Hypoxia-associated autophagy flux dysregulation in human cancers.

A general feature of cancer is hypoxia, determined as low oxygen levels. Low oxygen levels may cause cells to alter in ways that contribute to tumor growth and resistance to treatment. Hypoxia leads to variations in cancer cell metabolism, angiogenesis and metastasis. Furthermore, a hypoxic tumor microenvironment might induce immunosuppression. Moreover, hypoxia has the potential to impact cellular processes, such as autophagy. Autophagy refers to the catabolic process by which damaged organelles and toxic macromolecules are broken down. The abnormal activation of autophagy has been extensively recorded in human tumors and it serves as a regulator of cell growth, spread to other parts of the body, and resistance to treatment. There is a correlation between hypoxia and autophagy in human malignancies. Hypoxia can regulate the activity of AMPK, mTOR, Beclin-1, and ATGs to govern autophagy in human malignancies. Furthermore, HIF-1α, serving as an indicator of low oxygen levels, controls the process of autophagy. Hypoxia-induced autophagy has a crucial role in regulating the growth, spread, and resistance to treatment in human malignancies. Hypoxia-induced regulation of autophagy can impact other mechanisms of cell death, such as apoptosis. Chemoresistance and radioresistance have become significant challenges in recent years. Hypoxia-mediated autophagy plays a crucial role in determining the response to these therapeutic treatments.

Increased expression of LINC00323 correlates with tumor progression and poor prognosis of gastric cancer.

BACKGROUD/AIMS: LINC00323 is a novel lncRNA which has reported to play an important role in the development and recurrence in several cancers. However, the expression and predictive value of LINC00323 in gastric cancer (GC) remain mysterious. METHODS: LINC00323 expression in GC tissues and adjacent normal tissues was evaluated by quantitative reverse-transcription PCR (qRT-PCR). The relationship between LINC00323 expression and clinicopathological features and patients' survival were analyzed. Univariate and multivariate survival analyses were performed. RESULTS: LINC00323 expression were found to be significantly increased in GC tissues. High expression of LINC00323 exerted a pro-tumor effect in the late stage of GC development. Kaplan-Meier analysis showed that patients with high LINC00323 were associated with poor overall survival (OS) and progression-free survival (PFS). Moreover, the combination of TNM stage and drinking status better identified GC patient outcome than those of TNM stage alone. CONCLUSIONS: Our data showed that LINC00323 overexpression might serve as a novel independent prognostic factor for survival of GC patients, suggesting LINC00323 was a potential biomarker and therapeutic target for GC.

GABRP is a Promising Prognostic Biomarker and Associated with Immune Cell Infiltration in Lung Squamous Cell Carcinoma.

Background: GABRP has been reported to play an oncogenic role in various carcinomas. However, no report has been found for its involvement in lung squamous cell carcinoma (LUSC) development yet. We aimed to explore the expression and prognostic roles of GABRP and assessment of its association with tumor microenvironment in LUSC. Methods: The GABRP expression in LUSC was analyzed using TCGA, GEO, and HPA databases. The Kaplan-Meier, Cox regression analysis, and receiver operating characteristic (ROC) curve were applied to assess the prognostic and diagnostic values of GABRP in LUSC. We also performed ESTIMATE and ssGSEA to explore the association between GABRP expression and immune cell infiltrations. GABRP was highly expressed in LUSC patients, and up-regulation of GABRP was associated with shorter overall survival (OS). Cox regression analysis indicated that GABRP was an independent prognostic factor for LUSC patients. KEGG analysis revealed that GABRP may play an important role in starch and sucrose metabolism and nicotine addiction. Specifically, GABRP expression showed significant positive correlations with the infiltration levels of most types of immune cells, as well as immune checkpoint molecules expression. Conclusion: Up-regulation of GABRP in LUSC could be severed as a prognostic marker and a potential target for immunotherapy in LUSC.

LncRNA SNHG15 regulates hypoxic-ischemic brain injury via miR-153-3p/SETD7 axis.

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of fatality and morbidity in newborns. Long non-coding RNAs (lncRNAs) Small Nucleolar RNA Host Gene 15 (SNHG15) was elevated in the peripheral blood of patients with acute cerebral ischemia, but its role in HI brain injury remained elusive. Hence, this study aimed to investigate the effect of SNHG15 on HI brain injury and study the precise mechanism of action. In this study, a mouse model of HI brain injury was established through ligating right carotid arteries. The oxygen-glucose deprivation (OGD) model was established in PC12 cells. Results showed that SNHG15 was elevated in brain tissues of mice with HI brain injury, and knockdown of SNHG15 attenuated HI-induced impairment of neurobehavioral function, brain edema, brain injury, and cell apoptosis. Besides, SNHG15 acted as a miR-153-3p sponge. SETD7 was identified to be a target of miR-153-3p. Furthermore, down-regulation of SNHG15 inhibited the OGD-induced increase in SETD7 expression in PC12 cells. Moreover, SNHG15 modulated OGD-induced cell apoptosis and decrease of cell viability through the miR-153-3p/SETD7 axis. In conclusion, knockdown of SNHG15 alleviated HI brain injury through modulating the miR-153-3p/ SETD7 axis. SNHG15 may be a prospective target for HIE therapy.

