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Acute pancreatitis (AP) is a severe and frequently lethal disorder, but the precise mechanisms are not well understood and there is lack of effective drugs. Therefore, our study examined the in vivo intervention effects of genistein and elucidated its mechanism in acute experimental pancreatitis models. We used cerulein or taurocholate to induce acute pancreatitis (AP) in Sprague-Dawley rats with prior genistein treatment. Histological examination of the pancreas was performed and the expression of unfolded protein response (UPR) components and apoptotic mediators like caspase 12 and c-Jun N-terminal protein kinase (JNK) were measured. The amount of apoptosis in pancreatic acinar cells was also determined. Our studies found that the severity of cerulein- or taurocholate-induced AP was rescued by prior genistein treatment. Genistein stimulated the activation of multiple endoplasmic reticulum (ER) stress-related regulators like GRP78, PERK, eIF2α, and upregulated the expression of the apoptotic genes, caspase 12 and CHOP. Moreover, TUNEL assays showed that genistein treatment promoted acinar cell apoptosis. Taken together, we speculated that ER stress-associated apoptotic pathways in AP are induced by genistein, which showed cytoprotective capacity in the exocrine pancreas. These data suggest novel therapeutic strategies that employ genistein in the prevention of AP., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Hypoxia down-regulates the expression of the growth arrest-specific homeobox (Gax) in pulmonary arterial smooth muscle cells (PASMCs), resulting in increased cell proliferation and decreased apoptosis, but the mechanism for this response remains unclear. The present study investigated the role of Gax in the development of hypoxia-induced pulmonary hypertension (PH). We found that hypoxia suppressed the expression of endogenous Gax in rats, but not in those pretreated intratracheally with a Gax construct (Ad-Gax). Hypoxic rats pretreated with Ad-Gax were resistant to hypoxia-induced PH, right ventricular hypertrophy, increased wall thickness, and the muscularization of pulmonary arterioles. Hypoxia-induced PASMC proliferation and suppression of Gax expression were blocked by the Mitogen-activated protein kinase (MEK) inhibitor U0126. The PASMCs with Ad-Gax transfection exhibited hyperexpression of the Bcl-2-associated X protein (Bax) and hypoexpression of B-cell lymphoma 2 (Bcl-2), leading to cell apoptosis. Thus, our data indicate that the enhanced expression of Gax inhibits hypoxia-induced PASMC proliferation, probably via the extracellular-signal-regulated kinase (ERK) 1/2 pathway, and induces the apoptosis of hypoxic PASMCs via the Bcl-2/Bax pathway. Gax may be a potential new therapeutic target for pulmonary hypertension.

Diabetes mellitus increases the risk of dementia, and evidence suggests hyperglycemia is a key contributor to neurodegeneration. However, our understanding of diabetes-associated cognitive decline, an important complication of diabetes mellitus, is lacking and the underlying mechanism is unclear. Blood brain barrier (BBB) breakdown is a possible cause of dementia in diabetes mellitus and Alzheimer's disease. Accumulating evidence shows BBB dysfunction caused by hyperglycemia contributes to cognitive decline. A specific type of inflammatory programmed cell death, called pyroptosis, has potential as a therapeutic target for BBB-associated diseases. Potential inducers of pyroptosis include inflammasomes such as NLRP3, whose activation relies on damage-associated molecular patterns. High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein found in most cell types, and acts as a damage-associated molecular pattern when released from the nucleus. We propose that HMGB1 influences vascular inflammation by activating the NLRP3 inflammasome and thereby initiating pyroptosis in vascular cells. Moreover, HMGB1 plays a pivotal role in the pathogenesis of diabetes mellitus and diabetic complications. Here, we review the role of HMGB1 in BBB dysfunction induced by hyperglycemia and propose that HMGB1 is a promising therapeutic target for countering diabetes-associated cognitive decline. [Display omitted] • Diabetes mellitus makes a contribution to blood brain barrier breakdown. • Blood brain barrier disturbances in diabetes could be the possible link between dementia and diabetes. • Pyroptosis contributes to hyperglycemia induced BBB breakdown. • HMGB1 plays an important role in pyroptosis of injured blood brain barrier via activating NLRP3 inflammasome. [ABSTRACT FROM AUTHOR]