipsilateral CD8+ T cells predominantly produced interferon-γ (IFN-γ), while the day-30 ipsilateral CD8+ T cells co-expressed IFN-γ and interleukin-17A (IL-17A). In addition, evaluation of cytokines and transcription factors of the day-30 ipsilateral CD8+ T cells revealed the presence of T cytotoxic 1 (Tc1), T cytotoxic 17 (Tc17), and T cytotoxic 17/1 (Tc17/1) cells. Furthermore, based on the expression of a series of chemokine/cytokine receptors, viable ipsilateral Tc1, Tc17, and Tc17.1 cells were identified and enriched from the day-30 ipsilateral CD8+ T cells, respectively. Co-culture of microglia with ipsilateral Tc1, Tc17, or Tc17.1 cells indicated that the three CD8+ T cell subsets up-regulated the expression of pro-inflammatory mediators by microglia, with Tc17.1 cells being the most potent cell in doing so. Collectively, this study sheds light on the contributions of Tc1, Tc17, and Tc17.1 cells to long-term neuroinflammation after ischemic stroke.

Ultra-processed food consumption and chronic kidney disease risk: a systematic review and dose-response meta-analysis.

Background: High intake of ultra-processed food (UPF) has been associated with increased risk of chronic kidney disease(CKD), but the results remain inconsistent. We therefore performed this systematic review and dose­response meta-analysis of observational studies that shed light on the association between UPF consumption and the risk of CKD. Methods: A systematic literature search of PubMed, Embase, Web of Science, Scopus and China National Knowledge Infrastructure (CNKI) databases was carried out to find the eligible articles published up to October 31, 2023. Random-effects or fixed-effects models were used to pool the relative risks(RRs) and their 95% confidence intervals (CIs).The potential sources of heterogeneity across studies were examined using the Cochran's Q test and I-square(I2). Publication bias was examined using the visual inspection of asymmetry in funnel plots and quantified by Begg's and Egger's tests. Results: Eight studies (six cohort and two cross-sectional studies) exploring the association between UPF consumption and risk of CKD, were included in the final analysis. The pooled analyses revealed that high consumption of UPF was associated with an increased risk of CKD (RR = 1.25; 95%CI: 1.09­1.42, p < 0.0001). Moreover, a 10% increase of UPF consumption was associated with a 7% higher risk of CKD (RR = 1.07; 95%CI: 1.04­1.10, p < 0.001). Dose­response analysis of all included studies showed a linear association between UPF consumption and the risk of CKD (RR = 1.02; 95%CI:0.99­1.05, Pdose­response = 0.178, Pnonlinearity = 0.843). Conclusion: Our findings indicate that high consumption of UPF is significantly associated with an increased risk of CKD. Future research with prospective design is required to confirm this positive association.Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023478483, PROSPERO identifier CRD42023478483.

Non-alcoholic fatty liver disease and sleep disorders.

Studies have shown that non-alcoholic fatty liver disease (NAFLD) may be associated with sleep disorders. In order to explore the explicit relationship between the two, we systematically reviewed the effects of sleep disorders, especially obstructive sleep apnea (OSA), on the incidence of NAFLD, and analyzed the possible mechanisms after adjusting for confounding factors. NAFLD is independently associated with sleep disorders. Different sleep disorders may be the cause of the onset and aggravation of NAFLD. An excessive or insufficient sleep duration, poor sleep quality, insomnia, sleep-wake disorders, and OSA may increase the incidence of NAFLD. Despite that some research suggests a unidirectional causal link between the two, specifically, the onset of NAFLD is identified as a result of changes in sleep characteristics, and the reverse relationship does not hold true. Nevertheless, there is still a lack of specific research elucidating the reasons behind the higher risk of developing sleep disorders in individuals with NAFLD. Further research is needed to establish a clear relationship between NAFLD and sleep disorders. This will lay the groundwork for earlier identification of potential patients, which is crucial for earlier monitoring, diagnosis, effective prevention, and treatment of NAFLD.

CPLX2 is a novel tumor suppressor and improves the prognosis in glioma.

