Understanding, diagnosing, and treating pancreatic cancer from the perspective of telomeres and telomerase.

Telomerase is associated with cellular aging, and its presence limits cellular lifespan. Telomerase by preventing telomere shortening can extend the number of cell divisions for cancer cells. In adult pancreatic cells, telomeres gradually shorten, while in precancerous lesions of cancer, telomeres in cells are usually significantly shortened. At this time, telomerase is still in an inactive state, and it is not until before and after the onset of cancer that telomerase is reactivated, causing cancer cells to proliferate. Methylation of the telomerase reverse transcriptase (TERT) promoter and regulation of telomerase by lactate dehydrogenase B (LDHB) is the mechanism of telomerase reactivation in pancreatic cancer. Understanding the role of telomeres and telomerase in pancreatic cancer will help to diagnose and initiate targeted therapy as early as possible. This article reviews the role of telomeres and telomerase as biomarkers in the development of pancreatic cancer and the progress of research on telomeres and telomerase as targets for therapeutic intervention.

A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis.

BACKGROUND: CPUL1, a phenazine analog, has demonstrated potent antitumor properties against hepatocellular carcinoma (HCC) and indicates a promising prospect in pharmaceutical development. However, the underlying mechanisms remain largely obscure. METHODS: Multiple HCC cell lines were used to investigate the in vitro effects of CPUL1. The antineoplastic properties of CPUL1 were assessed in vivo by establishing a xenograft nude mice model. After that, metabolomics, transcriptomics, and bioinformatics were integrated to elucidate the mechanisms underlying the therapeutic efficacy of CPUL1, highlighting an unanticipated involvement of autophagy dysregulation. RESULTS: CPUL1 suppressed HCC cell proliferation in vitro and in vivo, thereby endorsing the potential as a leading agent for HCC therapy. Integrative omics characterized a deteriorating scenario of metabolic debilitation with CPUL1, presenting an issue in the autophagy contribution of autophagy. Subsequent observations indicated that CPUL1 treatment could impede autophagic flow by suppressing autophagosome degradation rather than its formation, which supposedly exacerbated cellular damage triggered by metabolic impairment. Moreover, the observed late autophagosome degradation may be attributed to lysosome dysfunction, which is essential for the final stage of autophagy and cargo disposal. CONCLUSIONS: Our study comprehensively profiled the anti-hepatoma characteristics and molecular mechanisms of CPUL1, highlighting the implications of progressive metabolic failure. This could partially be ascribed to autophagy blockage, which supposedly conveyed nutritional deprivation and intensified cellular vulnerability to stress.

Association between secondhand smoke and cancers in adults in the US population.

