The mediation effect of HDL-C: Non-HDL-C on the association between inflammatory score and recurrent coronary events.

Background: Inflammation and lipids are both involved in the pathogenesis of coronary heart disease (CHD). However, the mediation effect of lipoproteins on the association between inflammation and recurrent coronary events in CHD patients remains unclear. Methods: This was a retrospective study including CHD patients hospitalized in the Department of Cardiovascular Medicine in Sun Yat-sen Memorial Hospital between January 2011 and December 2012 with the endpoint of recurrent coronary events. The study calculated inflammatory score based on six serum inflammatory markers, including complement C3, complement C4, hyper-sensitive CRP, fibrinogen, D-dimer, and white blood cell count. Logistic regression analysis, subgroup analysis and mediation analysis were performed to assess the associations between inflammatory score and recurrent coronary events in different subpopulations and the identification of mediators. Inflammatory cytokine expression, cholesterol efflux capacity, and hepatic cholesterol influx were performed in additional CHD patients and healthy controls. Results: There were 191 CHD patients included in the analysis with a median inflammatory score of -0.78 (-2.17, 1.35) and 63 cases of recurrent coronary events. Subgroup logistic regression analysis demonstrated that inflammatory score was positively associated with recurrent coronary events only in the diabetic subgroup [OR: 1.241 (1.004, 1.534), P < 0.046]. HDL-cholesterol (HDL-C): non-HDL-C performed 46.74 % of negative mediation effect on this association. CHD patients had lower cholesterol efflux capacity than healthy controls, which was mediated by HDL: non-HDL ratio of 0.4. No difference was found in hepatic cholesterol influx between the two groups. Conclusion: Inflammatory score was associated with recurrent coronary events mediated by HDL-C: non-HDL-C ratio in diabetic CHD patients, indicating that lipoproteins might aggravate the inflammatory effect on atherosclerosis under hyperglycemia. Our findings suggested that anti-inflammatory and lipid-lowering therapies might be beneficial for this population.

Prognostic significance and relationship of SMAD3 phospho-isoforms and VEGFR-1 in gastric cancer: A clinicopathological study.

BACKGROUND: The TGF-ß/SMAD3 and VEGFR-1 signaling pathways play important roles in gastric cancer metastasis. SMAD3 phosphorylation is a crucial prognostic marker in gastric cancer. AIM: To determine the prognostic value and relationship of SMAD3 phospho-isoforms and VEGFR-1 in gastric cancer. METHODS: This was a single-center observational study which enrolled 98 gastric cancer patients and 82 adjacent normal gastric tissues from patients aged 32-84 years (median age 65) between July 2006 and April 2007. Patients were followed up until death or the study ended (median follow-up duration of 28.5 mo). The samples were used to generate tissue microarrays (TMAs) for immunohistochemical (IHC) staining. The expressions of TGF-ß1, pSMAD3C(S423/425), pSMAD3L(S204), and VEGFR-1 in gastric cancer (GC) tumor tissue and normal tissue were measured by IHC staining using TMAs obtained from 98 GC patients. Prognosis and survival information of the patients was recorded by Outdo Biotech from May 2007 to July 2015. The relationship between TGF-ß1, pSMAD3C(S423/425), pSMAD3L(S204), and VEGFR-1 protein expression levels was analyzed using Pearson's correlation coefficient. The relationship between protein expression levels and clinicopathological parameters was analyzed using the Chi-squared test. A survival curve was generated using the Kaplan-Meier survival analysis. RESULTS: TGFß-1 and VEGFR-1 expression was significantly upregulated in gastric cancer tissue compared to adjacent non-cancerous tissue. The positive expression of phosphorylated isoforms of Smad3 varied depending on the phosphorylation site [pSMAD3C(S423/425): 51.0% and pSMAD3L(S204): 31.6%]. High expression of pSMAD3L(S204) was significantly correlated with larger tumors (P = 0.038) and later N stages (P = 0.035). Additionally, high expression of VEGFR-1 was closely correlated with tumor size (P = 0.015) and pathological grading (P = 0.013). High expression of both pSMAD3L(S204) and VEGFR-1 was associated with unfavorable outcomes in terms of overall survival (OS). Multivariate analysis indicated that high expression of pSMAD3L(S204) and VEGFR-1 were independent risk factors for prognosis in GC patients. VEGFR-1 protein expression was correlated with TGF-ß1 (r = 0.220, P = 0.029), pSMAD3C(S423/425) (r = 0.302, P = 0.002), and pSMAD3L(S204) (r = 0.201, P = 0.047), respectively. Simultaneous overexpression of pSMAD3L(S204) and VEGFR-1 was associated with poor OS in gastric cancer patients. CONCLUSION: Co-upregulation of pSMAD3L(S204) and VEGFR-1 can serve as a predictive marker for poor gastric cancer prognosis, and pSMAD3L(204) may be involved in enhanced gastric cancer metastasis in a VEGFR-1-dependent manner.

