Showing papers by "Gang Wang published in 2018"

Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response.

Abstract: A diet rich in salt is linked to an increased risk of cerebrovascular diseases and dementia, but it remains unclear how dietary salt harms the brain. We report that, in mice, excess dietary salt suppresses resting cerebral blood flow and endothelial function, leading to cognitive impairment. The effect depends on expansion of TH17 cells in the small intestine, resulting in a marked increase in plasma interleukin-17 (IL-17). Circulating IL-17, in turn, promotes endothelial dysfunction and cognitive impairment by the Rho kinase–dependent inhibitory phosphorylation of endothelial nitric oxide synthase and reduced nitric oxide production in cerebral endothelial cells. The findings reveal a new gut–brain axis linking dietary habits to cognitive impairment through a gut-initiated adaptive immune response compromising brain function via circulating IL-17. Thus, the TH17 cell–IL-17 pathway is a putative target to counter the deleterious brain effects induced by dietary salt and other diseases associated with TH17 polarization.

Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle.

Abstract: Patients with metastatic cancer experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with poor prognosis and accelerated death in patients with cancer, yet its underlying mechanisms remain poorly understood. Here, we identify the metal-ion transporter ZRT- and IRT-like protein 14 (ZIP14) as a critical mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles of mice and in patients with metastatic cancer and can be induced by TNF-α and TGF-β cytokines. Strikingly, germline ablation or muscle-specific depletion of Zip14 markedly reduces muscle atrophy in metastatic cancer models. We find that ZIP14-mediated zinc uptake in muscle progenitor cells represses the expression of MyoD and Mef2c and blocks muscle-cell differentiation. Importantly, ZIP14-mediated zinc accumulation in differentiated muscle cells induces myosin heavy chain loss. These results highlight a previously unrecognized role for altered zinc homeostasis in metastatic cancer-induced muscle wasting and implicate ZIP14 as a therapeutic target for its treatment.

Apoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function

Abstract: The ApoE4 allele is associated with increased risk of small vessel disease, which is a cause of vascular cognitive impairment. Here, we report that mice with targeted replacement (TR) of the ApoE gene with human ApoE4 have reduced neocortical cerebral blood flow compared to ApoE3-TR mice, an effect due to reduced vascular density rather than slowing of microvascular red blood cell flow. Furthermore, homeostatic mechanisms matching local delivery of blood flow to brain activity are impaired in ApoE4-TR mice. In a model of cerebral hypoperfusion, these cerebrovascular alterations exacerbate damage to the white matter of the corpus callosum and worsen cognitive dysfunction. Using 3-photon microscopy we found that the increased white matter damage is linked to an enhanced reduction of microvascular flow resulting in local hypoxia. Such alterations may be responsible for the increased susceptibility to hypoxic-ischemic lesions in the subcortical white matter of individuals carrying the ApoE4 allele.

The Plk1 kinase negatively regulates the Hedgehog signaling pathway by phosphorylating Gli1

Abstract: Hedgehog (Hh) signaling is a highly conserved cell signaling pathway important for cell life, development and tumorigenesis. Increasing evidence suggests that the Hh signaling pathway functions in certain phases of the cell cycle. However, the coordination between Hh signaling and cell cycle control remains poorly understood. Here, we show that polo-like kinase-1 (Plk1), a critical protein kinase regulating many processes during the cell cycle, also regulates Hh signaling by phosphorylating and inhibiting Gli1, a downstream transcription factor of the Hh signaling pathway. Gli1 expression increases along with Hh signaling activation, leading to upregulation of Hh target genes, including cyclin E, during the G1 and S phases. Gli1 is phosphorylated at S481 by Plk1, and this phosphorylation facilitates the nuclear export and binding of Gli1 with its negative regulator Sufu, leading to a reduction in Hh signaling activity. Inhibition of Plk1 kinase activity led to Gli1 maintaining is role in promoting downstream gene expression. Collectively, our data reveal a novel mechanism regarding the crosstalk between Hh signaling and cell cycle control.