BACKGROUND: Tobacco use is the leading preventable cause of cancer and premature death, smoking has a clear causal relationship with a variety of cancers. However, the relationship between exposure to secondhand smoke (SHS) and other cancers besides lung cancer is not clear. In this study, we intend to investigate the cancers mortality risks especially other cancers besides lung cancer associated with exposure to SHS. METHODS: The National Health and Nutrition Examination Survey is a longitudinal population-based, nationally representative health survey and mortality rates linked to the National Death Index (NDI) database. In this study, the participants completed a questionnaire assessing sociodemographic data, anthropometry, and lifestyle information, including smoking and alcohol consumption, meanwhile, all the participants were screened for serum cotinine. First, Spearman correlation analysis was performed to confirm the correlation between serum cotinine level and exposure status. And then, exposure to SHS was divided into two groups: low exposure group (serum cotinine level between 0.015 and 10) and high exposure group (serum cotinine level ≥ 10), Cox proportional hazards regression modeling was used to evaluate the association between exposure to SHS and eight different types of smoke-related cancer. RESULTS: In this study, we evaluated a cohort of 25,794 US residents older than 19 years from 2005 to 2016 and were followed for mortality through the February 2019. We conducted Spearman correlation analysis to confirm the correlation between serum cotinine level and exposure status (including smoking and exposure to SHS), it demonstrated the correlation coefficient between serum cotinine level and exposure to smoke was 0.976, p < 0.00001. By Cox proportional hazards regression modeling, high exposure group were found to be positively associated with all neoplasms with a total Hazard Ratio (HR) of 1.748 (95% Confidence Interval (CI), 1.415-2.159), had higher all-cause mortality risks than non-exposure to tobacco smoke. Regarding the specific types, we found the following associations: cancer of the lung (HR, 1.484; 95% CI, 1.191-1.849), stomach (HR, 1.491; 95% CI, 1.199-1.854), bladder (HR, 1.487; 95% CI, 1.198,1.846), esophageal (HR, 1.487; 95% CI 1.194-1.852), kidney (HR, 1.497; 95% CI, 1.201-1.865), pancreatic (HR, 1.479; 95% CI 1.189-1.841), leukemia (HR, 1.479; 95% CI 1.190-1.839), cervical (HR, 1.490; 95% CI 1.198-1.853). However, low exposure group were non-existent statistically significant with a Hazard Ratio (HR) of 1.062 (95% Confidence Interval (CI), 0.953-1.183). CONCLUSIONS: The research demonstrated that serum cotinine has a significant correlation with smoke exposure status, which confirmed serum cotinine can be used as an indicator to reflect human smoke exposure. What's more, our results confirmed high exposure of SHS (serum cotinine level ≥ 10) has a significant effect on lung, stomach, bladder, esophagus, kidney, pancreatic, leukemia, cervical cancer.

Subacute oral toxicology and toxicokinetics of pterostilbene, a novel Top1/Tdp1 inhibiting anti-tumor reagent.

This study evaluated the subacute toxicity and toxicokinetics of a potential anti-cancer drug candidate, pterostilbene, in rats. Animals were orally administered at two repeated doses of 200 and 500 mg/kg for 28 days. No mortality was observed during the 28 days of continuous administration of pterostilbene. Body weight and food consumption in each group increased steadily, while no significant difference was found. Liver weight in the 500 mg/kg female, but not male group increased with mild cytoplasmic vacuoles observed in histopathological study. Toxicokinetics was assessed by measuring plasma concentrations of pterostilbene on the first and 28th day of administration using UPLC-MS/MS. Toxicokinetic parameters showed that AUC0-t significantly increased in all animals, while the increase in females was greater than males. System exposure of pterostilbene appeared to be linear within the administrated dose range. In conclusion, our findings suggested a minimal subacute toxicity profile of pterostilbene, which could strongly support further development of this compound as a novel anti-cancer agent.

Prediction model for elevated intraocular pressure risk after silicone oil filling based on clinical features.

Background: To evaluate risk factors and further develop prediction models for intraocular pressure elevation (IOP) after vitreoretinal surgery with silicone oil tamponade to support clinical management. Methods: A retrospective study analyzed 1,061 eyes of 1,061 consecutive patients that presented to the Jiangsu Province Hospital between December 2015 and December 2020, the IOP was measured from the preoperative visit and at the 1-week, 1-month, 3-month, and 6-month visits, and the final postoperative visit before silicone oil removal. Four machine learning methods were used to carried out the prediction of IOP elevation: Decision Tree, Logistic Regression, Random Forest, and Gradient-Boosted Decision Trees (GBDT) based on features including demographic and clinical characteristics, preoperative factors and surgical factors. Predictors were selected based on the p-value of the univariate analysis. Results: Elevated intraocular pressure developed in 26.01% of the eyes postoperatively. Elevated intraocular pressure primarily occurred within 1-2 weeks after surgery. Additionally, the majority of IOP values were distributed around 25-40 mmHg. GBDT utilizing features with p-values less than 0.5 from the hypothesis testing demonstrated the best predictive performance for 0.7944 in accuracy. The analysis revealed that age, sex, hypertension, diabetes, myopia, retinal detachment, lens status and biological parameters have predictive value. Conclusion: Age, sex, hypertension, diabetes, myopia, retinal detachment, lens status and biological parameters have influence on postoperative intraocular pressure elevation for patients with silicone oil tamponade after pars plana vitrectomy. The prediction model showed promising accuracy for the occurrence of IOP elevation. This may have some reference significance for reducing the incidence of high intraocular pressure after pars plana vitrectomy combined with silicone oil filling.