Etiological Changes and Prognosis of Hospitalized Patients with Acute Pancreatitis Over a 15-Year Period.

BACKGROUND: The worldwide incidence of acute pancreatitis (AP) is increasing, but the dominant etiology of AP may vary by country. Mixed etiologies are involved in the increase in the number of AP patients. AIMS: This study was to analyze the etiological changes and prognosis of AP patients and explore the prognosis of AP patients with mixed etiologies. METHODS: Using a retrospective analysis method, AP patients hospitalized from January 2007 to December 2021 were selected from a pancreatic center in Nanchang, China. Trends in the main etiologies were analyzed, and the severity and prognosis of different etiologies were compared. RESULTS: A total of 10,071 patients were included. Cholelithiasis (56.0%), hyperlipidemia (25.3%), and alcohol (6.5%) were the top three etiologies. The proportion of acute biliary pancreatitis (ABP) showed a decreasing trend, while the proportion of hypertriglyceridemic pancreatitis (HTGP) and alcoholic AP showed an increasing trend (all ptrend < 0.001). The incidence of organ failure and necrotizing pancreatitis was higher in patients with HTGP than in those with AP induced by other etiologies (all p < 0.05). There was no statistically significant difference in mortality among patients with different etiologies. Patients with AP due to a mixed hypertriglyceridemia-alcoholic etiology had higher ICU admission rates and were more severe than those with AP induced by other mixed etiologies. CONCLUSION: In the past 15 years, the proportion of ABP has trended downward, while those of HTGP and alcoholic AP have risen. Among patients with mixed etiologies, those with a mixed hypertriglyceridemia-alcoholic etiology had a worse prognosis.

Application of electrogastrogram in assessment of gastric motility in acute pancreatitis.

Background: Electrogastrogram (EGG) can reflect gastric motility disorders in many diseases, but its application in acute pancreatitis (AP) has not been studied. Therefore, our study aimed to investigate the value of EGG in assessing the existence of gastric motility disorder in patients with AP and in predicting the severity of AP. Methods: Patients with AP admitted to the First Affiliated Hospital of Nanchang University from June 2020 to December 2020 were enrolled. Five EGG parameters (Percentage of normal gastric slow wave (PNGSW), main frequency, average frequency, percentage of gastric tachycardia (PGT), percentage of gastric bradycardia (PGB)) were collected. The receiver operating characteristic (ROC) curve was constructed to judge the predictive value of EGG parameters to AP severity. Results: The PNGSW in AP patients was significantly lower than that of the control group (p < 0.05), and the PGB was higher in AP patients than that of the control group (p < 0.05). The area under curve (AUC) of the PNGSW and the PGB in diagnosing non-mild acute pancreatitis (N-MAP) were 0.777 (95% CI: 0.676-0.877, p < 0.001) and 0.775 (95% CI: 0.670-0.879, p < 0.001) respectively. After combining with C-reactive protein, the accuracy, sensitivity and specificity of predicting N-MAP were improved. Conclusion: EGG parameters can well reflect the gastric motility disorder of AP patients. The PNGSW and the PGB can be used to predict the occurrence of N-MAP.

RBMS3, a downstream target of AMPK, Exerts Inhibitory Effects on Invasion and Metastasis of Lung Cancer.

