A phosphoglycerate mutase 1 allosteric inhibitor overcomes drug resistance to EGFR-targeted therapy via disrupting IL-6/JAK2/STAT3 signaling pathway in lung adenocarcinoma.

Resistance to epidermal growth factor receptor (EGFR) inhibitors, from the first-generation erlotinib to the third generation osimertinib, is a clinical challenge in the treatment of patients with EGFR-mutant lung adenocarcinoma. Our previous work found that a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1), HKB99, restrains erlotinib resistance in lung adenocarcinoma cells. However, the role of HKB99 in osimertinib resistance and its underlying molecular mechanism remains to be elucidated. Herein, we found that IL-6/JAK2/STAT3 signaling pathway is aberrantly activated in both erlotinib and osimertinib resistant cells. Importantly, HKB99 significantly blocks the interaction of PGAM1 with JAK2 and STAT3 via the allosteric sites of PGAM1, which leads to inactivation of JAK2/STAT3 and thereby disrupts IL-6/JAK2/STAT3 signaling pathway. Consequently, HKB99 remarkably restores EGFR inhibitor sensitivity and exerts synergistic tumoricidal effect. Additionally, HKB99 alone or in combination with osimertinib down-regulated the level of p-STAT3 in xenograft tumor models. Collectively, this study identifies PGAM1 as a key regulator in IL-6/JAK2/STAT3 axis in the development of resistance to EGFR inhibitors, which could serve as a therapeutic target in lung adenocarcinoma with acquired resistance to EGFR inhibitors.

HKB99, an allosteric inhibitor of phosphoglycerate mutase 1, suppresses invasive pseudopodia formation and upregulates plasminogen activator inhibitor-2 in erlotinib-resistant non-small cell lung cancer cells.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, remains a major challenge in the targeted therapy of non-small cell lung cancer (NSCLC). HKB99 is a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1) that preferentially suppresses cell proliferation and induces more apoptosis in acquired erlotinib-resistant HCC827ER cells compared with its parental HCC827 cells. In this study we identified the molecular biomarkers for HKB99 response in erlotinib-resistant HCC827ER cells. We showed that HCC827ER cells displayed enhanced invasive pseudopodia structures as well as downregulated plasminogen activator inhibitor-2 (PAI-2). Meanwhile, PAI-2 knockdown by siPAI-2 candidates decreased the sensitivity of HCC827 parental cells to erlotinib. Moreover, HKB99 (5 µM) preferentially inhibited the invasive pseudopodia formation and increased the level of PAI-2 in HCC827ER cells. Collectively, this study provides new insight into the role of PAI-2 in regulating the sensitivity of erlotinib resistant NSCLC cells to PGAM1 inhibitor. Furthermore, PAI-2 level might be considered as a potential biomarker for predicting the efficacy of the PGAM1 allosteric inhibitor on the erlotinib resistant NSCLC cells.

Vectors, Hosts, and the Possible Risk Factors Associated with Severe Fever with Thrombocytopenia Syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is a disease caused by infection with the SFTS virus (SFTSV). SFTS has become a crucial public health concern because of the heavy burden, lack of vaccines, effective therapies, and high-fatality rate. Evidence suggests that SFTSV circulates between ticks and animals in nature and is transmitted to humans by tick bites. In particular, ticks have been implicated as vectors of SFTSV, where domestic or wild animals may play as the amplifying hosts. Many studies have identified antigens and antibodies against SFTSV in various animals such as sheep, goats, cattle, and rodents. Besides, person-to-person transmission through contact with blood or mucous of an infected person has also been reported. In this study, we reviewed the literature and summarized the vectors and hosts associated with SFTS and the possible risk factors.

Boosting Electrochemical Reduction of CO2 at a Low Overpotential by Amorphous Ag-Bi-S-O Decorated Bi0 Nanocrystals.

Bimetal-S-O composites have been rarely researched in electrochemical reduction of CO2 . Now, an amorphous Ag-Bi-S-O decorated Bi0 catalyst derived from Ag0.95 BiS0.75 O3.1 nanorods by electrochemical pre-treatment was used for catalyzing eCO2 RR, which exhibited a formate FE of 94.3 % with a formate partial current density of 12.52 mA cm-2 at an overpotential of only 450 mV. This superior performance was attributed to the attached amorphous Ag-Bi-S-O substance. S could be retained in the amorphous region after electrochemical pre-treatment only in samples derived from metal-S-O composites, and it would greatly enhance the formate selectivity by accelerating the dissociation of H2 O. The existence of Ag would increase the current density, resulting in a higher local pH, which made the role of S in activating H2 O more significantly and suppressed H2 evolution more effectively, thus endowing the catalyst with a higher formate FE at low overpotentials.

