First People's Hospital of Kunshan

The systemic immune-inflammation index (SII) based on peripheral lymphocyte, neutrophil and platelet counts has been considered a good index that reflects the local immune response and systemic inflammation. However, the use of the SII has not been reported in cervical cancer. In this study, Kaplan-Meier survival analysis showed that a high SII was associated with poor prognosis in cervical cancer patients in the primary and validation cohorts. A higher SII had a significant correlation with larger tumours but had no correlation with other clinicopathological parameters. Among all systemic immune indexes, the SII is the only independent prognostic factor for cervical cancer patients. Compared with the area under the curve for the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and monocyte/lymphocyte ratio (MLR), the area for the SII was larger at 3 and 5 years. In addition, the SII still retains it prognostic values across all FIGO stages. The SII can independently predict the overall survival of patients with cervical cancer receiving radical resection and is thus superior to existing systemic inflammatory indexes. The prognostic nomogram based on the SII is a reliable model for predicting the postoperative survival of patients with cervical cancer.

Abstract The aim of this study was to investigate the effect of quercetin on hepatic fibrosis, a characteristic response to acute or chronic liver injury. Mice were randomized to bile duct ligation (BDL) or carbon tetrachloride (CCl 4 ) cirrhosis models. Quercetin (100 mg/kg or 200 mg/kg daily) was administered by gavage for 2 or 4 weeks. Liver tissue and blood samples were collected for histological and molecular analysis. The results of our experiments showed that quercetin reduced BDL or CCl 4 liver fibrosis, inhibited extracellular matrix formation, and regulated matrix metallopeptidase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1. Quercetin attenuated liver damage by suppressing the TGF-β1/Smads signaling pathway and activating the PI3K/Akt signaling pathway to inhibit autophagy in BDL- or CCl 4 - induced liver fibrosis. Quercetin prevented hepatic fibrosis by attenuating hepatic stellate cell activation and reducing autophagy through regulating crosstalk between the TGF-β1/Smads and PI3K/Akt pathways.

We previously established a rat model of diabetic cardiomyopathy (DCM) and found that the expression of lncRNA H19 was significantly downregulated. The present study was designed to investigate the pathogenic role of H19 in the development of DCM. Overexpression of H19 in diabetic rats attenuated oxidative stress, inflammation and apoptosis, and consequently improved left ventricular function. High glucose was associated with reduced H19 expression and increased cardiomyocyte apoptosis. To explore the molecular mechanisms involved, we performed in vitro experiments using cultured neonatal rat cardiomyocytes. Our results showed that miR-675 expression was decreased in cardiomyocytes transfected with H19 siRNA. The 3'UTR of VDAC1 was cloned downstream of a luciferase reporter construct and cotransfected into HEK293 cells with miR-675 mimic. The results of luciferase assay indicated that VDAC1 might be a direct target of miR-675. The expression of VDAC1 was upregulated in cardiomyocytes transfected with miR-675 antagomir, which consequently promotes cellular apoptosis. Moreover, enforced expression of H19 was found to reduce VDAC1 expression and inhibit apoptosis in cardiomyocytes exposed to high glucose. In conclusion, our study demonstrates that H19/miR-675 axis is involved in the regulation of high glucose-induced apoptosis by targeting VDAC1, which may provide a novel therapeutic strategy for the treatment of DCM.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in the elderly and the ambient concentration of PM2.5 has been associated with several cardiovascular diseases. METHODS: We describe the present state of planetary air pollution, analyze epidemiological studies linking PM2.5 and CVD, and discuss multiple pathophysiological mechanisms linking PM2.5 and CVD. RESULTS: A few epidemiological studies show that the elderly appear specifically susceptible to adverse cardiovascular effects triggered by PM2.5 exposure. Plausible pathophysiological mechanisms include inflammatory dysfunction, oxidative stress, abnormal activation of the hemostatic system and disturbance of the autonomic nervous system. CONCLUSIONS: An in-depth knowledge of the chemical compounds, pathophysiological mechanisms, and epidemiological studies of PM2.5 are recommended to understand this important and modifiable factor contributing to geriatric CVD burden. We offer public health recommendations to reduce this preventable cause of disease and death.

