Translational research : the journal of laboratory and clinical medicine
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Glomerular endothelial cell (GEC) dysfunction occurs in diabetic kidney disease (DKD) and generally precedes albuminuria. We recently reported that hedgehog interacting protein (Hhip), highly expressed in GECs, contributes to DKD development in diabetic mice. Here, we hypothesized that urinary Hhip (uHhip) could identify early DKD; we tested uHhip in mice and humans with diabetes (DM). ⋯ TGFβ1 shares the similar staining pattern as Hhip in human DM kidneys. Thus, uHhip appears to be a novel indicator of diabetic GEC injury and is elevated in early DKD before the development of microalbuminuria in mice and humans. Clinical value for detecting early DKD warrants further investigation.
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Intracerebral hemorrhage (ICH), a subtype of stroke with high morbidity and mortality, occurs mainly in the basal ganglia and causes white matter injury (WMI), resulting in severe motor dysfunction and poor prognosis in patients. The preservation of the white matter around the hematoma is crucial for motor function recovery, but there is currently no effective treatment for WMI following ICH. Lithium has been widely used for the treatment of bipolar disorder for decades. ⋯ Furthermore, LiCl treatment decreased the death of mature oligodendrocytes (OLGs) in ICH mice, which may have been attributed to the enhanced expression of brain-derived neurotrophic factor (BDNF) regulated by the LiCl-induced inhibition of glycogen synthase kinase-3β (GSK-3β). The decreased death of OLGs was closely associated with decreased destruction of the myelin sheath and alleviated degradation of the axons. In summary, this study suggests that the protective effect of lithium on WMI after ICH might be related to an increased level of BDNF and that LiCl treatment may be a potential therapeutic method to palliate WMI after ICH.
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Metabolic remodeling contributes to the development and progression of some cancers and exposes them to vulnerabilities, including specific nutrient dependencies that can be targeted therapeutically. Arginine is a semiessential amino acid, and several cancers are unable to endogenously synthesize sufficient levels of arginine for survival and proliferation, most commonly due to reduced expression of argininosuccinate synthase (ASS1). Such cancers are dependent on arginine and they can be targeted via enzyme-mediated depletion of systemic arginine. ⋯ In an immune-competent syngeneic mouse model, pegzilarginase slowed tumor growth and promoted the recruitment of CD8+ tumor infiltrating lymphocytes. This is consistent with the known autophagy-inducing effects of arginine depletion, and the link between autophagy and major histocompatibility complex antigen presentation to T cells. Our work supports the ongoing clinical investigations of pegzilarginase in solid tumors and clinical combination of pegzilarginase with immune checkpoint inhibitors.
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Randomized Controlled Trial
Salt-sensitive blood pressure rise in type 1 diabetes patients is accompanied by disturbed skin macrophage influx and lymphatic dilation-a proof-of-concept study.
Type 1 diabetes patients are more prone to have hypertension than healthy individuals, possibly mediated by increased blood pressure (BP) sensitivity to high salt intake. The classical concept proposes that the kidney is central in salt-mediated BP rises, by insufficient renal sodium excretion leading to extracellular fluid volume expansion. Recent animal-derived findings, however, propose a causal role for disturbance of macrophage-mediated lymphangiogenesis. ⋯ In conclusion, we show that salt sensitivity in type 1 diabetes patients cannot be explained by the classical concept of extracellular fluid volume expansion. Rather, we open up a potential role for macrophages and the lymphatic system. Future studies on hypertension and diabetes need to scrutinize these phenomena.
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Survival of burn patients is contingent on effective wound healing, a complex process that requires coordinated responses of myeloid cells and inflammatory pathways. NLRP3, which serves as a platform for secretion of proinflammatory cytokines, is implicated as a central regulator of wound healing. However, its role during the acute dermal and epidermal regeneration in the context of burns is unknown. ⋯ Trichrome staining showed decreased collagen deposition compared to WT. We show that NLRP3 is protective in burn wound healing, primarily through production of inflammatory mediators, macrophage recruitment, and polarization to a proinflammatory phenotype. Our findings highlight a central role of NLRP3 in wound healing through regulation of inflammation and macrophage polarization after burns.