[Effects of different swimming exercises on alcoholic fatty liver formation in mice].

Objective: To investigate the effects of 7-week swimming exercise with different loads on the improvement of liver lipid metabolism in mice with alcoholic fatty liver disease (AFLD) and its relationship with the regulation of miR-34a/PPARα. Methods: Fifty male KM mice were randomly divided into control group (K, n=10) and alcoholic fatty liver group (AFLD, n=40). The AFLD model was constructed after feeding with 50% alcohol for 7 weeks with 1 d rest per week. After successful model construction, the mice were divided into a model group (M), a 30-min swimming exercise group (LE), a 60-min swimming exercise group (ME), and a 90-min loaded swimming exercise group (HE, 5% of body mass as tail lead load), with 10 mice in each group, for a total of 7 weeks of intervention. After completion, the serum and liver tissues were collected, the liver index, visceral fat ratio, hepatocyte injury indicators, alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GT), total cholesterol (TC), triglyceride (TG), and high/low density lipoprotein cholesterol (H/LDL-C) content were measured; HE staining was used to observe the changes in liver structure, Western blot was used to detect the protein levels of PPARα, FAS and TNF-α in liver tissues, and mRNA expression profiles were analyzed by sequencing After RT-PCR, the mRNA expressions of miR-34a, PPARα, FAS, TNF-α and CPT-1 were verified. Results: Compared with K group, the hepatic cord disorder, focal lipid vacuum, obvious lipid droplet vacuolation, abnormal ectopic nucleus were observed in AFLD group ; liver function was decreased significantly. Compared with the M group, the liver functions of the ME and HE groups were improved significantly, the serum levels of TG, TC and LDL-C were decreased, while the HDL-C level was increased (P<0.01 or P<0.05), and the liver index and visceral fat ratio were decreased (P< 0.01 or P<0.05), the focal lipid droplet degeneration of hepatocytes was decreased, and the structure of the hepatic cord was clearer; and the ME group showed a more significant intervention effect. Compared with the M group, the expression levels of PPARα protein in the liver tissues of the LE, ME, and HE groups were increased, while the protein expression levels of FAS and TNF-α were decreased (P<0.01 or P<0.05). Based on Illumina high-throughput sequencing and mRNA differential expression analysis, there are 38 differentially expressed genes in the PPARα pathway, including 9 up-regulated genes and 29 down-regulated genes, which are involved in liver fatty acid oxidation, lipid metabolism, and apoptosis inhibition. Compared with group M, the gene levels of miR-34a, FAS, and TNF-α in LE, ME, and HE groups were decreased, and the gene levels of PPARα and CPT-1 were increased (P<0.01 or P<0.05). Conclusion: Swimming with different loads can improve liver functions in AFLD mice, promote lipid droplet degradation, and regulate liver lipid metabolism. The mechanism may be related to the activation of miR-34a/PPARα, and the intervention effect of moderate-load swimming is better.

Development and validation of a liquid chromatography-tandem mass spectrometry method for CPUL1, a novel antitumor candidate compound, and its application to pharmacokinetic studies.

