Asarinin attenuates bleomycin-induced pulmonary fibrosis by activating PPARγ.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that lacks effective treatment modalities. Once patients are diagnosed with IPF, their median survival is approximately 3-5 years. PPARγ is an important target for the prevention and treatment of pulmonary fibrosis. Asarinin is a lignan compound that can be extracted from food plant Asarum heterotropoides. In this study, we investigated the therapeutic effects of asarinin in a pulmonary fibrosis model constructed using bleomycin in mice and explored the underlying mechanisms. Intraperitoneal administration of asarinin to mice with pulmonary fibrosis showed that asarinin effectively attenuated pulmonary fibrosis, and this effect was significantly inhibited by the PPARγ inhibitor GW9662. Asarinin inhibited TGF-ß1-induced fibroblast-to-myofibroblast transition in vitro, while GW9662 and PPARγ gene silencing significantly inhibited this effect. In addition, asarinin inhibited not only the canonical Smad pathway of TGF-ß but also the non-canonical AKT and MAPK pathways by activating PPARγ. Our study demonstrates that asarinin can be used as a therapeutic agent for pulmonary fibrosis, and that PPARγ is its key target.

Efficacy and safety of consolidation durvalumab after chemoradiation therapy for stage III non-small-cell lung cancer: a systematic review, meta-analysis, and meta-regression of real-world studies.

Background: The current review aimed to pool real-world evidence on the efficacy and toxicity of consolidation durvalumab for stage III unresectable non-small cell lung cancer (NSCLC) after curative chemoradiotherapy. Methods: PubMed, CENTRAL, ScienceDirect, Embase, and Google Scholar were searched for observational studies reporting the use of durvalumab for NSCLC till 12th April 2022. Twenty-three studies with 4,400 patients were included. Results: The pooled 1-year overall survival (OS) and progression-free survival rates (PFS) were 85% (95% CI: 81%-89%) and 60% (95% CI: 56%-64%) respectively. Pooled incidence of all-grade pneumonitis, grade ≥3 pneumonitis and discontinuation of durvalumab due to pneumonitis were 27% (95% CI: 19%-36%), 8% (95% CI: 6%-10%) and 17% (95% CI: 12%-23%) respectively. The pooled proportion of patients experiencing endocrine, cutaneous, musculoskeletal, and gastrointestinal adverse events was 11% (95% CI: 7%-18%), 8% (95% CI: 3%-17%), 5% (95% CI: 3%-6%), and 6% (95% CI: 3%-12%), respectively. Conclusion: Meta-regression indicated that performance status significantly influenced PFS, while age, time to durvalumab, and programmed death-ligand 1 status significantly affected pneumonitis rates. Real-world evidence suggests that the short-term efficacy and safety of durvalumab are consistent with that of the PACIFIC trial. The congruence of results lends support to durvalumab use in improving outcomes of unresectable stage III NSCLC. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022324663, identifier CRD42022324663.

Activation of metabotropic glutamate receptor 4 regulates proliferation and neural differentiation in neural stem/progenitor cells of the rat subventricular zone and increases phosphatase and tensin homolog protein expression.

Neural stem/progenitor cells (NSPCs) persist in the mammalian subventricular zone throughout life, where they can be activated in response to physiological and pathophysiological stimuli. A recent study indicates metabotropic glutamate receptor 4 (mGluR4) is involved in regulating NSPCs behaviors. Therefore, defining mGluR4 function in NSPCs is necessary for determining novel strategies to enhance the intrinsic potential for brain regeneration after injuries. In this study, mGluR4 was functionally expressed in SVZ-derived NSPCs from male Sprague-Dawley rats, in which the cyclic adenosine monophosphate concentration was reduced after treatment with the mGluR4-specific agonist VU0155041. Additionally, lateral ventricle injection of VU0155041 significantly decreased 5-bromo-2'-deoxyuridine (BrdU)+ and Ki67+ cells, while increased Doublecortin (DCX)/BrdU double-positive cells in SVZ. In cultured NSPCs, mGluR4 activation decreased the ratio of BrdU+ cells, G2/M-phase cells, and inhibited Cyclin D1 expression, whereas it increased neuron-specific class III ß-tubulin (Tuj1) expression and the number of Tuj1, DCX, and PSA-NCAM-positive cells. However, pharmacological blocking mGluR4 with the antagonist MSOP or knockdown of mGluR4 abolished the effects of VU0155041 on NSPCs proliferation and neuronal differentiation. Further investigation demonstrated that VU0155041 treatment down-regulated AKT phosphorylation and up-regulated expression of the phosphatase and tensin homolog protein (PTEN) in NSPCs culture. Moreover VU0155041-induced proliferating inhibition and neuronal differentiating amplification in NSPCs were significantly hampered by VO-OHpic, a PTEN inhibitor. We conclude that activation of mGluR4 in SVZ-derived NSPCs suppresses proliferation and enhances their neuronal differentiation, and regulation of PTEN may be involved as a potential intracellular target of mGluR4 signal. Cover Image for this issue: https://doi.org/10.1111/jnc.15052.

