Inhibition of xanthine oxidase alleviated pancreatic necrosis via HIF-1α-regulated LDHA and NLRP3 signaling pathway in acute pancreatitis

Acute pancreatitis(AP)is a potentially fatal condition with no targeted treatment options.Although inhibiting xanthine oxidase(XO)in the treatment of AP has been studied in several experimental models and clinical trials,whether XO is a target of AP and what its the main mechanism of action is remains unclear.Here,we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger AP.We first revealed that XO expression and enzyme activity were significantly elevated in the serum and pancreas of necrotizing AP models.We also found that allopurinol and febuxostat,as purine-like and non-purine XO inhibitors,respectively,exhibited protective effects against pancreatic acinar cell death in vitro and pancreatic damage in vivo at different doses and treatment time points.Moreover,we observed that conditional Xdh overexpression aggravated pancreatic necrosis and severity.Further mechanism analysis showed that XO inhibition restored the hypoxia-inducible factor 1-alpha(HIF-1α)-regulated lactate dehydrogenase A(LDHA)and NOD-like receptor family pyrin domain containing 3(NLRP3)signaling pathways and reduced the enrichment of^(13)C_(6)-glucose to^(13)C_(3)-lactate.Lastly,we observed that clinical circulatory XO activity was significantly elevated in severe cases and correlated with C-reactive protein levels,while pancreatic XO and urate were also increased in severe AP patients.These results together indicated that proper inhibition of XO might be a promising therapeutic strategy for alleviating pancreatic necrosis and preventing progression of severe AP by downregulating HIF-1α-mediated LDHA and NLRP3 signaling pathways.

Evolving landscape of treatments targeting the microenvironment of liver metastases in non-small cell lung cancer

Liver metastases(LMs)are common in lung cancer.Despite substantial advances in diagnosis and treatment,the survival rate of patients with LM remains low as the immune-suppressive microenvironment of the liver allows tumor cells to evade the immune system.The impact of LMs on the outcomes of immune checkpoint inhibitors in patients with solid tumors has been the main focus of recent translational and clinical research.Growing evidence indicates that the hepatic microenvironment delivers paracrine and autocrine signals from non-parenchymal and parenchymal cells.Overall,these microenvironments create pre-and post-metastatic conditions for the progression of LMs.Herein,we reviewed the epidemiology,physiology,pathology and immunology,of LMs associated with non-small cell lung cancer and the role and potential targets of the liver microenvironment in LM in each phase of metastasis.Additionally,we reviewed the current treatment strategies and challenges that should be overcome in preclinical and clinical investigations.These approaches target liver elements as the basis for future clinical trials,including combinatorial interventions reported to resolve hepatic immune suppression,such as immunotherapy plus chemotherapy,immunotherapy plus radiotherapy,immunotherapy plus anti-angiogenesis therapy,and surgical resection.

Tumor immune microenvironment-modulated nanostrategy for the treatment of lung cancer metastasis

As one of the most malignant tumors worldwide,lung cancer,fueled by metastasis,has shown rising mortality rates.However,effective clinical strategies aimed at preventing metastasis are lacking owing to its dynamic multi-step,complicated,and progressive nature.Immunotherapy has shown promise in treating cancer metastasis by reversing the immunosuppressive network of the tumor microenvironment.However,drug resistance inevitably develops due to inadequate delivery of immunostimulants and an uncontrolled immune response.Consequently,adverse effects occur,such as autoimmunity,from the non-specific immune activation and non-specific inflammation in off-target organs.Nanocarriers that improve drug solubility,permeability,stability,bioavailability,as well as sustained,controlled,and targeted delivery can effectively overcome drug resistance and enhance the therapeutic effect while reducing adverse effects.In particular,nanomedicine-based immunotherapy can be utilized to target tumor metastasis,presenting a promising therapeutic strategy for lung cancer.Nanotechnology strategies that boost the immunotherapy effect are classified based on the metastatic cascade related to the tumor immune microenvironment;the breaking away of primary tumors,circulating tumor cell dissemination,and premetastatic niche formation cause distant secondary site colonization.In this review,we focus on the opportunities and challenges of integrating immunotherapy with nanoparticle formulation to establish nanotechnology-based immunotherapy by modulating the tumor microenvironment for preclinical and clinical applications in the management of patients with metastatic lung cancer.We also discuss prospects for the emerging field and the clinical translation potential of these techniques.

Clinical efficacy and safety of linezolid in intensive care unit patients

Background:To characterize the population of critically ill patients and infections treated with linezolid in the intensive care unit(ICU),and to evaluate the clinical efficacy and safety of linezolid therapy.Methods::This multi-center,observational,real-world study was conducted across 52 hospitals between June 9,2018,and December 28,2019.Patients who met the following inclusion criteria were included:(1)admitted to the ICU,(2)of any age group,and(3)having a clinical or laboratory diagnosis of a Gram-positive bacterial infection.Clinical efficacy was categorized as success(cured or improved),failed,or non-evaluable.Adverse events and serious adverse events were recorded during treatment.Results::A total of 366 ICU patients who met the inclusion criteria were evaluated.Linezolid was used as second-and first-line treatment in 232(63.4%)and 134(36.6%)patients,respectively.The most common isolated strain was Staphylococcus aureus(methicillin-resistant Staphylococcus aureus:n=37/119,31.1%;methicillin-susceptible Staphylococcus aureus:n=15/119,12.6%);this was followed by Enterococci(vancomycin-resistant Enterococci:n=8/119,6.7%;vancomycin-susceptible Enterococci:n=11/119,9.2%)and Streptococcus pneumoniae(multidrug-resistant:n=4/119,3.4%;non-multidrug resistant:n=2/119,1.7%).The main infection sites where pathogens were detected included the lung(n=216/366,59.6%),skin and soft tissue(n=104/366,28.4%),and blood(n=50/366,13.7%).Clinical success was achieved in 301(82.2%)patients;34(9.3%)were cured and 267(73.0%)improved;treatment failure and non-evaluable outcomes were observed in 29(7.9%)in 36(9.8%)patients,respectively.Linezolid-related adverse events were reported in 8(2.2%)patients.No treatment-related serious adverse events were reported.Conclusions::Based on real-world results,linezolid was found to be effective and safe in the treatment of Gram-positive bacterial infections in critically ill patients.