Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of midbrain dopaminergic neurons. The miR-29s family, including miR-29a and miR-29b1 as well as miR-29b2 and miR-29c, are implicated in aging, metabolism, neuronal survival, and neurological disorders. In this study, the roles of miR-29a/b1 in aging and PD were investigated. miR-29a/b1 knockout mice (named as 29a KO hereafter) and their wild-type (WT) controls were used to analyze aging-related phenotypes. After challenged with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), dopaminergic injuries, glial activation, and mouse behaviors were evaluated. Primary glial cells were further cultured to explore the underlying mechanisms. Additionally, the levels of miR-29s in the cerebrospinal fluid (CSF) of PD patients (n = 18) and healthy subjects (n = 17) were quantified. 29a KO mice showed dramatic weight loss, kyphosis, and along with increased and deepened wrinkles in skins, when compared with WT mice. Moreover, both abdominal and brown adipose tissues reduced in 29a KO mice, compared to their WT counterpart. However, in MPTP-induced PD mouse model, the deficiency of miR-29a/b1 led to less severe damages of dopaminergic system and mitigated glial activation in the nigrostriatal pathway, and subsequently alleviated the motor impairments in 3-month-old mice. Eight-month-old mutant mice maintained such a resistance to MPTP intoxication. Mechanistically, the deficiency of miR-29a/b-1 promoted the expression of neurotrophic factors in 1-Methyl-4-phenylpyridinium (MPP+)-treated primary mixed glia and primary astrocytes. In lipopolysaccharide (LPS)-treated primary microglia, knockout of miR-29a/b-1 inhibited the expression of inflammatory factors, and promoted the expression of anti-inflammatory factors and neurotrophic factors. Knockout of miR-29a/b1 increased the activity of AMP-activated protein kinase (AMPK) and repressed NF-κB/p65 signaling in glial cells. Moreover, we found miR-29a level was increased in the CSF of patients with PD. Our results suggest that 29a KO mice display the peripheral premature senility. The combined effects of less activated glial cells might contribute to the mitigated inflammatory responses and elicit resistance to MPTP intoxication in miR-29a/b1 KO mice.
Effective therapies are urgently needed for the SARS-CoV-2 pandemic. Chloroquine has been proved to have antiviral effect against coronavirus in vitro. In this study, we aimed to assess the efficacy and safety of chloroquine with different doses in COVID-19. In this multicenter prospective observational study, we enrolled patients older than 18 years old with confirmed SARS-CoV-2 infection excluding critical cases from 12 hospitals in Guangdong and Hubei Provinces. Eligible patients received chloroquine phosphate 500 mg, orally, once (half dose) or twice (full dose) daily. Patients treated with non-chloroquine therapy were included as historical controls. The primary endpoint is the time to undetectable viral RNA. Secondary outcomes include the proportion of patients with undetectable viral RNA by day 10 and 14, hospitalization time, duration of fever, and adverse events. A total of 197 patients completed chloroquine treatment, and 176 patients were included as historical controls. The median time to achieve an undetectable viral RNA was shorter in chloroquine than in non-chloroquine (absolute difference in medians -6.0 days; 95% CI -6.0 to -4.0). The duration of fever is shorter in chloroquine (geometric mean ratio 0.6; 95% CI 0.5 to 0.8). No serious adverse events were observed in the chloroquine group. Patients treated with half dose experienced lower rate of adverse events than with full dose. Although randomized trials are needed for further evaluation, this study provides evidence for safety and efficacy of chloroquine in COVID-19 and suggests that chloroquine can be a cost-effective therapy for combating the COVID-19 pandemic.
This review explores the emerging role of gut microbiota in lung cancer and Chronic Obstructive Pulmonary Disease (COPD), emphasizing the gut-lung axis's integral role in these diseases. Lung cancer, the leading cause of cancer-related mortality, and COPD, a prevalent chronic respiratory condition, share common risk factors and pathophysiological pathways that may be influenced by the gut microbiota. Through a synthesis of current research, this article highlights the differences in gut microbiota composition observed in patients with lung cancer and COPD compared to healthy individuals, and discusses the potential mechanisms by which these microbial populations might impact disease development and progression. The review also delves into the promising therapeutic implications of modulating gut microbiota, including dietary interventions, probiotics, prebiotics, and fecal microbiota transplantation, as adjunctive treatments for these respiratory diseases. Future research directions are proposed, focusing on the need for a deeper understanding of the gut-lung axis and the translation of these findings into clinical practice. This review underscores the significance of gut microbiota in respiratory diseases and points towards a new frontier in personalized medicine, where microbiome modulation could complement traditional treatment approaches.
Sepsis is a highly heterogeneous disease and a major factor in increasing mortality from infection. N7-Methylguanosine (m7G) is a widely RNA modification in eukaryotes, which involved in regulation of different biological processes. Researchers have found that m7G methylation contributes to a variety of human diseases, but its research in sepsis is still limited. Here, we aim to establish the molecular classification of m7G gene-related sepsis, reveal its heterogeneity and explore the underlying mechanism. We first identified eight m7G related prognostic genes, and identified two different molecular subtypes of sepsis through Consensus Clustering. Among them, the prognosis of C2 subtype is worse than that of C1 subtype. The signal pathways enriched by the two subtypes were analyzed by ssGSEA, and the results showed that the amino acid metabolism activity of C2 subtype was more active than that of C1 subtype. In addition, the difference of immune microenvironment among different subtypes was explored through CIBERSORT algorithm, and the results showed that the contents of macrophages M0 and NK cells activated were significantly increased in C2 subtype, while the content of NK cells resting decreased significantly in C2 subtype. We further explored the relationship between immune regulatory genes and inflammation related genes between C2 subtype and C1 subtype, and found that C2 subtype showed higher expression of immune regulatory genes and inflammation related genes. Finally, we screened the key genes in sepsis by WGCNA analysis, namely NUDT4 and PARN, and verified their expression patterns in sepsis in the datasets GSE131761 and GSE65682. The RT-PCR test further confirmed the increased expression of NUDTA4 in sepsis patients. In conclusion, sepsis clustering based on eight m7G-related genes can well distinguish the heterogeneity of sepsis patients and help guide the personalized treatment of sepsis patients.