Contribution of xeroderma pigmentosum complementation group D gene polymorphisms in breast and ovarian cancer susceptibility: A protocol for systematic review and meta analysis.

BACKGROUND: The role of xeroderma pigmentosum complementation group D (XPD) gene polymorphisms in breast and ovarian cancer development has long been controversial and existing data were inconsistent. Here, we conducted a comprehensive systemic review and meta-analysis to better clarify the association. METHODS: Relevant case-control studies published in electronic data base from October 1999 to September 2019 were assessed. The statistical analyses of the pooled odds ratios (ORs) and the corresponding 95% confidence intervals (95%CIs) were calculated by using Revman 5.2 software (Cochrane Collaboration, Copenhagen). RESULTS: 31 articles including 38 case-control studies and 2 XPD polymorphisms (rs1799793 and rs238406) were analyzed. The results showed statistical significance in heterozygous mutants among Asian population for rs1799793 (GA vs GG + AA: OR = 1.38, 95%CI = 1.21-1.56), and Caucasian population for rs238406 (CA vs AA + CC: OR = 0.63, 95%CI = 0.49-0.80), while the rest comparisons including overall groups and subgroups stratified by cancer types and ethnicity failed to indicate any association with breast and ovarian cancer risk. CONCLUSIONS: The current meta-analysis suggested no concrete correlation of XPD rs1799793(G/A) and rs238406(C/A) polymorphisms with breast cancer or ovarian cancer susceptibility. However, it indicated that heterozygous genotypes might share different pathophysiologic mechanism from not only homozygous wildtypes but also homozygous mutants. More case-control studies with well-adjusted data and diverse populations are essential for validation of our conclusion.

[Effect of glutamate on vascular endothelial growth factor mRNA and protein expressions in hypoxic rat astrocytes in vitro].

OBJECTIVE: To study the effect of glutamate on the expression of vascular endothelial growth factor (VEGF) mRNA and protein in cultured rat astrocytes under hypoxia. METHODS: Cultured rat astrocytes were randomly divided control group, glutamate group, hypoxia group and hypoxia+glutamate group. The cells in the control and glutamate groups were cultured under nomoxic condition (95% air and 5% CO(2)), and those in the other two groups under hypoxic condition (94% N(2), 5% CO(2) and 1% O(2)). The total RNA was extracted from the cells at different time points of hypoxic exposure for real-time FQ-PCR and ELISA to detect the expression of VEGF mRNA and protein in cultured astrocytes, respectively. RESULTS: The expressions of VEGF mRNA and protein underwent no significant changes in the control glutamate groups, but increased obviously in both hypoxia and hypoxia+glutamate groups at 2, 4, 6, 8 and 12 h of hypoxic exposure. At these time points, VEGF expressions at both the mRNA and protein levels were significantly higher in hypoxia+glutamate group than in hypoxia group. CONCLUSION: Glutamate at 1 micromol/L can further increase the expression of VEGF mRNA and protein in astrocytes exposed to hypoxia, which may result from the adaptive changes of glutamate receptors in hypoxic astrocytes.

Adenovirus-mediated brain-derived neurotrophic factor expression regulated by hypoxia response element protects brain from injury of transient middle cerebral artery occlusion in mice.

Some gene expression may be regulated by hypoxia-responsive element (HRE) that is bound by hypoxia-inducible factor-1 (HIF-1) which is up-regulated during cerebral ischemia. To explore ischemia/hypoxia-controlled expression and the neuroprotective effects of brain-derived neurotrophic factor (BDNF) after ischemic brain injury, an adenoviral vector using five copies of hypoxia response element (HRE) in the vascular endothelial growth factor gene to regulate the expression of BDNF gene (Ad5HRE:BDNF) was constructed, and its efficacy was verified for driving BDNF expression in cultured Hela cells under hypoxic condition by ELISA. We found that the concentration of BDNF in the Ad5HRE:BDNF-transfected culture media was 28-fold greater in a hypoxic condition than under normoxia. To examine the effect of Ad5HRE:BDNF on ischemic brain injury in vivo, Ad5HRE:BDNF was injected into right caudate putamen of adult mice 7 days prior to 60 min transient middle cerebral artery occlusion (MCAO). It was found that exogenous BDNF expression was increased in the Ad5HRE-BDNF-treated group and infarct volume of the Ad5HRE:BDNF-treated group at 3 days after MCAO was significantly smaller than that of vehicle- or AdNull-treated groups. Moreover, Ad5HRE:BDNF injection resulted in significantly improved sensorimotor scores 7 days after MCAO and induced a reduction in the number of Fluoro-Jade B-positive neurons and TUNEL-positive cells, compared with vehicle- or AdNull-injection. Our findings suggest that BDNF expression could be regulated in hypoxia/ischemia condition with five copies of HRE and ameliorates ischemic brain injury in a mouse focal cerebral ischemia model.