An active substance of pyrano[3,2-a]phenazine, also called CPUL1, is a synthesized phenazine derivative and displays broad-spectrum anticancer activities. Quantitative assessment of CPUL1 in biological samples has not been well established, hindering pharmaceutical development and application. According to international guidelines, a sensitive and selective liquid chromatography-tandem mass spectrometry method in negative ion mode was developed and validated for quantification of CPUL1 in human plasma, colorectal cancer cell lines, and rat plasma, whereby linearity and accuracy were demonstrated for the range of 1-1000 ng/ml. The validated liquid chromatography-tandem mass spectrometry method was successfully employed in pharmacokinetic studies of CPUL1 in vitro and in vivo. Notably, the cellular pharmacokinetic behavior of CPUL1 varies in colorectal cancer cell lines. Regarding the pharmacokinetic processes in vivo, oral absorption was less effective than an injection, with a bioavailability of 23.66%. CPUL1 was linearly eliminated after a single administration; however, it could accumulate in tissues (heart, liver, spleen, lung, and kidney) after multiple injections. In summary, this study established a capable bioanalytical method for CPUL1 and provided exploratory pharmacokinetic data, paving the way for use of this promising derivative in disease models.

Physical Exercise Repairs Obstructive Jaundice-Induced Damage to Intestinal Mucosal Barrier Function via H2S-Mediated Regulation of the HMGB1/Toll Like Receptors 4/Nuclear Factor Kappa B Pathway.

The present study aimed to determine the effect of aerobic exercise on improving damage to intestinal mucosal barrier function caused by obstructive jaundice (OJ) and explore the mechanism. Fifty male KM mice were divided into five groups: sham operation group (S), model group (M), exercise group (TM), DL-propargylglycine + exercise (PT) group, and sodium hydrosulfide + exercise (NT) group. Additionally, mice in S group underwent common bile duct ligation for 48 h to establish a murine obstructive jaundice model. In PT group, propargylglycine (40 mg/kg) was intraperitoneally injected 7 days after surgery. NaHS (50 µmol/kg) was intraperitoneally injected into mice in the NT group 7 days after surgery. The TM group, NT group and PT group exercised on a slope of 0% at a speed of 10 m/min without weight training (30 min/day). HE staining showed that the intestinal mucosa of group M was atrophied and that the villi were broken. The intestinal mucosal structure of mice in the TM group was improved. Serum assays showed that H2S levels were higher in the TM group than in the M group; compared with the levels in the TM group, the PT group levels were decreased and the NT group levels were increased. In addition, aerobic exercise inhibits the HMGB1/TLR4/NF-κB signaling pathway by promoting endogenous H2S production, thereby exerting a protective effect on the intestinal mucosal barrier.

Effect of the valine-to-lysine ratio on the performance of sows and piglets in a hot, humid environment.

To determine the effect of the valine-to-lysine (Val: Lys) ratio on the performance of sows and piglets in a hot, humid environment, eleven Large White × Landrace sows (parity 2 or 3) were selected and randomly assigned to 3 groups. The diets contained total dietary Val: Lys ratios of 0.72, 0.87, or 1.01:1. Sows were fed from d 29 prepartum to d 21 postpartum in a hot, humid environment (temperature: 22-31 ℃, relative humidity: 69-96%). The results showed that dietary valine improved the average daily feed intake (ADFI) of the sows in wk3 of the lactation and the average daily gain (ADG) of the piglets from day 7-14 after farrowing. Dietary valine increased the concentrations of lactose in colostrum and immunoglobulin M (IgM) in piglet serum. Additionally, dietary valine affected metabolite and metabolic hormone concentrations. The increase in the ratio of dietary Val: Lys decreased the blood urea nitrogen and increased serum glucose in the sows and increased serum albumin in the piglets. In addition, increasing dietary Val: Lys increased the serum concentration of estradiol-17ß in the sows. In conclusion, in a hot, humid environment, dietary valine could improve the performance of sows and piglets by increasing colostrum lactose and serum immunoglobulin concentration in piglets and by influencing serum glucose in sows.

Effects of Macrothele raven venom on intrarenal invasion and metastasis of H22 liver cancer cells in mice.