Impact of Smoking on Response to the First-Line Treatment of Advanced ALK-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis.

Background: The impact of smoking on the efficacy of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) treatment is controversial and has not been systematically explored in the first-line setting. We performed a systematic review based on a pairwise meta-analysis and a Bayesian network meta-analysis (NMA) to address this issue. Methods: PubMed, Embase, Web of Science, Cochrane Library, Clinical-Trials.gov, and other resources were searched until 5 January 2022. Progression-free survival (PFS) was considered the main outcome of interest. Randomized controlled trials with smoking status analysis were included. Cochrane Risk of Bias Tool was performed to assess the risk of bias. Random effects models were adopted conservatively in meta-analysis. The NMA was performed in a Bayesian framework using the "gemtc" version 1.0-1 package of R-4.1.2 software. Results: A total of 2,484 patients from nine studies were eligible for this study, with 1,547 never-smokers (62.3%) and 937 smokers (37.7%). In a pairwise meta-analysis, in the overall population, no significant difference was found between never-smokers and smokers. However, in the subgroup analyses based on crizotinib-controlled studies, anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) derived better PFS in the smoking group over the never-smoking group in the Asian population (HR = 0.17, 95%CI = 0.09-0.31 in the smoking group, HR = 0.39, 95%CI = 0.24-0.65 in the never-smoking group, p = 0.04, low quality of evidence). In NMA, among never-smokers, lorlatinib ranked the highest for PFS (SUCRA = 96.2%), but no significant superiority was found among the new-generation ALK-TKIs except for ceritinib. In smokers, low-dose alectinib performed best (SUCRA = 95.5%) and also demonstrated a significant superiority over ensartinib (HR = 0.23, 95%CI = 0.08-0.68, very low quality of evidence), brigatinib (HR = 0.38, 95%CI = 0.14-0.99, low quality of evidence), ceritinib (HR = 0.24, 95%CI = 0.09-0.66, low quality of evidence), crizotinib (HR = 0.18, 95%CI = 0.08-0.41, moderate quality of evidence), and chemotherapy (HR = 0.11, 95%CI = 0.05-0.28, low quality of evidence). Conclusion: In general, smoking may not affect the treatment efficacy of advanced ALK-positive NSCLC in the first-line setting. However, alectinib may perform better in the smoking Asian population. Moreover, lorlatinib in never-smokers and low-dose alectinib in smokers could be considered optimal first-line therapy for advanced ALK-positive NSCLC. Acceptable limitations of evidence, such as study risk of bias, inconsistency, and imprecision, were present in this NMA.

Atractylenolide III alleviates sepsis-mediated lung injury via inhibition of FoxO1 and VNN1 protein.

PURPOSE: To evaluate the influence of atractylenolide (Atr) III on sepsis-induced lung damage. METHODS: We constructed a mouse sepsis model through cecal ligation and puncture. These mice were allocated to the normal, sepsis, sepsis + Atr III-L (2 mg/kg), as well as Atr III-H (8 mg/kg) group. Lung injury and pulmonary fibrosis were accessed via hematoxylin-eosin (HE) and Masson's staining. We used terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and flow cytometry for detecting sepsis-induced lung cell apoptosis. The contents of the inflammatory cytokines in lung tissue were measured via enzyme-linked immunosorbent assay (ELISA). RESULTS: Atr III-H did not only reduce sepsis-induced lung injury and apoptosis level, but also curbed the secretion of inflammatory factors. Atr III-H substantially ameliorated lung function and raised Bcl-2 expression. Atr III-H eased the pulmonary fibrosis damage and Bax, caspase-3, Vanin-1 (VNN1), as well as Forkhead Box Protein O1 (FoxO1) expression. CONCLUSIONS: Atr III alleviates sepsis-mediated lung injury via inhibition of FoxO1 and VNN1 protein.

Atractylenolide III alleviates sepsis-mediated lung injury via inhibition of FoxO1 and VNN1 protein

ABSTRACT Purpose: To evaluate the influence of atractylenolide (Atr) III on sepsis-induced lung damage. Methods: We constructed a mouse sepsis model through cecal ligation and puncture. These mice were allocated to the normal, sepsis, sepsis + Atr III-L (2 mg/kg), as well as Atr III-H (8 mg/kg) group. Lung injury and pulmonary fibrosis were accessed via hematoxylin-eosin (HE) and Masson's staining. We used terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and flow cytometry for detecting sepsis-induced lung cell apoptosis. The contents of the inflammatory cytokines in lung tissue were measured via enzyme-linked immunosorbent assay (ELISA). Results: Atr III-H did not only reduce sepsis-induced lung injury and apoptosis level, but also curbed the secretion of inflammatory factors. Atr III-H substantially ameliorated lung function and raised Bcl-2 expression. Atr III-H eased the pulmonary fibrosis damage and Bax, caspase-3, Vanin-1 (VNN1), as well as Forkhead Box Protein O1 (FoxO1) expression. Conclusions: Atr III alleviates sepsis-mediated lung injury via inhibition of FoxO1 and VNN1 protein.