Effect of ulinastatin on serum inflammatory factors in Asian patients with acute pancreatitis before and after treatment: a meta-analysis
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OBJECTIVE: We applied a meta-analysis to explore the effect of ulinastatin (UTI) on the serum levels of C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) in Asian patients with acute pancreatitis (AP). METHODS: Various databases were searched based on stringent inclusion and exclusion criteria to extract relevant cohort studies. Comprehensive Meta-analysis 2.0 (Biostat Inc., Englewood, NJ, USA) was applied for statistical analyses. RESULTS: A total of 113 relevant studies (67 in Chinese, 46 in English) were initially retrieved. Finally, 11 eligible studies were enrolled in our meta-analysis with 399 pancreatitis patients. Meta-analysis results showed that after being treated with UTI, the serum levels of CRP, IL-6, and TNF-α were evidently decreased (CRP: SMD = -2.697, 95% CI = -4.399 ~ -0.994, p = 0.002; IL-6: SMD = -5.268, 95% CI = -9.850 ~ -0.687, p = 0.024; TNF-α: SMD = -5.666, 95% CI = -11.083 ~ -0.249, p = 0.040). CONCLUSION: UTI can effectively reduce the serum levels of CRP, IL-6, and TNF-α in Asian patients with AP, suggesting that UTI has anti-inflammatory effect on Asian patients with AP.
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GSTO1 aggravates EGFR-TKIs resistance and tumor metastasis via deglutathionylation of NPM1 in lung adenocarcinoma.

Despite significantly improved clinical outcomes in EGFR-mutant lung adenocarcinoma, all patients develop acquired resistance and malignancy on the treatment of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Understanding the resistance mechanisms is crucial to uncover novel therapeutic targets to improve the efficacy of EGFR-TKI treatment. Here, integrated analysis using RNA-Seq and shRNAs metabolic screening reveals glutathione S-transferase omega 1 (GSTO1) as one of the key metabolic enzymes that is required for EGFR-TKIs resistance in lung adenocarcinoma cells. Aberrant upregulation of GSTO1 confers EGFR-TKIs resistance and tumor metastasis in vitro and in vivo dependent on its active-site cysteine 32 (C32). Pharmacological inhibition or knockdown of GSTO1 restores sensitivity to EGFR-TKIs and synergistically enhances tumoricidal effects. Importantly, nucleophosmin 1 (NPM1) cysteine 104 is deglutathionylated by GSTO1 through its active C32 site, which leads to activation of the AKT/NF-κB signaling pathway. In addition, clinical data illustrates that GSTO1 level is positively correlated with NPM1 level, NF-κB-mediated transcriptions and progression of human lung adenocarcinoma. Overall, our study highlights a novel mechanism of GSTO1 mediating EGFR-TKIs resistance and malignant progression via protein deglutathionylation, and GSTO1/NPM1/AKT/NF-κB axis as a potential therapeutic vulnerability in lung adenocarcinoma.

Metabolic and Nonmetabolic Functions of PSAT1 Coordinate Signaling Cascades to Confer EGFR Inhibitor Resistance and Drive Progression in Lung Adenocarcinoma.

Emerging evidence demonstrates that the dysregulated metabolic enzymes can accelerate tumorigenesis and progression via both metabolic and nonmetabolic functions. Further elucidation of the role of metabolic enzymes in EGFR inhibitor resistance and metastasis, two of the leading causes of death in lung adenocarcinoma, could help improve patient outcomes. Here, we found that aberrant upregulation of phosphoserine aminotransferase 1 (PSAT1) confers erlotinib resistance and tumor metastasis in lung adenocarcinoma. Depletion of PSAT1 restored sensitivity to erlotinib and synergistically augmented the tumoricidal effect. Mechanistically, inhibition of PSAT1 activated the ROS-dependent JNK/c-Jun pathway to induce cell apoptosis. In addition, PSAT1 interacted with IQGAP1, subsequently activating STAT3-mediated cell migration independent of its metabolic activity. Clinical analyses showed that PSAT1 expression positively correlated with the progression of human lung adenocarcinoma. Collectively, these findings reveal the multifunctionality of PSAT1 in promoting tumor malignancy through its metabolic and nonmetabolic activities. SIGNIFICANCE: Metabolic and nonmetabolic functions of PSAT1 confer EGFR inhibitor resistance and promote metastasis in lung adenocarcinoma, suggesting therapeutic targeting of PSAT1 may attenuate the malignant features of lung cancer.