BACKGROUND: We have previously discovered a relationship between the low expression of protein tyrosine phosphatase, receptor type O (PTPRO) in tumor-infiltrating T cells and immunosuppression. The aim of the present study was to investigate the relationship between decreased PTPRO and increased programmed death ligand 1 (PD-L1) in both the peripheral monocytes and tumor-infiltrating macrophages of human hepatocellular carcinoma (HCC). METHODS: The expression and correlation of all the indices were explored in monocytes and tumor-infiltrating macrophages within both human and mice HCC. The mechanic regulations were studied by using both in vitro and in vivo studies. RESULTS: We found a significant decrease in PTPRO in HCC peripheral monocytes that was associated with increased PD-L1 expression in peripheral monocytes and tumor-associated macrophages (TAMs) in HCC. Monocyte PD-L1 and PTPRO therefore could serve as valuable prognostic indicators for post-surgery patients with HCC and were associated with increased T-cell exhaustion (Tim3+T cells). A depletion of PTPRO promoted PD-L1 secretion in both monocytes and macrophages through the JAK2/STAT1 and JAK2/STAT3/c-MYC pathways. Increased IL-6 expression was associated with activation of JAK2/STAT3/c-MYC and with decreased PTPRO expression through the STAT3/c-MYC/miR-25-3 p axis. Monocytes and TAMs showed significantly increased miR-25-3 p expression, which could target the 3' untranslated region of PTPRO. The miR-25-3 p expression positively correlated with serum IL-6 levels, but inversely correlated with PTPRO in HCC monocytes. IL-6/STAT3/c-MYC activation enhanced in vitro miR-25-3 p transcription and decreased PTPRO, while further promoting PD-L1 secretion. Adoptive cell transfer of c-MYC/miR-25-3 p-modified monocytes promoted tumor growth by downregulating PTPRO and causing a PD-L1-induced immunosuppression in an orthotopic tumor transplantation model. CONCLUSIONS: Increased serum IL-6 downregulated PTPRO expression in HCC monocytes and macrophages by activating STAT3/c-MYC/miR-25-3 p and by further enhancing PD-L1 expression through JAK2/STAT1 and JAK2/STAT3/c-MYC signaling.

BACKGROUND: Several studies have suggested that neuron-specific enolase (NSE) in serum may be a biomarker of traumatic brain injury. However, whether serum NSE levels correlate with outcomes remains unclear. The purpose of this review was to evaluate the prognostic value of serum NSE protein after traumatic brain injury. METHODS: PubMed and Embase were searched for relevant studies published up to October 2013. Full-text publications on the relationship of NSE to TBI were included if the studies concerned patients with closed head injury, NSE levels in serum after injury, and Glasgow Outcome Scale (GOS) or Extended GOS (GOSE) scores or mortality. Study design, inclusion criteria, assay, blood sample collection time, NSE cutoff, sensitivity and specificity of NSE for mortality prediction (if sufficient information was provided to calculate these values), and main outcomes were recorded. RESULTS: Sixteen studies were eligible for the current meta-analysis. In the six studies comparing NSE concentrations between TBI patients who died and those who survived, NSE concentrations correlated with mortality (M.D. 0.28, 95% confidence interval (CI), 0.21 to 0.34; I2 55%). In the eight studies evaluating GOS or GOSE, patients with unfavorable outcomes had significantly higher NSE concentrations than those with favorable outcomes (M.D. 0.24, 95% CI, 0.17 to 0.31; I2 64%). From the studies providing sufficient data, the pooled sensitivity and specificity for mortality were 0.79 and 0.50, and 0.72 and 0.66 for unfavorable neurological prognosis, respectively. The areas under the SROC curve (AUC) of NSE concentrations were 0.73 (95% CI, 0.66-0.80) for unfavorable outcome and 0.76 (95% CI, 0.62-0.90) for mortality. CONCLUSIONS: Mortality and unfavorable outcome were significantly associated with greater NSE concentrations. In addition, NSE has moderate discriminatory ability to predict mortality and neurological outcome in TBI patients. The optimal discrimination cutoff values and optimal sampling time remain uncertain because of significant variations between studies.

