Abstract
Background
DNA Polymerase Theta (POLQ) is a DNA polymerase involved in error-prone translesion DNA synthesis (TLS) and error-prone repair of DNA double-strand breaks (DSBs), whose function ...in hepatocellular carcinoma has not been investigated.
Methods
In the present study, both the data collected from the Cancer Genome Atlas (TCGA) and our group’s results showed higher POLQ expression in HCC tissues than the para-cancerous tissues, which was associated with higher malignancy and poor prognosis. POLQ knockdown HCC cell model (shPOLQ) was constructed along with the corresponding negative control (shCtrl) through lentivirus infection for loss-of-function study.
Results
We found that, upon knockdown of POLQ, the proliferation and migration of HCC cells decreased and apoptosis percentage increased. Moreover, the percentage of cells in G2 phase significantly increased in shPOLQ group compared with shCtrl group. Xenografts in mice grafted with shPOLQ cells grew much slower than that transplanted with shCtrl cells, and expressed lower Ki67 level. Furthermore, an apoptosis-related signaling array was used to explore the involvement of downstream signaling pathways, suggesting the enhanced phosphorylation of HSP27 and JNK, and the de-activation of mTOR, PRAS40, ERK1/2 and STAT3 pathways.
Conclusions
Collectively, our study revealed that POLQ may participate in the development of HCC, depletion of which may be a promising treatment strategy for HCC.
Inflammatory bowel diseases have been a risk factor of colorectal cancer (CRC). The reactive oxygen species (ROS) generated by inflammatory cells create oxidative stress and contribute to neoplastic ...transformation, proliferation, and even metastasis. Previously, resveratrol (RS) and pterostilbene (PS) had been reported to prevent chemical-induced colon carcinogenesis by anti-inflammatory and pro-apoptotic properties. In this study, we investigated whether RS and PS could prevent the azoxymethane (AOM)-induced colon tumorigenesis via antioxidant action and to explore possible molecular mechanisms. Male BALB/c mice were injected with AOM (5 mg/kg of body weight) with or without RS or PS, and at the end of the protocol, all of the mice were euthanized and colons were analyzed. Administrations of PS can be more effective than RS in reducing AOM-induced formation of aberrant crypt foci (ACF), lymphoid nodules (LNs), and tumors. We also find that PS is functioning more effectively than RS to reduce nuclear factor-κB (NF-κB) activation by inhibiting the phosphorylation of protein kinase C-β2 (PKC-β2) and decreasing downstream target gene expression, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and aldose reductase (AR) in mouse colon stimulated by AOM. Moreover, administration of RS and PS for 6 weeks significantly enhanced expression of antioxidant enzymes, such as heme oxygenase-1 (HO-1) and glutathione reductase (GR), via activation of NF-E2-related factor 2 (Nrf2) signaling. When the above findings are taken together, they suggest that both stilbenes block cellular inflammation and oxidative stress through induction of HO-1 and GR, thereby preventing AOM-induced colon carcinogenesis. In comparison, PS was a more potent chemopreventive agent than RS for the prevention of colon cancer. This is also the first study to demonstrate that PS is a Nrf2 inducer and AR inhibitor in the AOM-treated colon carcinogenesis model.
While fecal microbiota transplantation (FMT) shows promise in treating human diseases, oral capsule FMT is more accepted and accessible to patients. However, microbe selection in the upper ...gastrointestinal tract (UGIT) through oral administration remains unclear. Here, we demonstrate that short-term oral fecal gavage (OFG) alleviates acetaminophen-induced acute liver injury (AILI) in mice, regardless of the divergent effects of commensal gut microbes. Pasteurized fecal gavage yields similar therapeutic effects. OFG enriches gut Lachnospiraceae and butyrate compared to donor feces. Butyrate mitigates AILI-induced ferroptosis via AMPK-ULK1-p62 signaling to simultaneously induce mitophagy and Nrf2 antioxidant responses. Combined N-acetylcysteine and butyrate administration significantly improves AILI mouse survival rates. These observations indicate the significance of the UGIT in modulating the implanted fecal microbes through oral administration and its potential biological and clinical impacts. Our findings also highlight a possible strategy for applying microbial metabolites to treat acute liver injury.