A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer.

Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and tumor progression via its metabolic activity and interaction with other proteins like α-smooth muscle actin (ACTA2). Allosteric regulation is considered to be an innovative strategy to discover a highly selective and potent inhibitor targeting PGAM1. Here, we identified a novel PGAM1 allosteric inhibitor, HKB99, via structure-based optimization. HKB99 acted to allosterically block conformational change of PGAM1 during catalytic process and PGAM1-ACTA2 interaction. HKB99 suppressed tumor growth and metastasis and overcame erlotinib resistance in non-small-cell lung cancer (NSCLC). Mechanistically, HKB99 enhanced the oxidative stress and altered multiple signaling pathways including the activation of JNK/c-Jun and suppression of AKT and ERK. Collectively, the study highlights the potential of PGAM1 as a therapeutic target in NSCLC and reveals a distinct mechanism by which HKB99 inhibits both metabolic activity and nonmetabolic function of PGAM1 by allosteric regulation.

Regulating effect of activated NF-κB on edema induced by traumatic brain injury of rats.

OBJECTIVE: To observe the effect of nuclear transcription factor-κB (NF-κB) on cerebral edema in rats with traumatic brain injury (TBI). METHODS: Male SD rats with fluid percussion injury (FPI) were selected. After separation and culture, rats' astrocytes all suffered FPI. The expression of NF-κB and the water content were detected at the animal and cellular levels, while the activity of NOX was evaluated at the cellular level. RESULTS: According to the results, the positive expression of NF-κB and expression of mRNA were significantly increased and the water content was increased for rats after TBI, while NF-κB inhibitor BAY11-7082 could significantly reduce the effect of TBI. 1 and 3 h after FPI of astrocytes, the activation of NF-κB was increased and BAY 11-7082 could significantly improve the injury-induced swelling of astrocytes. After the injury of astrocytes, the activity of NOX was also increased, while BAY 11-7082 could reduce the activity of NOX. CONCLUSIONS: The results show that the activation of NF-κB in astrocytes is a key factor in the process of cerebral edema after TBI of rats.

[Application of partial costectomy and costophrenic angle closure to supplement high intensity focused ultrasound treatment for liver tumor].

OBJECTIVE: To investigate the application of partial costectomy and costophrenic angle closure (PCCAC) and perioperative management in the treatment of liver tumor by high intensity focused ultrasound (HIFU). METHODS: The clinical data of 69 patients with liver tumor underwent HIFU within the recent four years were retrospectively reviewed. RESULTS: 92.8% of these 69 liver tumor patients had had concomitant diseases and 13.0% of them developed postoperative complications without anyone died. There was no significant postoperative dysfunctions of kidney or lung as compared with the preoperative ones (P > 0.05). CONCLUSION: In the treatment of liver tumor by HIFU, PCCAC, as an auxillary means, giving few complications and little harmful effects on respiratory physiology, is highly safe.

Lifestyle of Chinese centenarians and their key beneficial factors in Chongqing, China.

OBJECTIVE: This study aims to describe the lifestyle of Chinese centenarians and to identify the beneficial factors that are correlated to their longevity. METHODS: A census-based survey was conducted among centenarians in Chongqing, Southwest China, to identify the lifestyle factors affecting their health. From screening identification cards, 878 centenarians (age range 100-117, mean 102) were identified and interviewed. RESULTS: The survey indicated that 64% centenarians were able to take care of themselves. The majority of centenarians were nonsmokers (92%) and non-drinkers (83%). No significant difference was observed between urban and rural distributions (Χ2=0.939, p=0.625). Moreover, 43% centenarians maintained a regular diet, and only 33% had a sedentary lifestyle. CONCLUSIONS: A nutritious diet, adequate physical exercise, and a harmonious family environment may be the key lifestyle factors for their longevity of centenarians in Chongqing. These observations might be helpful in designing health promotion and welfare strategies for the elderly.