Over-expression of TROP2 (the trophoblast cell surface antigen 2) was reported to predict poor prognosis in various solid tumors in number of studies. However, the results remained not comprehensive. Therefore, we here carried out this meta-analysis of relevant studies published on this topic to quantitatively evaluate the clinicopathological significance of TROP2 in solid tumors. Relevant articles were identified through searching the PubMed, Web of Science and Embase database. The primary outcomes were overall survival (OS) and disease-free survival (DFS). In this meta-analysis, 16 studies involving 2,569 participants were included, and we drew the conclusion that TROP2 overexpression was significantly associated with poor OS (pooled HR = 1.896, 95% CI = 1.599-2.247, P < 0.001) and short DFS (pooled HR = 2.336, 95% CI = 1.596-3.419, P < 0.001). Furthermore, the subgroup analysis revealed that the associations between TROP2 overexpression and the outcome endpoints (OS or DFS) were significant in in patients with female genital system neoplasms, as well in gastrointestine neoplasms. In addition, subgroup analysis found no difference HR across populations of different descent.Taken together, TROP2 overexpression was associated with poor survival in human solid tumors. TROP2 may be a valuable prognosis predictive biomarker and a potential therapeutic target in human solid tumors.

BACKGROUND: Genistein is a natural isoflavone with many health benefits, including antitumour effects. Increased hypoxia-inducible factor 1 α (HIF-1α) levels and glycolysis in tumour cells are associated with an increased risk of mortality, cancer progression, and resistance to therapy. However, the effect of genistein on HIF-1α and glycolysis in hepatocellular carcinoma (HCC) is still unclear. METHODS: Cell viability, apoptosis rate, lactate production, and glucose uptake were measured in HCC cell lines with genistein incubation. Lentivirus-expressed glucose transporter 1 (GLUT1) or/and hexokinase 2 (HK2) and siRNA of HIF-1α were used to test the direct target of genistein. Subcutaneous xenograft mouse models were used to measure in vivo efficacy of genistein and its combination with sorafenib. RESULTS: Genistein inhibited aerobic glycolysis and induced mitochondrial apoptosis in HCC cells. Neither inhibitors nor overexpression of HK2 or GLUTs enhance or alleviate this effect. Although stabiliser of HIF-1α reversed the effect of genistein, genistein no longer has effects on HIF-1α siRNA knockdown HCC cells. In addition, genistein enhanced the antitumour effect of sorafenib in sorafenib-resistant HCC cells and HCC-bearing mice. CONCLUSIONS: Genistein sensitised aerobic glycolytic HCC cells to apoptosis by directly downregulating HIF-1α, therefore inactivating GLUT1 and HK2 to suppress aerobic glycolysis. The inhibitory effect of genistein on tumour cell growth and glycolysis may help identify effective treatments for HCC patients at advanced stages.

Abstract Vascularization is fundamental for bone formation and bone tissue homeostasis. However, in human subjects, a direct molecular relationship has not been identified between angiogenesis and agents that promote bone disease or factors related to age. Osteopenia is a condition in which bone mineral density is lower than normal, and it represents a sign of normal aging. Here we tested whether the type H vessel, which was recently identified as strongly positive for CD31 and Endomucin (CD31 hi Emcn hi ) in mice, is an important indicator of aging and osteopenia in human subjects. We found that age-dependent losses of type H vessels in human bone sections conform to the observations in aged mice. The abundance of human type H vessels and osteoprogenitors may be relevant to changes in the skeletal microarchitecture and advanced osteopenia. Furthermore, ovariectomized mice, a widely used model for postmenopausal osteoporosis, exhibited significantly reduced type H vessels accompanied by reduced osteoprogenitors, which is consistent with impaired bone microarchitecture and osteoporosis, suggesting that this feature is an indicator of bone mass independent of aging. More importantly, administration of desferrioxamine led to significantly increased bone mass via enhanced angiogenesis and increased type H vessels in ovariectomized mice. Altogether, these data represent a novel finding that type H vessels are regulated in aged and osteopenia subjects. The abundance of human type H vessels is an early marker of bone loss and represents a potential target for improving bone quality via the induction of type H vessels.

