bims-stacyt 2019-11-10 papers

J Ethnopharmacol. 2019 Oct 30. pii: S0378-8741(19)33699-2. [Epub ahead of print] 112365

Ginkgo diterpene lactones inhibit cerebral ischemia/reperfusion induced inflammatory response in astrocytes via TLR4/NF-κB pathway in rats.

Xiang Li, Liangliang Huang, Ge Liu, Wenxiang Fan, Binbin Li, Rui Liu, Ziyu Wang, Qiru Fan, Wei Xiao, Yunman Li, Weirong Fang.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba L. (Ginkgoaceae) is a traditional Chinese medicine known to treating stroke and other cardio-cerebrovascular diseases for thousands of years in China. Ginkgo diterpene lactones (GDL) attracted much attention because of their neuroprotective properties.
AIM OF THE STUDY: To uncover the effects of GDL, which consist of ginkgolide A (GA), ginkgolide B (GB), and ginkgolide K (GK), on ischemic stroke, as well as the underlying molecular mechanisms.
MATERIALS AND METHODS: We used middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R) models mimicking the process of ischemia/reperfusion in vivo and in vitro, respectively. Anticoagulant effects of GDL were investigated on platelet activating factor (PAF), arachidonic acid (AA) and adenosine diphosphate (ADP)-induced platelet aggregation both in vivo and in vitro. We also evaluated the effects of GDL on lipopolysaccharide (LPS)-induced inflammatory responses in primary cultured rats' astrocytes. Infarct size, neurological deficit score, and brain edema were measured at 72 h after MCAO. Immunohistochemistry was utilized to analyze neurons necrosis and astrocytes activation. Expression of pro-inflammatory cytokines, including tumor necrotic factor-α (TNF-α) and interleukin-1β (IL-1β) were detected using enzyme-linked immunosorbent assay (ELISA) and real time PCR. The levels of toll-like receptor 4 (TLR4) and nuclear factor κB (NF-κB) were assessed by real time PCR or Western blot.
RESULTS: Compared with MCAO/R rats, GDL significantly reduced infarct size and brain edema, improved neurological deficit score. Meanwhile, GDL suppressed platelet aggregation, astrocytes activation, pro-inflammatory cytokines releasing, TLR4 mRNA expression and transfer of NF-κB from cytoplasm to nucleus. Furthermore, GDL alleviated OGD/R injury and LPS-induced inflammatory responses in primary astrocytes, characterized by promoting cell viability, decreasing lactate dehydrogenase (LDH) activity, and inhibiting IL-1β and TNF-α releasing.
CONCLUSIONS: In summary, GDL attenuate cerebral ischemic injury, inhibits platelet aggregation and astrocytes activation. The anti-inflammatory activity might be associated with the downregulation of TLR4/NF-κB signal pathway. Our present findings provide an innovative insight into the novel treatment of GDL in ischemic stroke therapy.

Keywords: Astrocytes activation; Ginkgo diterpene lactones; Inflammation; Ischemic stroke; TLR4/NF-κB

DOI: https://doi.org/10.1016/j.jep.2019.112365

Biochem Biophys Res Commun. 2019 Oct 31. pii: S0006-291X(19)32072-8. [Epub ahead of print]

Hypoxic adipocytes induce macrophages to release inflammatory cytokines that render skeletal muscle cells insulin resistant.

Chang Zhang, Xianjun Luo, Da Zhang, Bangli Deng, Jingkai Tong, Mo Zhang, Liming Chen, Hongquan Duan, Wenyan Niu.

Adipose tissue hypoxia occurs early in obesity and is associated with increased tissue macrophages and systemic inflammation that impacts muscle insulin responsiveness. We investigated how hypoxia interacted with adipocyte-macrophage crosstalk and inflammatory cytokine release, using co-culture and conditioned media (CM). Murine primary adipocytes from lean or obese mice were cultured under normoxic (21% O2) or hypoxic (1% O2) conditions. RAW264.7 macrophages were incubated under normoxic or hypoxic conditions with or without adipocyte conditioned media. Macrophage and adipocyte-macrophage co-culture CM were also collected. We found hypoxia did not elicit direct cytokine release from macrophages. However, adipocyte CM or adipocyte co-culture, synergistically stimulated TNFα and MCP-1 release from macrophages that was not further impacted by hypoxia. Exposure of muscle cells to elevated cytokines led to reduced insulin and muscle stress/inflammatory signaling. We conclude hypoxia or obesity induces release of inflammatory TNFα and MCP-1 from mice primary adipocytes but the two environmental conditions do not synergize to worsen macrophage signal transduction or insulin responsiveness.

Keywords: Conditioned medium; Hypoxia; Inflammation; Insulin signaling; Obesity

DOI: https://doi.org/10.1016/j.bbrc.2019.10.162

Diabetes Metab J. 2019 Oct;43(5): 549-559

Regulation of Systemic Glucose Homeostasis by T Helper Type 2 Cytokines.

Yea Eun Kang, Hyun Jin Kim, Minho Shong.

Obesity results in an inflammatory microenvironment in adipose tissue, leading to the deterioration of tissue protective mechanisms. Although recent studies suggested the importance of type 2 immunity in an anti-inflammatory microenvironment in adipose tissue, the regulatory effects of T helper 2 (Th2) cytokines on systemic metabolic regulation are not fully understood. Recently, we identified the roles of the Th2 cytokine (interleukin 4 [IL-4] and IL-13)-induced adipokine, growth differentiation factor 15 (GDF15), in adipose tissue in regulating systemic glucose metabolism via signal transducer and activator of transcription 6 (STAT6) activation. Moreover, we showed that mitochondrial oxidative phosphorylation is required to maintain these macrophage-regulating autocrine and paracrine signaling pathways via Th2 cytokine-induced secretion of GDF15. In this review, we discuss how the type 2 immune response and Th2 cytokines regulate metabolism in adipose tissue. Specifically, we review the systemic regulatory roles of Th2 cytokines in metabolic disease and the role of mitochondria in maintenance of type 2 responses in adipose tissue homeostasis.

Keywords: Adipokines; Adipose tissue; Cytokines; Immunity; Metabolic diseases; Obesity

DOI: https://doi.org/10.4093/dmj.2019.0157