Background: Lung cancer is a highly malignant disease, primarily due to its propensity for metastasis. AMP-activated protein kinase (AMPK), the principal downstream effector of Liver Kinase B1 (LKB1), orchestrates a broad spectrum of molecular targets, thereby constraining tumor invasion and metastasis. In parallel, the RNA-binding protein RBMS3 (RNA-binding motif, single-stranded-interacting protein 3) plays a pivotal role in the epithelial-mesenchymal transition (EMT), a pivotal process in tumorigenesis. Therefore, our research aims to clarify the important role of RBMS3 as a mediator in the LKB1/AMPK inhibition of tumor invasion and metastasis. Methods: We investigated the expression and correlation between RBMS3 and LKB1 in lung cancer tissues utilizing immunohistochemistry and TCGA-LUAD data, respectively. The relationship between RBMS3 and clinical pathological features and prognosis of lung cancer was also analyzed. The functions of RBMS3 in lung cancer cell proliferation, invasion, and migration were investigated in real-time in vitro. Additionally, we investigated the effects of AMPK agonists and inhibitors to explore the mediating role of RBMS3 in AMPK-induced inhibition of lung cancer invasion and migration. Results: The IHC and TCGA data both revealed low expression of RBMS3 in lung cancer. Moreover, we found that low expression of RBMS3 was positively associated with lung cancer's histological grade, clinical stage, and N stage. Additionally, low RBMS3 expression was associated with poor overall survival. Cox regression analysis revealed that RBMS3 was an independent prognostic factor for lung cancer patients. In vitro experiments verified that RBMS3 inhibited lung cancer cell proliferation, invasion, and migration. Furthermore, our findings suggested that RBMS3 played an essential role in mediating AMPK's inhibitory effect on lung cancer invasion and migration. Conclusion: Our study highlights a novel mechanism by which LKB1/AMPK pathway activation inhibits lung cancer invasion and metastasis by promoting RBMS3 expression, offering insights in developing innovative lung cancer therapies.

Elevated CK-MB levels are associated with adverse clinical outcomes in acute pancreatitis: a propensity score-matched study.

Aim: Cardiac injury, reflected by the measured concentrations of chemicals released from injured cardiac muscle, is common in acute pancreatitis (AP). However, there is no adequate evidence assessing the impact of cardiac injury on AP-related outcomes. Creatine kinase-myocardial band (CK-MB) mainly exists in the myocardium. Therefore, we sought to evaluate the relationship between the increase in CK-MB and the adverse clinical outcomes of AP. Methods: This propensity score-matched study analyzed AP patients admitted to the Department of Gastroenterology in the First Affiliated Hospital of Nanchang University from June 2017 to July 2022. Propensity score matching and multivariate logistic regression analysis were used to explore the relationship between CK-MB elevation and AP outcome variables. Results: A total of 5,944 patients were screened for eligibility, of whom 4,802 were ultimately enrolled. Overall, 896 (18.66%) of AP patients had elevated (>24 U/ml) CK-MB levels, and 895 (99.89%) were paired with controls using propensity score matching. The propensity score-matched cohort analysis demonstrated that mortality (OR, 5.87; 95% CI, 3.89-8.84; P < 0.001), severe acute pancreatitis (SAP) (OR, 2.74; 95% CI, 2.23-3.35; P < 0.001), and infected necrotizing pancreatitis (INP) (OR, 3.40; 95% CI, 2.34-4.94; P < 0.001) were more frequent in the elevated CK-MB (>24 U/ml) group than in the normal CK-MB (≤ 24 U/ml) group. Using the multivariate logistic regression analysis, elevated CK-MB levels were independently associated with increased mortality (OR, 2.753, 95% CI, 2.095-3.617, P < 0.001), SAP incidence (OR, 2.223, CI, 1.870-2.643, P < 0.001), and INP incidence (OR, 1.913, 95% CI, 1.467-2.494, P < 0.001). CK-MB elevation was an independent risk factor for adverse clinical outcomes in AP patients. Conclusion: CK-MB elevation was significantly related to adverse outcomes in AP patients, which makes it a potentially useful laboratory parameter for predicting adverse clinical outcomes of AP.

Roles of salt­inducible kinases in cancer (Review).