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 (HLA-DRA and DPB1), 17q12 (ORMDL3), 3q13.33 (CD80), 2q32.3 (STAT1/STAT4), 3q25.33 (IL12A), 4q24 (NF-κB) and 22q13.1 (RPL3/SYNGR1). We also identified variants in IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC.

BACKGROUND: The aim of this study is to investigate clinical significance of miR-155 expression in breast cancer. METHODS: TaqMan real-time RT-PCR was performed to detect miR-155 expression in breast cancer tissues. The correlation of miR-155 expression with clinicopathological factors and prognosis of breast cancer patients was analyzed. Then, the prognostic value of miR-155 expression was analyzed by univariate and multivariate analyses. Moreover, the effect of miR-155 expression on phenotypes of breast cancer cell was determined by antisense technology. RESULTS: The relative expression of miR-155 was significantly higher in breast cancer tissues than in corresponding nontumor tissues. High miR-155 expression was correlated with higher tumor grade, advanced tumor stage and lymph node metastasis (P = 0.012, 0.001, and 0.003, respectively). Kaplan-Meier survival analysis indicated that the disease-free and overall survival rates of high miR-155 group were significantly lower than those of low miR-155 group (P = 0.038 and 0.029, respectively). Multivariate analysis showed that high miR-155 expression was a poor prognostic factor (P = 0.009). Furthermore, antisense targeting miR-155 could inhibit growth, induce cell arrest in G(0) /G(1) phase, enhance apoptosis, and increase radiosensitivity in breast cancer cells. CONCLUSIONS: MiR-155 expression might be an independent prognostic factor and a therapeutic target for human breast cancer.

MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate protein expression by cleaving or repressing the translation of target mRNAs. miR-125b, one of the neuronal miRNAs, was recently found to be necessary for stem cell fission and for making stem cells insensitive to chemotherapy signals. Temozolomide (TMZ) is a promising chemotherapeutic agent for treating glioblastomas. However, resistance develops quickly and with a high frequency. Given the insensitivity of some glioblastomas to TMZ and the hypothesis that glioma stem cells cause resistance to drug therapy, exploring the functions and mechanisms of miR-125b action on TMZ-treated glioblastoma stem cells would be valuable. In this study, we found that miR-125b-2 is overexpressed in glioblastoma multiforme tissues and the corresponding stem cells (GBMSC); downregulation of miR-125b-2 expression in GBMSC could allow TMZ to induce GBMSC apoptosis. Additionally, the expression of the anti-apoptotic protein Bcl-2 was decreased after the TMZ+miR-125b-2 inhibitor treatment, while the expression of the proapoptotic protein Bax was increased. Further research demonstrated that the induction of apoptosis in GBMSC is also associated with increased cytochrome c release from mitochondria, induction of Apaf-1, activation of caspase-3 and poly-ADP-ribose polymerase (PARP). Taken together, these results suggest that miR-125b-2 overexpression might confer glioblastoma stem cells resistance to TMZ.

Purpose: Biomimetic approaches for the synthesis of silver nanoparticles (AgNPs) had created a substantial impression among the research community that focuses on nano-bio interactions. In this study, an eco-friendly method using Rhizophora apiculata aqueous leaf extract as a reductant-rich hydrosol was followed to synthesize AgNPs and test its cytotoxicity. Methods: To optimise the parameters for the synthesis of AgNPs, central composite design based on response surface methodology was used. The particles synthesized at a nano-scale were characterized in our previously published report. The present report further characterizes the nanoparticles by X-ray diffraction, SEM and TEM at varying sites and magnifications. The characterized AgNPs were tested for their cytotoxic effects on HEK-293 and HeLa cells. Results: The cytotoxicity on the cell lines was dose-dependent. At a concentration of 2.5 μL/mL of the AgNPs-containing hydrosol, 100% inhibition of HEK-293 cells and 75% inhibition of the HeLa cells were observed. The IC 50 value for AgNPs on HEK-293 was 0.622 μL/mL (12.135 ng), whereas, for HeLa cells, it was 1.98 μL/mL (38.629 ng). Conclusion: The nanoparticles were three-fold toxic towards the HEK-293 cells in comparison to the HeLa cells. Therefore, the therapeutic index is low for R. apiculata derived AgNPs on HeLa cells when tested in comparison with the HEK-293 cells. The nanotoxicity profile of the synthesized AgNPs seems more prominent than the nanotherapeutic index. According to our knowledge, this is the first-ever report on the optimization of synthesis of AgNPs using response surface methodology and identifying the therapeutic index of mangrove leaf-derived AgNPs. Keywords: AgNPs, XRD, HEK-293, HeLa, nanotoxicity