BACKGROUND: Glioma is a type of malignant cancer that affect the central nervous system. New predictive biomarkers have been investigated in recent years, but the clinical prognosis for glioma remains poor. The function of CPLX2 in glioma and the probable molecular mechanism of tumor suppression were the focus of this investigation. METHODS: The glioma transcriptome profile was downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases for analysis of CPLX2 expression in glioma. RT-qPCR was performed to detect the expression of CPLX2 in 68 glioma subjects who have been followed up. Kaplan-Meier survival analyses were conducted to assess the effect of CPLX2 on the prognosis of glioma patients. The knockdown and overexpressed cell lines of CPLX2 were constructed to investigate the impact of CPLX2 on glioma. The cell growth, colony formation, and tumor formation in xenograft were performed. RESULTS: The expression of CPLX2 was downregulated in glioma and was negatively correlated with the grade of glioma. The higher expression of CPLX2 predicted a longer survival, as indicated by the analysis of Kaplan-Meier survival curves. Overexpressed CPLX2 impaired tumorigenesis in glioma progression both in vivo and in vitro. Knocking down CPLX2 promoted the proliferation of glioma cells. The analysis of GSEA and co-expression analysis revealed that CPLX2 may affect the malignancy of glioma by regulating the hypoxia and inflammation pathways. CONCLUSIONS: Our data indicated that CPLX2 functions as a tumor suppressor and could be used as a potential prognostic marker in glioma.

Engineering Sizable and Broad-Spectrum Antibacterial Fabrics through Hydrogen Bonding Interaction and Electrostatic Interaction.

Long-lasting and highly efficient antibacterial fabrics play a key role in public health occurrences caused by bacterial and viral infections. However, the production of antibacterial fabrics with a large size, highly efficient, and broad-spectrum antibacterial performance remains a great challenge due to the complex processes. Herein, we demonstrate sizable and highly efficient antibacterial fabrics through hydrogen bonding interaction and electrostatic interaction between surface groups of ZnO nanoparticles and fabric fibers. The production process can be carried out at room temperature and achieve a production rate of 300 × 1 m2 within 1 h. Under both visible light and dark conditions, the bactericidal rate against Gram-positive (S. aureus), Gram-negative (E. coli), and multidrug-resistant (MRSA) bacteria can reach an impressive 99.99%. Furthermore, the fabricated ZnO nanoparticle-decorated antibacterial fabrics (ZnO@fabric) show high stability and long-lasting antibacterial performance, making them easy to develop into variable antibacterial blocks for protection suits.

BRCC36 Deubiquitinates HMGCR to Regulate the Interplay Between Ferroptosis and Pyroptosis.

Various forms of programmed cell death (PCD) exhibit distinct characteristics depending on their specific molecular mechanisms, and there are interactions among these different forms. Ferroptosis, which is related to autophagy and apoptosis, has an unknown potential interaction with pyroptosis. This study revealed a mutually antagonistic relationship between ferroptosis and pyroptosis, with 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) playing a key role in their interaction. It is found that HMGCR predominantly localized to mitochondria during ferroptosis but shifted to the endoplasmic reticulum following treatment with a pyroptosis inducer. Furthermore, this study demonstrated that BRCC36 (BRCA1/BRCA2-containing complex subunit 36) deubiquitinated HMGCR in a manner dependent on deubiquitinating enzyme (DUB) activity, and inhibited ferroptosis and promoted pyroptosis. Moreover, as an oncogene in hepatocellular carcinoma (HCC), BRCC36 promoted cancer cell proliferation, migration, invasion, and tumor growth. Thiolutin, an inhibitor of BRCC36, effectively suppressed the interaction between BRCC36 and HMGCR, leading to the inhibition of HCC growth. Therefore, targeting BRCC36 can offer a novel and promising therapeutic strategy for HCC treatment. In conclusion, these findings provide new theoretical evidence for further characterizing tumor heterogeneity and offer new molecular targets for the diagnosis and treatment of HCC.

Disulfidptosis-related signature predicts prognosis and characterizes the immune microenvironment in hepatocellular carcinoma.