Salt inducible kinases (SIKs) with three subtypes SIK1, SIK2 and SIK3, belong to the AMP­activated protein kinase family. They are expressed ubiquitously in humans. Under normal circumstances, SIK1 regulates adrenocortical function in response to high salt or adrenocorticotropic hormone stimulation, SIK2 is involved in cell metabolism, controlling insulin signaling and gluconeogenesis and SIK3 coordinates with the mTOR complex, promoting cancer. The dysregulation of SIKs has been widely detected in various types of cancers. Based on most of the existing studies, SIK1 is mostly considered a tumor inhibitor, SIK2 and SIK3 are usually associated with tumor promotion. However, the functions of SIKs have shown contradictory in certain tumors, suggesting that SIKs cannot be simply classified as oncogenes or tumor suppressor genes. The present review provided a comprehensive summary of the roles of SIKs in the initiation and progression of different cancers, aiming to elucidate their clinical value and discuss potential strategies for targeting SIKs in cancer therapy.

Early evaluation of waist-to-height ratio for the prediction of worsening acute pancreatitis.

The purpose of this study was to evaluate the association between the waist-to-height ratio (WHtR) and the aggravation of acute pancreatitis (AP). This prospective study included AP patients treated from May 2019 to December 2019 in the Department of Gastroenterology, the First Affiliated Hospital of Nanchang University. Receiver operating characteristic curves were constructed to determine the optimal threshold values for predicting the aggravation of AP. Risk factor analysis was performed via logistic regression analysis. Of 258 patients included in this study, 77 (29.84%) were diagnosed with mild acute pancreatitis, 120 (46.51%) with moderately severe acute pancreatitis, and 61 (23.64%) with severe acute pancreatitis (SAP). WHtR, waist circumference, weight, and body mass index were all associated with AP severity, and the highest area under the receiver operating characteristic value was observed for WHtR. The optimal threshold WHtR value for predicting SAP was 0.567. Multivariate logistic regression analysis identified WHtR ≥ 0.567 as independent risk factor for SAP. Moreover, the hospital stay was longer and intensive care unit admission rate was higher among AP patients with a WHtR ≥ 0.567. The WHtR was found to be closely related to the severity of AP and an independent risk factor for the aggravation of AP. This simple parameter can aid the early prediction of AP progression, thereby facilitating early intervention and improving patient outcomes.

Defined, low threshold for caesarean section and multidisciplinary team management improves fetal outcome from acute pancreatitis in pregnancy.

BACKGROUND: Acute pancreatitis in pregnancy (APIP) is associated with increased maternal and fetal mortality. OBJECTIVES: We sought to determine whether a low threshold for cesarean section (C-section) in severe acute pancreatitis (SAP) or Predict SAP improves maternal and fetal outcomes in patients with APIP. METHODS: We identified patients with APIP at a single institution from a prospective database and studied fetal and maternal health in APIP before (2005-2014) and after (2015-2019) introduction of multidisciplinary team management with a defined, lowered threshold for C-section. The primary end point was fetal mortality comprising abortion and perinatal death. Risk factors associated with fetal mortality were analyzed by univariable and multivariable logistic regression analysis. RESULTS: A total of 165 patients with APIP were eligible for analysis. There was a highly significant increase in patients undergoing C-section from 37 (30.8%) of 120 during 2005-2014 to 27 (60%) of 45 in 2015-2019 (P = 0.001), with a highly significant fall in fetal mortality from 37 (30.8%) of 120 to 3 (6.7%) of 45 between the same periods (P = 0.001), when maternal mortality fell from 6 to zero (P = 0.19). Maternal early systemic inflammatory response syndrome (SIRS) (odds ratio [OR] 6.98, 95% confidence interval [CI] 1.53, 30.80, P = 0.01) and SAP (OR 3.64, 95%CI 1.25, 10.60, P = 0.02) were two independent risk factors associated with fetal mortality. CONCLUSIONS: Multidisciplinary collaboration and a defined, low threshold for C-section improve fetal outcomes in patients with APIP.

Serum triglyceride levels are associated with recurrence in patients with acute hypertriglyceridemic pancreatitis.