The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been presented to be a prognostic indicator in several types of cancer. However, these issues have not been concluded yet. The present study was therefore performed to determine the prognostic value of NLR and PLR in gastric cancer (GC).A total of 182 GC patients, diagnosed between January 2011 and January 2014, were enrolled in the study. The clinicopathological parameters, laboratory analyses, and outcomes were collected. The association between NLR, PLR, and clinicopathological characters was analyzed with univariate and multivariate analyses.NLR was significantly related to age (P = .026), surgery (P = .006), node status (P = .004), and clinical stage (P = .009). The median overall survival (OS) and progression-free survival (PFS) were poor in the High-NLR group (OS: 36.0 vs 20.5 months, P < .001, PFS: 33.0 vs 12.0 months, P < .001) and High-PLR group (OS: 31.5 vs 18.5 months, P = .003, PFS: 26.0 vs 11.0 months, P = .01). Multivariate analyses indicated both surgery [for OS hazard ratio (HR) = 2.092, 95% confidence interval (95% CI): 1.345-3.253, P = .001; for PFS HR = 1.939, 95% CI: 1.259-2.988, P = .003] and NLR (for OS HR = 1.585, 95% CI: 1.011-2.485, P = .045) were independent prognostic factors.Elevated NLR and PLR were related with poor prognosis in GC patients before treatment. The NLR was an independent prognostic factor for OS. More studies should be conducted to address the potential prognostic value of NLR and PLR in GC.

Hepatocellular carcinoma (HCC) is one of the few cancers with a continuous increase in incidence and mortality. Drug resistance is a major problem in the treatment of HCC. In this study, two sorafenib-resistant HCC cell lines and a nude mouse subcutaneously tumor model were used to explore the possible mechanisms leading to sorafenib resistance, and to investigate whether aspirin could increase the sensitivity of hepatoma cells to sorafenib. The combination of aspirin and sorafenib resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. High glycolysis and PFKFB3 overexpression occupied a dominant position in sorafenib resistance, and can be targeted and overcome by aspirin. Aspirin plus sorafenib induced apoptosis in tumors without inducing weight loss, hepatotoxicity or inflammation. Our results suggest that aspirin overcomes sorafenib resistance and their combination may be an effective treatment approach for HCC.