Display omitted
•Oral fecal gavage (OFG) or pasteurized fecal gavage (OPG) mitigates AILI in mice•OFG and OPG enrich gut Lachnospiraceae and butyrate by UGI tract•Butyrate suppresses ferroptosis via activating AMPK-P62-Nrf2 signaling and mitophagy•Combined N-acetylcysteine and butyrate therapy significantly reduces AILI mortality
Yang et al. show that oral fecal gavage (OFG) reshapes gut microbiota, protecting mice from acetaminophen-induced liver injury (AILI). OFG enriches gut Lachnospiraceae and butyrate. Butyrate counteracts AILI-related ferroptosis through Nrf2 antioxidant signaling and mitophagy, highlighting upper gastrointestinal tract microbial selection and potential for microbial metabolites in AILI treatment.
During biological aging, significant metabolic dysregulation in the central nervous system may lead to cognitive decline and neurodegeneration. However, the metabolomics of the aging process in ...cerebrospinal fluid (CSF) has not been thoroughly explored.
In this cohort study of CSF metabolomics using liquid chromatography-mass spectrometry (LC-MS), fasting CSF samples collected from 92 cognitively unimpaired adults aged 20-87 years without obesity or diabetes were analyzed.
We identified 37 metabolites in these CSF samples with significant positive correlations with aging, including cysteine, pantothenic acid, 5-hydroxyindoleacetic acid (5-HIAA), aspartic acid, and glutamate; and two metabolites with negative correlations, asparagine and glycerophosphocholine. The combined alterations of asparagine, cysteine, glycerophosphocholine, pantothenic acid, sucrose, and 5-HIAA showed a superior correlation with aging (AUC = 0.982). These age-correlated changes in CSF metabolites might reflect blood-brain barrier breakdown, neuroinflammation, and mitochondrial dysfunction in the aging brain. We also found sex differences in CSF metabolites with higher levels of taurine and 5-HIAA in women using propensity-matched comparison.
Our LC-MS metabolomics of the aging process in a Taiwanese population revealed several significantly altered CSF metabolites during aging and between the sexes. These metabolic alterations in CSF might provide clues for healthy brain aging and deserve further exploration.
Sarcopenia is defined as the disease of muscle loss and dysfunction. The prevalence of sarcopenia is strongly age-dependent. It could bring about disability, hospitalization, and mortality. The ...purpose of this study was to identify plasma metabolites associated with possible sarcopenia and muscle function to improve disease monitoring and understand the mechanism of muscle strength and function decline.
The participants were a group of healthy older adult who live in retirement homes in Asia (Taiwan) and can manage their daily lives without assistance. The participants were enrolled and divided into four groups: control (Con, n = 57); low physical function (LPF, n = 104); sarcopenia (S, n = 63); and severe sarcopenia (SS, n = 65) according to Asian countries that used Asian Working Group for Sarcopenia (AWGS) criteria. The plasma metabolites were used and the results were calculated as the difference between the control and other groups.
Clinical parameters, age, gender, body mass index (BMI), hand grip strength (HGS), gait speed (GS), blood urea nitrogen (BUN), hemoglobin, and hematocrit were significantly different between the control and LPF groups. Metabolite patterns of LPF, S, and SS were explored in our study. Plasma kynurenine (KYN) and acylcarnitines (C0, C4, C6, and C18:1-OH) were identified with higher concentrations in older Taiwanese adults with possible sarcopenia and S compared to the Con group. After multivariable adjustment, the data indicate that age, BMI, and butyrylcarnitine (C4) are more important factors to identify individuals with low physical function and sarcopenia.
This metabolomic study raises the importance of acylcarnitines on muscle mass and function. It suggests that age, BMI, BUN, KYN, and C4/Cr can be important evaluation markers for LPF (AUC: 0.766), S (AUC: 0.787), and SS (AUC: 0.919).