Aim: To analyze the clinical profile of patients with acute hypertriglyceridemic pancreatitis (HTGP) and explore risk factors for recurrence. Methods: A retrospective observational study was conducted in patients who experienced an attack of HTGP for the first time. Patients were followed until the recurrence of acute pancreatitis (AP) or 1 year. The detailed clinical profile was compared between patients with or without recurrence. Multivariate logistic regression analysis was conducted to explore independent risk factors for recurrence. Results: A total of 108 HTGP patients were included in this study with 73.1% being male, and the median age being 37 (interquartile range, IQR, 30.3-44.8) years. Recurrence occurred in 70 patients (64.8%). Compared with the nonrecurrent group, serum triglyceride (TG) levels before discharge [4.1 (2.8,6.3) mmol/L vs. 2.9 (2.2,4.2) mmol/L; p = 0.002], at 1 month [3.7 (2.3,9.7) mmol/L vs. 2.0 (1.4,2.7) mmol/L; p = 0.001], at 6 months [6.1 (3.1,13.1) mmol/L vs. 2.5 (1.1,3.5) mmol/L; p = 0.003] and 12 months [9.6 (3.5,20.0) mmol/L vs. 2.7 (1.6,5.5) mmol/L; p = 0.001] after discharge were higher in the recurrent group. Poor control of TG levels (TG > 3.1 mmol/l) at the 1-month follow-up after discharge and a high Charlson's Comorbidity Index score (≥ 2 points) increased the risk of recurrence of HTGP. Conclusion: High TG levels during follow-up and Charlson's Comorbidity Index score were independently associated with recurrence in patients with HTGP.

Clinical characteristics and risk factors of organ failure and death in necrotizing pancreatitis.

BACKGROUND: Organ failure (OF) and death are considered the most significant adverse outcomes in necrotizing pancreatitis (NP). However, there are few NP-related studies describing the clinical traits of OF and aggravated outcomes. PURPOSE: An improved insight into the details of OF and death will be helpful to the management of NP. Thus, in our research, we addressed the risk factors of OF and death in NP patients. METHODS: We performed a study of 432 NP patients from May 2017 to December 2021. All patients with NP were followed up for 36 months. The primary end-points were risk factors of OF and death in NP patients. The risk factors were evaluated by logistic regression analysis. RESULTS: NP patients with OF or death patients were generally older, had a higher APACHE II score, longer hospital stay, longer ICU stay, as well as a higher incidence of severe acute pancreatitis (SAP), shock and pancreatic necrosis. Independent risk factors related to OF included BMI, APACHE II score and SAP (P < 0.05). Age, shock and APACHE II score (P < 0.05) were the most significant factors correlated with the risk of death in NP patients. Notably, increased mortality was linked to the number of failed organs. CONCLUSIONS: NP is a potentially fatal disease with a long hospital or ICU stay. Our study indicated that the incidence of OF and death in NP patients was 69.9% and 10.2%, respectively. BMI, SAP, APACHE II score, age and shock are potential risk factors of OF and death in NP patients. Clinicians should focus on these factors for early diagnosis and appropriate therapy.

Recurrence for patients with first episode of hypertriglyceridemia-induced acute pancreatitis: A prospective cohort study.

BACKGROUND: Data on recurrent hypertriglyceridemia-induced acute pancreatitis (HTG-AP) are scarce. OBJECTIVE: To investigate the incidence and risk factors for recurrence of HTG-AP, and the effect of triglyceride (TG) lowering drugs post index attack on recurrence. METHODS: This study was a prospective cohort study of adult patients with first episode of HTG-AP from December 2019 to February 2021 who were followed until recurrence or death, or February 2022. The cumulative incidence function and Fine and Gray's competing-risk model were applied to the analyses. RESULTS: A total of 317 patients were enrolled, and the 12-month and 18-month cumulative recurrence incidences were 8% and 22%, respectively. The cumulative recurrence incidence was 2 times higher in patients whose serum TG levels post index attack were ≥5.65 mmol/L (subdistribution hazard ratio [SHR], 2.00; 95% confidence interval [CI], 1.05-3.80; P = 0.034) compared to patients with TG <5.65 mmol/L. The recurrence rate was 3.3 times higher in patients whose glucose levels post index attack were ≥7.0 mmol/L (SHR, 3.31; 95% CI, 1.56-7.03; P = 0.002) than in patients with glucose <7.0 mmol/L). Compared to TG lowering drugs for less than 1 month post index attack, treatment for longer than 12 months decreased the incidence of recurrence by 75% (SHR, 0.25; 95% CI, 0.08-0.80; P = 0.019). CONCLUSIONS: The HTG-AP recurrence incidence is high and closely associated with high levels of TGs and glucose post index attack. Long-term TG lowering drugs treatment significantly decreases this recurrence.