BACKGROUND: Disulfidptosis is a type of programmed cell death caused by excessive cysteine-induced disulfide bond denaturation leading to actin collapse. Liver cancer has a poor prognosis and requires more effective intervention strategies. Currently, the prognostic and therapeutic value of disulfidptosis in liver cancer is not clear. METHODS: We investigated the features of 16 disulfidptosis-related genes (DRGs) of HCC patients in the TCGA and classified the patients into two disulfidptosis pattern clusters by consensus clustering analysis. Then, we constructed a prognostic model using LASSO Cox regression. Next, the microenvironment and drug sensitivity were evaluated. Finally, we used qPCR and functional analysis to verify the reliability of hub DRGs. RESULTS: Most of the DRGs showed significantly higher expression in cancer tissues than in adjacent tissues. Our prognostic model, the DRG score, can well predict the survival of HCC patients. There were significant differences in survival, features of the microenvironment, effects of immunotherapy, and drug sensitivity between the high- and low-DRG score groups. Ultimately, we demonstrated that a few hub DRGs have differential mRNA expression between liver cancer cells and normal cells and that the protective gene LCAT can inhibit liver cancer metastasis in vitro. CONCLUSION: We established a novel risk model based on DRG scores to predict HCC patient prognosis, drug sensitivity and immunotherapy efficacy, which provides new insight into the relationship between disulfidptosis and HCC and provides valuable assistance for the personalized treatment of HCC.

Carbazole-based mitochondria-targeted fluorescent probes for in vivo viscosity and cyanide detection in cells and zebrafish.

Cells of most eukaryotic species contain mitochondria, which play a role in physiological processes such as cellular senescence, metabolism, and autophagy. Viscosity is considered a key marker for many illnesses and is involved in several crucial physiological processes. Cyanide (CN-) can target cytochrome-c oxidase, disrupting the mitochondrial electron transport chain and causing cell death through asphyxiation. In this study, a fluorescent probe named HL-1, which targets mitochondria and measures viscosity and CN- levels, was designed and synthesized. HL-1 is viscosity-sensitive, with a linear correlation coefficient of up to 0.992. In addition, HL-1 was found to change color substantially during a nucleophilic addition reaction with CN-, which has a low detection limit of 47 nM. HL-1 not only detects viscosity and exogenous CN- in SKOV-3 cells and zebrafish but also monitors viscosity changes during mitochondrial autophagy in real time. Furthermore, HL-1 has been used successfully to monitor changes in mitochondrial membrane potential during apoptosis. Endogenous CN- in plant samples was quantified. HL-1 provides new ideas for studying viscosity and CN-.

Highly Antibacterial and Antioxidative Carbon Nanodots/Silk Fibroin Films for Fruit Preservation.

The issues of fruit waste and safety resulting from rot have spurred a demand for improved packaging systems. Herein, we present highly antibacterial and antioxidative carbon nanodot/silk fibroin (CD/SF) films for fruit preservation. The films are composed of CDs and SF together with a small amount of glycerol via hydrogen bonding, exhibiting outstanding biosafety, transparency, and stretchability. The films effectively integrate key functionalities (atmosphere control, resistance to food-borne pathogens, and antioxidation properties) and can be manufactured in large sizes (about 20 × 30 cm), boasting a transmission rate of 13 183 cm3/m2·day for oxygen and 2860 g/m2·day for water vapor, favoring the preservation of fresh fruits. A convenient dip-coating method enables in situ fabrication of films with a thickness of approximately 14 µm directly on the fruits' surface providing comprehensive protection. Importantly, the films are washable and biodegradable. This work presents a promising technology to produce multifunctional and eco-friendly antibacterial packaging systems.

Mechanism Exploration of Euphorbia fischeriana Steud. for Liver Cancer Based on Aspartic Acid Identification in Metabolomics.