BACKGROUND: Extrahepatic metastatic hepatocellular carcinoma (HCC) and its insensitivity to chemotherapy are the main causes of poor prognosis in patients with HCC. This study investigated the anti-cancer effect of Macrothele raveni venom on intrarenal metastatic HCC. MATERIALS AND METHODS: Subrenal capsule xenograft model of HCC was established by inoculation of H22 liver cancer cells. RESULTS: The general health, histology, and molecular changes were observed after administering 10 times of different dose of Macrothele raven venom injections. A volume of 0.8 µg/ml and 1.0 µg/ml of Macrothele raven venom significantly improved general health status in mice with subrenal capsule HCC tumors. Hematoxylin and eosin staining showed that Macrothele raven venom dose-dependently reduced invasion and metastasis of liver cancer cells in the kidney. Immunohistochemistry and real-time polymerase chain reaction showed that Macrothele raven venom injection dose-dependently decreased PI3K mRNA and protein, Akt protein, and mTOR mRNA expression, but increased Bad mRNA and protein expression in the kidney with H22 tumor cell invasion. 0.8 µg/ml is the most effective dose for the treatment of intrarenal metastatic HCC. CONCLUSIONS: Macrothele raven venom dose-dependently inhibits invasion and metastasis of intrarenal metastatic HCC through inhibition of PI3K-Akt-mTOR signaling and increase of Bad expression.

Bama miniature pigs' liver possess great heat tolerance through upregulation of Nrf2-mediated antioxidative enzymes.

The liver is one of the most crucial organs affected by high ambient temperature. Bama miniature pig show a heat tolerance in hot summer months. However, the physiological condition of liver under high ambient temperature has not been well elucidated in Bama miniature pig. Here we performed an experiment to investigate the effects of high ambient temperature on liver function, redox status and Nrf2 antioxidant pathway in Bama miniature pigs. Twelve pigs were randomly divided into two groups and separately exposed to the neutral temperature (NT, 25°C) and high temperature (HT, 40°C) for 8 days. The hepatic damage marker, such as total bilirubin (TBIL), alkaline phosphatase (AKP), γ-glutamyl transpeptidas (γ-GT), alanine transaminase (ALT) and aspartase transminase (AST), didn't reach statistical significance between NT and HT group. Moreover, abnormal observation of hepatic histology and hepatocyte ultrastructure were not detected in HT group. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) as well as glutathione (GSH) content, were dramatically increased after heat exposure. Heat treatment didn't increase hydrogen peroxide (H2O2) and malondialdehyde (MDA) concentrations. The expression of Nrf2-regulated genes, such as nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H: quinine oxidoreductase 1 (NQO1), superoxide dismutase 1 (SOD1), heme oxygenase-1 (HO-1) and glutamate cysteine ligase catalytic subunit (GCLC), were significantly increased in HT group. Nrf2 protein was accumulated in HT group through immunohistochemical analysis. The current data provide clear evidence that Bama miniature pigs' liver possess great capacity of heat tolerance, which related to activation of Nrf2 antioxidant pathway.

Effect of Huwentoxin-I on the Fas and TNF apoptosis pathway in the hippocampus of rat with global cerebral ischemia.

Neuronal injury is the most important reason for various brain injuries. Cytosolic Ca(2+) overloading has been proposed as one of the main cellular processes leading to neuronal death during cerebral ischemia. It is well accepted that Ca(2+) channel blockers can protect cerebral neurons from ischemic injury. In the present studies, we investigated the molecular mechanism for the neuro-protective effect of Huwentoxin-I (HWTX-I), a spider toxin selectively blocking N-type voltage-dependent Ca((2+)) channel, on rat models with global cerebral ischemia-reperfusion injury. Our studies demonstrated that HWTX-I could maintain the morphological stability of pyramidal cells in this model. Furthermore, HWTX-I could decrease the concentration of malon-dialdehyde, but increase the activity of superoxide dismutase and glutathione peroxidase. It also reduced the expression level of related factors of Fas and tumor necrosis factor death receptor apoptosis pathways in the hippocampus. In summary, HWTX-I has an obvious neuroprotective effect, which may act through its inhibition on a certain apoptosis pathway.