Background. Triglyceride-glucose (TyG) index is a convenient indicator of insulin resistance. It has been shown to be associated with macrovascular and microvascular complications in nonhospitalized diabetic patients. However, whether TyG index is a risk factor of diabetes vascular complications in hospitalized type 2 diabetic patients is unclear. We sought to explore the association between TyG index and the risk of macrovascular and microvascular complications in a large Chinese cohort of hospitalized patients. Method. A total of 4,721 patients with type 2 diabetes (T2D) who were hospitalized in the Department of Endocrinology, Kunshan Hospital Affiliated to Jiangsu University were enrolled between January 2015 and November 2020. TyG index was calculated as <a:math xmlns:a="http://www.w3.org/1998/Math/MathML" id="M1"> <a:mi mathvariant="normal">ln</a:mi> <a:mfenced open="[" close="]"> <a:mrow> <a:mtext>fasting</a:mtext> <a:mtext> </a:mtext> <a:mtext>triglycerides</a:mtext> <a:mtext> </a:mtext> <a:mfenced open="(" close=")"> <a:mrow> <a:mtext>mg</a:mtext> <a:mo>/</a:mo> <a:mtext>dL</a:mtext> </a:mrow> </a:mfenced> <a:mo>×</a:mo> <a:mtext>fasting</a:mtext> <a:mtext> </a:mtext> <a:mtext>glucose</a:mtext> <a:mtext> </a:mtext> <a:mfenced open="(" close=")"> <a:mrow> <a:mtext>mg</a:mtext> <a:mo>/</a:mo> <a:mtext>dL</a:mtext> </a:mrow> </a:mfenced> <a:mo>/</a:mo> <a:mn>2</a:mn> </a:mrow> </a:mfenced> </a:math> . Measures of macrovascular complications included brachial-ankle pulse wave velocity (ba-PWV) and ankle-brachial index (ABI), whilst urine microalbumin (MAU), chronic kidney disease (CKD), and diabetic retinopathy (DR) were evaluated for microvascular complications. Logistic regressions were used to examine the association between TyG index and diabetes complications. Results. In univariate logistic regressions, higher TyG index was significantly ( <j:math xmlns:j="http://www.w3.org/1998/Math/MathML" id="M2"> <j:mi>p</j:mi> <j:mo>&lt;</j:mo> <j:mn>0.002</j:mn> </j:math> ) associated with increased odds of MAU ( <l:math xmlns:l="http://www.w3.org/1998/Math/MathML" id="M3"> <l:mtext>OR</l:mtext> <l:mo>=</l:mo> <l:mn>1.39</l:mn> </l:math> , 95% CI: [1.22~1.59]) and ABI ( <n:math xmlns:n="http://www.w3.org/1998/Math/MathML" id="M4"> <n:mtext>OR</n:mtext> <n:mo>=</n:mo> <n:mn>1.31</n:mn> </n:math> , 95% CI: [1.10-1.57]) but not CKD, DR, or ba-PWV. After controlling for confounders such as age, sex, and body mass index (BMI), TyG index remained strongly ( <p:math xmlns:p="http://www.w3.org/1998/Math/MathML" id="M5"> <p:mi>p</p:mi> <p:mo>&lt;</p:mo> <p:mn>0.002</p:mn> </p:math> ) associated with MAU and ABI. These associations were more pronounced ( <r:math xmlns:r="http://www.w3.org/1998/Math/MathML" id="M6"> <r:mi>p</r:mi> <r:mo>&lt;</r:mo> <r:mn>0.001</r:mn> </r:math> ) in patients with poor glycemic control or in the elderly. Conclusion. Hospitalized patients with an elevated TyG index were at a higher risk of lower limb vascular stenosis and nephric microvascular damage. Close monitoring of TyG index in patients with younger age or poor glycemic control could potentially reduce the burden of diabetes complications and prevent readmission.

BACKGROUND: Alanine transaminase (ALT) plays an important role in gluconeogenesis by converting alanine into pyruvate for glucose production. Early studies have shown that ALT activities are upregulated in gluconeogenic conditions and may be implicated in the development of diabetes. ALT consists of two isoforms, ALT1 and ALT2, with distinctive subcellular and tissue distributions. Whether and how they are regulated are largely unknown. METHODS: By using Western blotting analysis, we measured hepatic ALT isoforms at the protein level in obese and diabetic animals and in Fao hepatoma cells treated with dexamethasone and insulin. In addition, we measured glucose output in Fao cells over-expressing ALT1 and ALT2. RESULTS: Both ALT isoforms in the liver were increased in diabetic Goto-Kakizaki rats and during fasting. However, in ob/ob mice, only ALT2, but not ALT1, protein levels were elevated, and the increase of ALT2 was correlated with that of ALT activity. We further demonstrated that, in vitro, both ALT1 and ALT2 were induced by glucocorticoid dexamethasone, but suppressed by insulin in Fao cells. Finally, we showed that the over-expression of ALT1 and ALT2 in Fao cells directly increased glucose output. CONCLUSIONS: We have shown the similarity and difference in the regulation of ALT isoforms in gluconeogenic conditions at the protein level, supporting that ALT isoenzymes play an important role in glucose metabolism and may be implicated the development of insulin resistance and diabetes.