OBJECTIVE: To investigate the anti-liver cancer effects and aspartic acid (Asp)-related action mechanism of Euphorbia fischeriana Steud. (Lang Du, LD). METHODS: The mice model of liver cancer was established by injection of H22 cells. After 5 days, mice were randomly divided into model group, sorafenib group (20 mg/kg), LD high-dose (LDH, 1.36 g/kg) group, LD medium-dose (LDM, 0.68 g/kg) group, and LD low-dose (LDL, 0.34 g/kg) group, 10 mice each group. Drugs were intragastrically administered to the mice once daily for 10 days, respectively. Body weight, tumor size and tumor weight were recorded. Hepatic index was calculated. Pathological changes of liver cancer tissues were evaluated by hematoxylin and eosin staining and TUNEL staining. Liquid chromatography-mass spectrometer was used to analyze different metabolites between the model and LDH groups. RESULTS: After LD treatment, tumor weight, tumor size and hepatic index were reduced compared with the model group. Necrocytosis and karyorrhexis of tumor cells were found. Moreover, 61 differential metabolites (18 up-regulated, 43 down-regulated) were affirmed and 20 pathways of KEGG (P<0.05) were gotten. In addition, Bel-7402, HepG2 and H22 cell viabilities were significantly increased after adding Asp into the medium. And then, the cell proliferation effect induced by Asp was ameliorated by LD. CONCLUSION: The anti-liver cancer efficacy of LD extract was validated in H22 mice model, and inhibition of Asp level might be the underlying mechanism.

Plasma cell signatures predict prognosis and treatment efficacy for lung adenocarcinoma.

PURPOSE: This study aims to identify key genes regulating tumor infiltrating plasma cells (PC) and provide new insights for innovative immunotherapy. METHODS: Key genes related to PC were identified using machine learning in lung adenocarcinoma (LUAD) patients. A prognostic model called PC scores was developed using TCGA data and validated with GEO cohorts. We assessed the molecular background, immune features, and drug sensitivity of the high PC scores group. Real-time PCR was utilized to assess the expression of hub genes in both localized LUAD patients and LUAD cell lines. RESULTS: We constructed PC scores based on seventeen PC-related hub genes (ELOVL6, MFI2, FURIN, DOK1, ERO1LB, CLEC7A, ZNF431, KIAA1324, NUCB2, TXNDC11, ICAM3, CR2, CLIC6, CARNS1, P2RY13, KLF15, and SLC24A4). Higher age, TNM stage, and PC scores independently predicted shorter overall survival. The AUC value of PC scores for one year, three years, and five years of overall survival were 0.713, 0.716, and 0.690, separately. The nomogram model that integrated age, stage, and PC scores showed significantly higher predictive value than stage alone (P < 0.01). High PC scores group exhibited an immune suppressing microenvironment with lower B, CD8 + T, CD4 + T, and dendritic cell infiltration. Docetaxel, gefitinib, and erlotinib had lower IC50 in high PC groups (P < 0.001). After validation through the local cohort and in vitro experiments, we ultimately confirmed three key potential targets: MFI2, KLF15, and CLEC7A. CONCLUSION: We proposed a prediction mode which can effectively identify high-risk LUAD patients and found three novel genes closely correlated with PC tumor infiltration.

Association between ultra-processed food consumption and risk of breast cancer: a systematic review and dose-response meta-analysis of observational studies.

Background: Some epidemiological studies have examined the association between consumption of ultra-processed food (UPF) and the risk of breast cancer. However, the results were inconsistent. Therefore, we carried out a systematic review and dose-response meta-analysis to examine whether an association exists between high consumption of UPF and breast cancer risk. Methods: PubMed/MEDLINE, ISI Web of Science, EBSCO and CNKI databases were systematically searched from inception to May 2023. The summary relative risks (RRs) and 95% confidence intervals (CIs) associated with UPF consumption and breast cancer were calculated using a random-effects model (DerSimonian-Laird method). Heterogeneity between included studies was examined using the Cochran's Q test and I-square (I2) statistics. Publication bias was studied by visual inspection of funnel plot asymmetry and Begg's and Egger's tests. Results: Overall, six articles involving 462,292 participants, were eligible to be included in this study. Compared to the lowest consumption, highest consumption of UPF was related to a higher risk of breast cancer (RR = 1.10; 95%CI: 1.00-1.22, p = 0.056). Besides, the linear dose-response analysis showed that each 10% increment in UPF consumption was related to a 5% higher risk of breast cancer (RR = 1.05; 95%CI: 1.00-1.10, p = 0.048). Subgroup analyses suggested that UPF consumption was positively associated with breast cancer risk in case-control studies (RR = 1.13; 95%CI: 1.01-1.26, p = 0.028). Additionally, there was also a significant positive association between UPF consumption and breast cancer risk in the subgroup with sample size<5,000(RR = 1.17; 95%CI: 1.02-1.35, p = 0.028). Conclusion: Our results indicate that higher consumption of UPF is slightly related to a higher risk of breast cancer. Further studies in particular of large prospective cohort studies are warranted to confirm these results.