The development of rosacea is suggested to be closely associated with lipid metabolism, inflammation, and anxiety/depression. Gamma linolenic acid (GLA) is a key factor participating in lipid ...metabolism, which is also confirmed to regulate the inflammatory response. However, the associations of serum GLA levels with rosacea severity and psychological status still remain unclear.
The present study aimed to investigate the associations of gamma linolenic acid (GLA), a key factor participating in lipid metabolism and the inflammatory response, with rosacea severity and psychological status. The present study still had some limitations. First, this study is a cross-sectional study and does not provide longitudinal evidence about the relationship between GLA and rosacea; Second, the cohort in this study is also relatively small, and a larger cohort is needed in further investigation to reveal the potential role of lipid metabolism in the pathogenesis of rosacea.
A total of 62 rosacea patients were consecutively recruited. Patient’s Self-Assessment (PSA) scale and Clinician Erythema Assessment (CEA) as well as 7-item Generalized Anxiety Disorder (GAD-7) and 9-item Patient Health Questionnaire (PHQ-9) were conducted to evaluate the degree of erythema severity and anxiety/depression, respectively. Serum GLA levels were determined by gas chromatography mass.
Lower levels of serum GLA in rosacea patients were observed (p<0.001), and subgroup analysis revealed that patients with higher-level GLA had lower scores of PSA, CEA, GAD-7 and PHQ-9. Moreover, Spearman correlation analysis uncovered that serum GLA levels were negatively associated with PSA, CEA, GAD-7 as well and PHQ-9 scores, respectively. Linear regression model found that serum GLA levels at baseline were a predictive factor for prognosis of clinical outcomes after 1-month conventional treatment.
The present study indicates that lower levels of serum GLA in rosacea patients are negatively associated with the degree of erythema and anxiety/depression status.
Aging is defined as a normal decline in survival with advancing age; however, the recent researches have showed that physiological functions of the body change during the aging process. Majority of ...the changes are often subject to a higher risk of developing diseases, such as cardiovascular disease, type II diabetes, Alzheimer's disease, Parkinson's disease, as well as the dysregulated immune and inflammatory disorders. Aging process is controlled by a complicated and precise signaling network that involved in energy homeostasis, cellular metabolism and stress resistance. Over the past few decades, research in natural dietary compounds by various organism and animal models provides a new strategy for anti‐aging. Natural dietary compounds act through a variety mechanisms to extend lifespan and prevent age‐related diseases. This review summarizes the current understanding on signaling pathways of aging and knowledge and underlying mechanism of natural dietary compounds that provide potential application on anti‐aging and improve heath in human.
Impairment of adiponectin production and function is closely associated with insulin resistance and type 2 diabetes, which are linked to obesity. Studies in animal models have documented the ...anti-diabetic effects of tetrahydrocurcumin (THC). Although several possible mechanisms have been proposed, the contribution of adiponectin signaling on THC-mediated antihyperglycemic effects remains unknown. Here, we report that adiposity, steatosis, and hyperglycemia were potently attenuated in high-fat diet/streptozotocin-induced diabetic obese mice after they received 20 and 100 mg/kg THC for 14 weeks. THC upregulated UCP-1 in adipose tissue and elevated adiponectin levels in the circulation. THC upregulated the AdipoR1/R2-APPL1-mediated pathway in the liver and skeletal muscle, which contributes to improved insulin signaling, glucose utilization, and lipid metabolism. Furthermore, THC treatment significantly (
< 0.05) preserved islet mass, reduced apoptosis, and restored defective insulin expression in the pancreatic β-cells of diabetic obese mice, which was accompanied by an elevation of AdipoR1 and APPL1. These results demonstrated a potential mechanism underlying the beneficial effects of THC against hyperglycemia via the adiponectin-AdipoR pathway, and thus, may lead to a novel therapeutic use for type 2 diabetes.
PDF