Ferroptosis and cuproptosis, regulated forms of cell death resulting from metal ion accumulation, are closely related in terms of occurrence, cell metabolism, signaling pathways, and drug resistance. Notably, it is now understood that these processes play crucial roles in regulating physiological and pathological processes, especially in tumor development. Consequently, ferroptosis and cuproptosis have gained increasing significance as potential targets for anti-cancer drug development. This article systematically outlines the molecular mechanisms and cross-talk components of both ferroptosis and cuproptosis, elucidating their impacts on cancer. Furthermore, it investigates the clinical perspective of targeted ferroptosis and cuproptosis in cancer chemotherapy, immunotherapy, and radiotherapy. Our discussion extends to a comparative analysis of nanoparticles developed based on the mechanisms of ferroptosis and cuproptosis in cancer, contrasting them with current conventional therapies. Opportunities and challenges in cancer treatment are explored, emphasizing the potential therapeutic direction of co-targeting ferroptosis and cuproptosis. The article also attempts to analyze the clinical applications of this co-targeting approach for cancer treatment while summarizing the existing barriers that require overcoming.

MicroRNA-21 was upexpressed in gastric cancer (GC) indicating that it is a potential diagnostic biomarker for GC. In this study, 50 GC patients and 50 healthy controls were recruited. miR-21 levels in serum and peripheral blood mononuclear cells (PBMCs) were quantified using quantitative real-time PCR. CA199, and CEA were measured using electrochemiluminescence assay. The sensitivity and specificity of circulating miR-21, CA199 and CEA in GC diagnosis, the correlation of circulating miR-21 to clinicopathological features, and the diagnostic value of miR-21 in different GC stages were determined. The levels of miR-21 in both serum and PBMCs increased significantly in GC patients comparing to healthy controls; however, no correlation was observed between circulating miR-21 level and clinicopathological features. The sensitivity and specificity of miR-21 in serum and PBMCs, and CA199 and CEA in GC diagnosis were 88.4%, 79.6%, 81.3%, 73.4%, 60.5%, 55.9%, and 68.6%, 59.3%, respectively. The positive prediction rates of circulating miR-21 in GC stages I to IV were all around 90%, while those of CA199 and CEA were around or less than 50%. Our data suggest circulating miR-21 (both in serum and in PBMCs) can serve as a good biomarker for GC and could be used in diagnosis of early (stage I) and late GC (stage IV).

Four-octyl itaconate (OI), the itaconate’s cell-permeable derivative, can activate Nrf2 signaling via alkylation of Keap1 at its cysteine residues. The current study tested the potential neuroprotective function of OI in hydrogen peroxide (H2O2)-treated neuronal cells. SH-SY5Y neuronal cells and epigenetically de-repressed (by TSA treatment) primary murine neurons were treated with OI and/or H2O2. Nrf2 pathway genes were examined by Western blotting assay and real-time quantitative PCR analysis. Neuronal cell death was tested by the LDH and trypan blue staining assays. Apoptosis was tested by TUNEL and Annexin V assays. In SH-SY5Y neuronal cells and primary murine neurons, OI activated Nrf2 signaling, causing Keap1-Nrf2 disassociation, Nrf2 protein stabilization and nuclear translocation, as well as expression of Nrf2-regulated genes (HO1, NQO1 and GCLC) and ninjurin2 (Ninj2). Functional studies showed that OI attenuated H2O2-induced reactive oxygen species (ROS) production, lipid peroxidation and DNA damage as well as neuronal cell death and apoptosis. shRNA-mediated knockdown, or CRISPR/Cas9-induced knockout of Nrf2 almost abolished OI-induced neuroprotection against H2O2. Keap1 is the primary target of OI. Keap1 knockout by CRISPR/Cas9 method mimicked and abolished OI-induced actions in SH-SY5Y cells. Introduction of a Cys151S mutant Keap1 in SH-SY5Y cells reversed OI-induced Nrf2 activation and anti-H2O2 neuroprotection. OI activates Keap1-Nrf2 signaling to protect SH-SY5Y cells and epigenetically de-repressed primary neurons from H2O2 in vitro.