Adherence to the Mediterranean diet and risk of gastric cancer: a systematic review and dose-response meta-analysis.

Background: Despite growing evidence for the association of adherence to the Mediterranean diet with gastric cancer risk, the results remain inconclusive. The purpose of this systematic review and meta-analysis was to summarize the evidence from previous observational studies and assess the potential association between adherence to the Mediterranean diet and risk of gastric cancer using a dose-response meta-analysis. Methods: A comprehensive literature search for all observational studies published up to June 30, 2023 was conducted using the databases of PubMed, ISI Web of Science, EBSCO, China National Knowledge Infrastructure (CNKI) and Wanfang Data. The pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated for the highest versus the lowest categories of Mediterranean diet score in relation to gastric cancer risk, using random-effects models. The Cochran's Q test and I-squared (I2) statistic were used to detect the sources of heterogeneity among the included studies. Results: Overall, 11 studies (five cohort and six case-control studies) with a total number of 1,366,318 participants were included in the final analysis. Combining 14 effect sizes from 11 studies revealed that compared with the lowest category, the highest adherence to the Mediterranean diet was associated with a 29% reduction in the risk of gastric cancer (RR:0.71; 95%CI:0.59-0.84, p < 0.001). In addition, linear dose-response analysis showed that each 1-score increment in Mediterranean diet score was associated with a 5% lower risk of gastric cancer (RR:0.95; 95%CI: 0.94-0.96, p < 0.001). Stratified analysis showed a significant association between adherence to the Mediterranean diet and risk of gastric cancer in case-control studies (RR = 0.44;95%CI:0.32-0.61, p < 0.001), and a marginally significant association in prospective cohort studies (RR = 0.88; 95%CI: 0.79-0.98, p = 0.024), respectively. At the same time, a more significant association between Mediterranean diet and reduced risk of gastric cancer was observed in other countries (RR = 0.28; 95%CI:0.16-0.49, p < 0.001) than in Western countries (RR = 0.75; 95%CI:0.64-0.88, p = 0.001). Conclusion: Our results demonstrate that high adherence to the Mediterranean diet is associated with 29% reduced risk of gastric cancer. Further large prospective studies and randomized controlled trials are warranted to confirm our findings.

Tribulus terrestris L. induces cell apoptosis of breast cancer by regulating sphingolipid metabolism signaling pathways.