Global research trends of immunotherapy and biotherapy for inflammatory bowel disease: a bibliometric analysis from 2002 to 2021.

BACKGROUND: It is known that inflammatory bowel disease is the result of a defective immune system, and immunotherapy and biological therapy have gradually become important means to treat it. This paper focused on the bibliometric statistical analysis of the current research progress to summarize the research status of this field and analyze the research trends in recent years. METHODS: Two visualization tools, CiteSpace and VOSviewer, were used to explore the data of journals, institutions, countries/regions, authors, references, and keywords for the literature included in the Web of Science Core Collection from January 1, 2002, to December 31, 2021. RESULTS: A total of 312 papers were published in 120 journals by 603 institutions from 40 countries/regions, with 9463 co-cited references. The United States has the most publications with the highest total citations in the world. Inflammatory Bowel Diseases published the maximum number of papers, and Gastroenterology devoted the most co-citations to immunotherapy and biological therapy for IBD. In addition, we found that the studies before 2009 mostly focused on clinical trials while researchers have paid more attention to clinical management in therapy for IBD since 2009. Combination therapy and management of the treatment for the disease have become research hotspots. CONCLUSION: The focus of immunotherapy and biotherapy for IBD has shifted from clinical trials to the management of the risks and benefits of immunotherapy.

Trilobatin promotes angiogenesis after cerebral ischemia-reperfusion injury via SIRT7/VEGFA signaling pathway in rats.

Angiogenesis plays a pivotal role in the recovery of neurological function after ischemia stroke. Herein, we investigated the effect of trilobatin (TLB) on angiogenesis after cerebral ischemia-reperfusion injury (CIRI). The effect of TLB on angiogenesis after CIRI were investigated in mouse brain microvascular endothelium bEnd.3 cells and middle cerebral artery occlusion (MCAO)-induced CIRI rat model. The cell proliferation and angiogenesis were observed using immunofluorescence staining. The cell cycle, expressions of cell cycle-related proteins and SIRT 1-7 were determined by flow cytometry and western blot, respectively. The binding affinity of TLB with SIRT7 was predicted by molecular docking. The results showed that TLB concentration-dependently promoted bEnd.3 cell proportion in the S-phase. TLB significantly increased the protein expressions of SIRT6, SIRT7, and VEGFA, but not affected SIRT1-SIRT5 protein expressions. Moreover, TLB not only dramatically alleviated neurological impairment after CIRI, but also enhanced post-stroke neovascularization and newly formed functional vessels in cerebral ischemic penumbra. Furthermore, TLB up-regulated the protein expressions of CDK4, cyclin D1, VEGFA and its receptor VEGFR-2. Intriguingly, TLB not only directly bound to SIRT7, but also increased SIRT7 expression at day 28. Our findings reveal that TLB promotes cerebral microvascular endothelial cells proliferation, and facilitates angiogenesis after CIRI via mediating SIRT7/VEGFA signaling pathway in rats. Therefore, TLB might be a novel restorative agent to rescue ischemia stroke.

AMP-activated protein kinase re-sensitizes A549 to paclitaxel via up-regulating solute carrier organic anion transporter family member 1B3 expression.

Paclitaxel (PTX) is a common antineoplastic drug whose functionality is often restricted by drug resistance. Solute carrier organic anion transporter family member 1B3 (SLCO1B3) is a PTX influx transporter and its low expression has been proved to be relevant with PTX resistance. It has been widely reported that AMP-activated protein kinase (AMPK) could re-sensitize tumor cells to PTX. Our gene array result demonstrates AMPK up-regulated SLCO1B3. In this paper, we have tried to explain the relationships between PTX, SLCO1B3 and AMPK. First, we have verified the proliferative inhibition of PTX on A549 and found that PTX could inhibit A549 cells proliferation. Then, we have explored the relationship between SLCO1B3 and PTX: SLCO1B3 expression significantly decreased when A549 cells were treated with PTX or in A549 PTX resistant cells (A549-PTX) and the intracellular PTX concentration in A549-PTX was also lower. When treated with metformin/LKB1, both SLCO1B3 expression and intracellular PTX concentration have increased. Knockdown of AMPK has induced decreased SLCO1B3 expression. Moreover, in vitro and in vivo experiments have showed that metformin not only obviously inhibited A549-PTX tumor xenograft and A549-PTX proliferation alone, but also enhanced PTX efficacy to A549-PTX and this may be relevant to SLCO1B3. To verify it, we have treated A549 cells with AMPK both activators and an inhibitor, and then found that AMPK activators could weaken the PTX effect in inhibiting SLCO1B3 while its inhibitor has opposite effect. With knockdown of SLCO1B3, the effect of AMPK in re-sensitizing A549 to paclitaxel has decreased. To sum up, activation of AMPK can up-regulate SLCO1B3 expression, enhance the sensitivity of A549 cells to PTX, providing a new way to re-sensitize PTX resistance.