UPVA (Unilateral pulmonary vein atresia) is the failure of connection between the common pulmonary vein and the left atrium. UPVA is a rare malformation of common pulmonary vein caused by embryonic development defects. Isolated UPVA is uncommon, the diagnosis commonly occurs during early childhood because of asthma, recurrent pneumonia or hemoptysis, but diagnosis in adults is unusual. Some patients can be asymptomatic until adulthood. In this report, we describe a case about UPVA presenting with recurrent hydrothorax in an adult. We gradually carried out routine diagnostic methods and eventually confirmed the rare UPVA according to the two common clinical manifestations of repeated pleural effusion and hilar soft tissue shadow.
Non-small cell lung cancer (NSCLC) is the most deadly cancer worldwide. LncRNA KCNQ1OT1 has been reported to be involved in the progression of various tumors, including NSCLC. However, the precise mechanism of KCNQ1OT1 in NSCLC requires further investigation.The expression levels of KCNQ1OT1, miR-129-5p and JAG1 were detected by qRT-PCR or western blot. Kaplan-Meier survival analysis was used to assess the correlation between KCNQ1OT1 expression and the overall survival of NSCLC patients. CCK-8 assay was used to measure cell viability. Cell migration and invasion were detected by transwell assay. The targets of KCNQ1OT1 and miR-129-5p were predicted by bioinformatics, which was confirmed by dual-luciferase reporter assay or pull-down assay.KCNQ1OT1 expression was significantly enhanced, while miR-129-5p expression was dramatically reduced in NSCLC tissues and cells. Higher KCNQ1OT1 shortened overall survival and was positively associated with tumor stage and lymph node metastasis. KCNQ1OT1 knockdown inhibited proliferation, migration and invasion of NSCLC cells. Inhibition of miR-129-5p attenuated the inhibition of NSCLC cell viability, migration and invasion induced by KCNQ1OT1 knockdown. In addition, JAG1 was confirmed as a target of miR-129-5p. Knockdown of JAG1 reversed the effects of miR-129-5p knockdown on NSCLC progression. KCNQ1OT1 regulated JAG1 expression by sponging miR-129-5p in NSCLC cells.KCNQ1OT1 induced proliferation, migration and invasion of NSCLC cells by sponging miR-129-5p and regulating JAG1 expression, indicating that KCNQ1OT1 was a therapeutic target for NSCLC.
The KRAS proto-oncogene, GTPase (KRAS) harbors the most frequent oncogenic mutations in human cancers and serves as an important biomarker in the treatment of lung cancer. Meanwhile, mutations in Liver kinase B1 (LKB1), also known as STK11, are found in 17–23% of non-small cell lung cancer (NSCLC) patients. The LKB1 mutations typically result in loss of function and frequently co-occur with KRAS mutations, collectively contributing to resistance of NSCLC to immune checkpoint inhibitor (ICI) therapies. Therefore, while ICI therapy has been approved for treating non-small cell lung cancer, strategies to enhance the efficacy of checkpoint inhibitor therapy (CIT) remain to be explored. Inhibitors targeting KRAS mutations represent another promising therapeutic option for KRAS-mutant NSCLC. Several studies have demonstrated that inhibition of mutant KRAS effectively reverses the immunosuppressive tumor microenvironment and enhances tumor sensitivity to ICIs through diverse mechanisms. Therefore, there is growing interest in developing new preclinical models with competent immune systems to efficiently assess the efficacy of tested drugs and ICIs on KRAS and LKB double mutant NSCLC tumors.
Methods
We engineered mice in C57BL/6 background with the KRAS(G12D) mutation, LKB deficiency, and expression of firefly luciferase, resulting in spontaneous non-small cell lung cancer tumors. We named this spontaneously arising tumor cell line the KLL cell line.
Results
The KLL cell line can be used for subcutaneous and orthotopic lung tumor transplantation in immunocompetent C57BL/6 mice to establish syngeneic tumor models. Compared to the commonly used LLC2 mouse lung cancer cell line, the KLL syngeneic model exhibits a distinct immune profile, demonstrating different responses to KRAS mutation inhibitors and ICIs, while effectively simulating complex tumor microenvironments.
Conclusions
We established a new syngeneic preclinical model of lung cancer with dual mutations in KRAS and LKB, which can assist scientists in studying optimal treatment strategies for NSCLC, particularly the combination of targeted therapy and immunotherapy.
The outbreak of SARS-CoV-2 rapidly spread across China and worldwide. Remdesivir had been proposed as a promising option for treating coronavirus disease 2019 (COVID-19). We provided a rapid review to critically assess the potential anti-coronavirus effect of remdesivir on COVID-19 and other coronaviruses based on the most up-to-date evidence. Even though remdesivir was proposed as a promising option for treating COVID-19 based on laboratory experiments and reports from compassionate use, its safety and effect in humans requires high-quality evidence from well-designed and adequately-powered clinical trials for further clarification.
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