BACKGROUND: Tribulus terrestris L. (TT) was initially documented in Shen-Nong-Ben-Cao-Jing and has been used for thousands of years in China as a herb to calm liver, dispel melancholy and wind, promote blood circulation, improve eyesight, and relieve itching. Moreover, it was also used to treat breast cancer in ancient China. However, the pharmacological activities of TT extract on breast cancer have received little attention. PURPOSE: In this study, we investigated the anti-breast cancer effects and possible mechanisms of action of this herbal drug. METHODS: Network pharmacology analysis the study of network pharmacology was done to analyze the possibility of TT's anti-breast cancer effect. And then, molecular docking between TT7/TT8 and vascular endothelial growth factor receptor 2 (VEGFR2) were performed by Autodock software as well as the related protein expressions were analyzed by western blot to verify this effect. In vivo experiment: The mouse model of breast cancer was established by injection of 4T1 cells. Then drugs were intragastrically administered to the mice once daily for fourteen days. Body weight, tumor size, and tumor weight were recorded at the end of the experiment. Moreover, tumor inhibitory rate was calculated. Finally, pathological changes and apoptosis of breast cancer tissues were respectively evaluated by HE and Hoechst staining. Proteomics and metabonomics analyses: The tumor tissues were chosen to perform conjoint analysis. Firstly, differential proteins and metabolites were found. Furthermore, the functional analyses of them were analyzed by software. At the last, immunofluorescent staining of SGPP1, SPHK1 and p-SPHK1 in tumor tissue were done. RESULTS: 12 active ingredients of TT, 127 targets of active ingredients, 15,253 targets of breast cancer, 1,225 targets of Ru yan, and 123 overlapping genes were obtained in the network pharmacology study. There was firm conjunction between TT7/TT8 and VEGFR2. Besides, tumor size and weight were markedly reduced in TT groups compared to the model group. The tumor inhibitory rate was more than 26% in TTM group. After drug treatment, many adipocytes and cracks between tumor and apoptosis were discovered. The western blot results showed that TT aqueous extract lowered the levels of VEGFR2, ERK1/2, p-ERK1/2 (Thr202, Tyr204) and Bcl2, while increasing the levels of Bax and the ratio of Bax/Bcl2. Furthermore, 495 differential proteins and 76 differential metabolites were found between TTM and model groups with the sphingolipid metabolism pathway being enriched. At last, TT treatment significantly reduced the levels of SGPP1, SPHK1 and p-SPHK1 in tumor tissue. CONCLUSIONS: In conclusion, TT demonstrates therapeutic effects in a mouse model of breast cancer, and its mechanism of action involves the regulations of sphingolipid metabolism signaling pathways. This study lends credence to the pharmacological potential of TT extract as a breast cancer therapy.

Association between ultra-processed food intake and risk of colorectal cancer: a systematic review and meta-analysis.

Background: Although some epidemiological studies have shown a positive relationship between high intake of ultra-processed food (UPF) and risk of colorectal cancer (CRC), the results remain inconsistent. Therefore, we conducted this systematic review and meta-analysis to clarify the association between UPF intake and CRC risk. Methods: PubMed/MEDLINE, Web of Science, EMBASE, China National Knowledge Infrastructure (CNKI) and Wan fang databases were used to search the relevant studies published up to February 2023. The summary relative risks (RRs) with the corresponding 95% confidence intervals (CIs) were estimated by comparing the highest category vs. the lowest category of UPF intake, using the random-effects models (DerSimonian-Laird method). Heterogeneity between studies was explored using the Cochran's Q test and I-square (I2). Publication bias was assessed by examining the funnel plots, and quantified by Begg's or Egger's tests. Results: A total of seven articles (three cohort and four case-control studies), involving 18,673 CRC cases and 462,292 participants, were included in our study. Combining nine effect sizes from seven articles, an increased risk of CRC was shown in the highest compared with the lowest category of UPF intake (RR = 1.26; 95%CI:1.14-1.38, p < 0.0001). Subgroup analyses showed a positive association between UPF intake and CRC risk in case-control studies (RR = 1.41; 95%CI: 1.22-1.63, p < 0.0001). When we conducted analyses separately by study area, there was a significant association between UPF intake and CRC risk in developed countries (RR = 1.20; 95%CI: 1.11-1.30, p < 0.0001). Conclusion: Our results show that high UPF intake is significantly associated with a higher risk of CRC, in the absence, however, of a dose-response association. Further studies in particular of large prospective cohort studies are necessary to confirm these results.

The ubiquitin-specific protease 5 mediated deubiquitination of LSH links metabolic regulation of ferroptosis to hepatocellular carcinoma progression.

Epigenetic regulators and posttranslational modifications of proteins play important roles in various kinds of cancer cell death, including ferroptosis, a non-apoptotic form of cell death. However, the interplay of chromatin modifiers and deubiquitinase (DUB) in ferroptosis remains unclear. Here, we found that ubiquitin-specific protease 5 (USP5) is regarded as a bona fide DUB of lymphoid-specific helicase (LSH), a DNA methylation repressor, in hepatocellular carcinoma (HCC). Functional studies reveal that USP5 interacts with LSH and stabilizes LSH by a deubiquitylation activity-dependent process. Furthermore, the USP5-mediated deubiquitination of LSH facilitates the tumorigenesis of HCC by upregulating solute carrier family 7 member 11 (SLC7A11) to suppress ferroptosis of liver cancer cells. Moreover, the USP5 inhibitor degrasyn inhibits DUB activities of USP5 to LSH to suppress the progression of HCC. Additionally, USP5 and LSH are positively correlated and both are overexpressed and linked to poor prognosis in HCC patients. Together, our findings show that USP5 interacts with LSH directly and enhances LSH protein stability through deubiquitination, which, in turn, promotes the development of HCC by suppressing ferroptosis of liver cancer cells, suggesting that USP5 may be a potential therapeutic target for HCC.