Regulation of gene transcription of B lymphoma Mo-MLV insertion region 1 homolog (Review).

B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is a core protein component of the polycomb repressive complex 1 that inhibits cell senescence and maintains the self-renewal ability of stem cells via downregulation of p16Ink4a and p19Arf expression. Bmi-1 serves an important role in hematopoietic stem cell maintenance and neurodevelopment during embryonic development, and it has been shown to enhance tumorigenesis by promoting cancer stem cell self-renewal and epithelial to mesenchymal transition. Emerging evidence suggests that Bmi-1 overexpression is closely related to the development and progression of various types of cancer, and that downregulation of Bmi-1 expression can inhibit the proliferation, invasion and metastasis of cancer cells. It is therefore important to elucidate the mechanisms underlying the regulation of Bmi-1 expression both under normal growth conditions and in malignant tissues. In the present review, the current body of knowledge pertaining to the transcriptional and post-transcriptional regulation of the BMI-1 gene is discussed, and the potential mechanisms by which Bmi-1 is dysregulated in various types of cancer are highlighted. Bmi-1 expression is primarily controlled via transcriptional regulation, and is regulated by the transcription https://www.ushuaia.pl/hyphen/?ln=en factors of the Myc family, including Myb, Twist1, SALL4 and E2F-1. Post-transcriptionally, regulation of Bmi-1 expression is inhibited by several microRNAs and certain small-molecule drugs. Thus, regulatory transcriptional factors are potential therapeutic targets to reduce Bmi-1 expression in cancer cells. Thus, the present review provides an up-to-date review on the regulation of BMI-1 gene expression at the transcriptional and post-transcriptional level.

AMPK inhibits Smad3-mediated autoinduction of TGF-ß1 in gastric cancer cells.

We have previously shown that adenine monophosphate-activated protein kinase (AMPK) regulates transforming growth factor ß (TGF-ß)-triggered Smad3 phosphorylation. Here we report that AMPK inhibits TGF-ß1 production. First, metformin reduced mRNA levels of TGF-ß1 in gastric cancer cells, in parallel to the decrease of its protein abundance. The effects were more prominent in the cells containing LKB1, an upstream kinase of AMPK. Second, knockdown of Smad3 by siRNA abrogated the expression of TGF-ß1. Third, metformin suppressed firefly luciferase activity whose transcription was driven by TGF-ß1 promoter. In accordance, deletion of the putative binding site of Smad3 in the TGF-ß1 promoter region severely impaired the promoter activity and response to metformin. Fourth, in support of our in vitro study, clinical treatment of type 2 diabetes with metformin significantly reduced the plasma level of TGF-ß1. Finally, immunohistochemical studies revealed that TGF-ß1 was highly expressed in human gastric cancer tissues as compared with adjacent normal tissues. In contrast, p-AMPK exhibited opposite changes. Furthermore, the survival rate of gastric cancer patients was positively correlated with p-AMPK and negative with TGF-ß1. Therefore, our present studies depict a mechanism underlying AMPK suppression of TGF-ß1 autoinduction, which is mediated through inhibition of Smad3 phosphorylation and activation. Collectively, our study sheds a light on the potential usage of AMPK activators in the treatment of TGF-ß1-mediated gastric cancer progression.

Metformin attenuates trauma-induced heterotopic ossification via inhibition of Bone Morphogenetic Protein signalling.