Promoting liver cancer cell apoptosis effect of Tribulus terrestris L. via reducing sphingosine level was confirmed by network pharmacology with metabolomics.

Background: Tribulus terrestris L. (TT) is one of the most common Chinese herbs and distributes in various regions in China. TT was first documented to treat breast cancer in Shen-Nong-Ben-Cao-Jing. However, the pharmacological activities of TT extract on liver cancer have not been reported. In this study, we investigated its anti-liver cancer activity and underlying mechanism. Methods: Traditional Chinese Medicine Systems Pharmacology (TCMSP) and PharmMapper databases were used to obtain the active ingredients and the targets of TT. Genecards database was employed to acquire TT targets in liver cancer. Furthermore, Venny 2.1, Cytoscape 3.8.2, DAVID 6.8 software were utilized to analyze the relationship between TT and liver cancer. In vivo experiment: The animal model of liver cancer was established by injection of H22 cells into Balb/c mice. After five days, drugs were intragastrically administered to the mice daily for 10 days. Body weight, tumor size and tumor weight were recorded. Tumor inhibitory rate was calculated. Protein levels were examined by Western blotting. Pathological changes of liver cancer tissues were evaluated by HE and Tunel staining. Metabolomics study: LC-MS was used to analyze different metabolites between model and TTM groups. Results: 12 active ingredients of TT, 127 targets of active ingredients, 17,378 targets of liver cancer, and 125 overlapping genes were obtained. And then, 118 items of GO biological processes (BP), 54 items of GO molecular function (MF), 35 items of GO cellular component (CC) and 128 pathways of KEGG were gotten (P < 0.05). Moreover, 47 differential metabolites were affirmed and 66 pathways of KEGG (P < 0.05) were obtained. In addition, after TT and sorafenib treatment, tumor size was markedly reduced, respectively, compared with model group. Tumor weight was significantly decreased and tumor inhibitory rate was more than 44% in TTM group. After TT treatment, many adipocytes, cracks between tumor cells and apoptosis were found. The levels of pro-Cathepsin B, Cathepsin B, Bax, Bax/Bcl2, Caspase3 and Caspase7 were markedly increased, but the level of Bcl2 was significantly reduced after TT treatment. Conclusion: TT has a broad range of effects on various signaling pathways and biological processes, including the regulation of apoptosis. It exhibits antitumor activity in an animal model of liver cancer and activates the apoptotic pathway by decreasing Sph level. This study provides valuable information regarding the potential use of TT extract in the treatment of liver cancer and highlights the importance of investigating the underlying molecular mechanisms of traditional medicines for the development of new therapeutic drugs in liver cancer.

Nitric Oxide Synthases in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe joint damage and disability. However, the specific mechanism of RA has not been thoroughly clarified over the past decade. Nitric oxide (NO), a kind of gas messenger molecule with many molecular targets, is demonstrated to have significant roles in histopathology and homeostasis. Three nitric oxide synthases (NOS) are related to producing NO and regulating the generation of NO. Based on the latest studies, NOS/NO signaling pathways play a key role in the pathogenesis of RA. Overproduction of NO can induce the generation and release of inflammatory cytokines and act as free radical gas to accumulate and trigger oxidative stress, which can involve in the pathogenesis of RA. Therefore, targeting NOS and its upstream and downstream signaling pathways may be an effective approach to managing RA. This review clearly summarizes the NOS/NO signaling pathway, the pathological changes of RA, the involvement of NOS/NO in RA pathogenesis and the conventional and novel drugs based on NOS/NO signaling pathways that are still in clinical trials and have good therapeutic potential in recent years, with an aim to provide a theoretical basis for further exploration of the role of NOS/NO in the pathogenesis, prevention and treatment of RA.