AMP-activated protein kinase (AMPK) is an intracellular sensor of energy homoeostasis that is activated under energy stress and suppressed in energy surplus. AMPK activation leads to inhibition of anabolic processes that consume ATP. Osteogenic differentiation is a process that highly demands ATP during which AMPK is inhibited. The bone morphogenetic proteins (BMPs) signalling pathway plays an essential role in osteogenic differentiation. The present study examines the inhibitory effect of metformin on BMP signalling, osteogenic differentiation and trauma-induced heterotopic ossification. Our results showed that metformin inhibited Smad1/5 phosphorylation induced by BMP6 in osteoblast MC3T3-E1 cells, concurrent with up-regulation of Smad6, and this effect was attenuated by knockdown of Smad6. Furthermore, we found that metformin suppressed ALP activity and mineralization of the cells, an event that was attenuated by the dominant negative mutant of AMPK and mimicked by its constitutively active mutant. Finally, administration of metformin prevented the trauma-induced heterotopic ossification in mice. In conjuncture, AMPK activity and Smad6 and Smurf1 expression were enhanced by metformin treatment in the muscle of injured area, concurrently with the reduction of ALK2. Collectively, our study suggests that metformin prevents heterotopic ossification via activation of AMPK and subsequent up-regulation of Smad6. Therefore, metformin could be a potential therapeutic drug for heterotopic ossification induced by traumatic injury.

Inonotus obliquus polysaccharides induces apoptosis of lung cancer cells and alters energy metabolism via the LKB1/AMPK axis.

The present study explores the mechanisms underlying the anti-cancer action of Inonotus obliquus polysaccharides (IOP). Thus, we characterized the IOP components extracted from Chaga sclerotium and, found that the extracts contained 70% polysaccharides with an average molecular weight of 4.5 × 104 Da consisting of 75% glucose. We then showed that IOP extract activated AMPK in lung cancer cells expressing LKB1, suppressed cell viability, colony-formation, and triggered cell apoptosis. In conjunction, IOP downregulated Bcl-2, upregulated Bax, and enhanced cleavage of Caspase-3 and PARP. All of these effects were prevented by treatment with Compound C, a chemical inhibitor of AMPK. IOP diminished mitochondrial membrane potential (MMP), concurrent with decreases in oxidative phosphorylation and glycolysis, which was dependent on LKB1/AMPK. Finally, IOP at a dosage of 50 mg/kg significantly inhibited allograft tumor growth of the LLC1 cells in association with increased apoptosis. Collectively, our results demonstrate that IOP acts on cancer cells through a mechanism by which AMPK triggers the apoptotic pathway via the opening of mitochondrial permeability transition pore, and reducing MMP, leading to an inhibition of ATP production. Therefore, our study provides a solid foundation for the use of IOP as a promising alternative or supplementary medicine for cancer therapy.

AMP-activated protein kinase regulates cancer cell growth and metabolism via nuclear and mitochondria events.

Adenine monophosphate-activated protein kinase (AMPK) is a fuel sensing enzyme that is activated in shortage of energy and inhibited in its surplus. Cancer is a metabolic disease characteristic of aerobic glycolysis, namely Warburg effect, and possesses heterogeneity featured by spatiotemporal hypoxia and normoxia, where AMPK is deeply implicated. The present study delineates the regulation of mitochondrial functions by AMPK in cancer cells. On the one hand, AMPKα subunit binds to mitochondria independently of ß subunit and targeting AMPK to mitochondria facilitates oxidative phosphorylation and fatty acid oxidation, and inhibits glycolysis. As such, mitochondrial AMPK inhibits the growth of cancer cells and tumorigenesis. On the other hand, ablation of the ß subunits completely abolishes AMPK activity and simultaneously leads to decreases in mitochondria DNA and protein contents. The effect of the ß deletion is rescued by overexpression of the active mutant of bulky AMPKα1 subunit. In conjunction, the transcriptional factors PGC1α and Nrf-1 are up-regulated by LKB1/AMPK, an event that is abolished in the absence of the ß subunits. Intriguingly, the stimulation of mitochondria biogenesis is not achieved by mitochondria-targeted AMPK. Therefore, our study suggests that AMPK inhibits cancer cell growth and tumorigenesis via regulation of mitochondria-mediated metabolism.