Polymer hydrogels are widely used as cell scaffolds for biomedical applications. While the biochemical and biophysical properties of hydrogels have been extensively investigated, little attention has been paid to their potential photonic functionalities. Here, we report cell-integrated polyethylene glycol-based hydrogels for in-vivo optical sensing and therapy applications. Hydrogel patches containing cells were implanted in awake, freely moving mice for several days and shown to offer long-term transparency, biocompatibility, cell-viability, and light-guiding properties (loss: <1 dB/cm). Using optogenetic, glucagon-like peptide-1 (GLP-1) secreting cells, we conducted light-controlled therapy using the hydrogel in a mouse model with type-2 diabetes and attained improved glucose homeostasis. Furthermore, real-time optical readout of encapsulated heat-shock-protein-coupled fluorescent reporter cells made it possible to measure the nanotoxicity of cadmium-based bare and shelled quantum dots (CdTe; CdSe/ZnS) in vivo.

Glutathione peroxidase 3 (GPx3) accounts for the major antioxidant activity in the plasma. Here, we demonstrate that down-regulation of GPx3 in the plasma of obese subjects is associated with adipose GPx3 dysregulation, resulting from the increase of inflammatory signals and oxidative stress. Although GPx3 was abundantly expressed in kidney, lung, and adipose tissue, we observed that GPx3 expression was reduced selectively in the adipose tissue of several obese animal models as decreasing plasma GPx3 level. Adipose GPx3 expression was greatly suppressed by prooxidative conditions such as high levels of TNFalpha and hypoxia. In contrast, the antioxidant N-acetyl cysteine and the antidiabetic drug rosiglitazone increased adipose GPx3 expression in obese and diabetic db/db mice. Moreover, GPx3 overexpression in adipocytes improved high glucose-induced insulin resistance and attenuated inflammatory gene expression whereas GPx3 neutralization in adipocytes promoted expression of proinflammatory genes. Taken together, these data suggest that suppression of GPx3 expression in the adipose tissue of obese subjects might constitute a vicious cycle to expand local reactive oxygen species accumulation in adipose tissue potentially into systemic oxidative stress and obesity-related metabolic complications.

Orosomucoid (ORM), also called ␣-1 acid glycoprotein, is an abundant plasma protein that is an immunomodulator induced by stressful conditions such as infections. In this study, we reveal that Orm is induced selectively in the adipose tissue of obese mice to suppress excess inflammation that otherwise disturbs energy homeostasis. Adipose Orm levels were elevated by metabolic signals, including insulin, high glucose, and free fatty acid, as well as by the proinflammatory cytokine tumor necrosis factor-␣, which is found in increased levels in the adipose tissue of morbid obese subjects. In both adipocytes and macrophages, ORM suppressed proinflammatory gene expression and pathways such as NF-B and mitogen-activated protein kinase signalings and reactive oxygen species generation. Concomitantly, ORM relieved hyperglycemia-induced insulin resistance as well as tumor necrosis factor-␣-mediated lipolysis in adipocytes. Accordingly, ORM improved glucose and insulin tolerance in obese and diabetic db/db mice. Taken together, our results suggest that ORM integrates inflammatory and metabolic signals to modulate immune responses to protect adipose tissue from excessive inflammation and thereby from metabolic dysfunction.

Lysyl-tRNA synthetase (KRS), a protein synthesis enzyme in the cytosol, relocates to the plasma membrane after a laminin signal and stabilizes a 67-kDa laminin receptor (67LR) that is implicated in cancer metastasis; however, its potential as an antimetastatic therapeutic target has not been explored. We found that the small compound BC-K-YH16899, which binds to KRS, impinged on interaction of KRS with 67LR and suppressed metastasis in 3 different mouse models. The compound inhibited KRS–67LR interaction in two ways. First, it directly blocked the association between KRS and 67LR. Second, it suppressed the dynamic movement of the N-terminal extension of KRS and reduced membrane localization of KRS. However, it did not affect the catalytic activity of KRS. Our results suggest that specific modulation of a cancer-related KRS–67LR interaction may offer a way to control metastasis while avoiding the toxicities associated with inhibition of the normal functions of KRS.

AIMP2 (aminoacyl-tRNA synthetase interacting multifunctional protein 2; also known as JTV-1) was first identified as p38 in a macromolecular protein complex that consisted of nine different aminoacyl-tRNA synthetases and two other auxiliary factors. AIMP2 also plays pivotal roles in the regulation of cell proliferation and death. Although AIMP2 was previously shown to augment TNFα-induced cell death, its working mechanism in this signal pathway was not understood. Here, we investigate the functional significance and mode of action of AIMP2 in TNFα signaling. TNFα-induced cell death was compromised in AIMP2-deficient or -suppressed cells and exogenous supplementation of AIMP2 augmented apoptotic sensitivity to TNFα signaling. This activity was confirmed by the AIMP2-dependent increase of IκB and suppression of NFκB. We found binding of AIMP2 to TRAF2, a key player in the TNFα signaling pathway. AIMP2 augmented the association of an E3 ubiquitin ligase, c-IAP1, with TRAF2, causing ubiquitin-dependent degradation of TRAF2. These findings suggest that AIMP2 can mediate the pro-apoptotic activity of TNFα via the downregulation of TRAF2 expression.

This prospective randomized study compared the effects of two types of anaesthesia on peri-operative anaesthetic profiles from induction to recovery and on immunological and neurohormonal responses to anaesthesia and surgical stress. Forty patients were assigned to undergo either volatile induction and maintenance of anaesthesia (VIMA) with sevoflurane or total intravenous anaesthesia (TIVA) with propofol and remifentanil. Plasma adrenaline, noradrenaline, cortisol, glucose and interleukin-6 (IL-6) levels were measured at baseline, induction, incision and extubation. TIVA produced a significantly lower intubation score, shorter time to intubation and faster waking time than VIMA, but recovery profiles did not differ. Adrenaline, noradrenaline, cortisol and glucose levels were significantly lower with TIVA than VIMA, but there was no difference in IL-6 levels between the two groups.TIVA with propofol and remifentanil may be preferable to VIMA with sevoflurane alone because it leads to smoother, more rapid induction, more rapid awakening and lower stress responses to surgical stimuli.

Studies have shown that high levels of serum free fatty acids (FFAs) are associated with lipotoxicity and type 2 diabetes. Palmitic acid (PA) is the predominant circulating saturated FFA, yet its role in the pathogenesis of diabetic nephropathy (DN) is not clear. Recently, one study suggested that mitochondrial superoxide production is related to AMP-activated protein kinase (AMPK) activity in diabetic mice kidneys. To elucidate the link between PA and oxidative stress and AMPK activity in DN, we compared the cultured murine podocytes exposed to PA and oleic acid (OA). Incubation of cells with 250 μM PA or OA induced a translocation of CD36, a fatty acid transport protein, with intracellular lipid accumulation. PA, but not OA, induced mitochondrial superoxide and hydrogen peroxide (H O ) generation in podocytes, as shown by enhanced fluorescence of MitoSOX Red and dichlorofluorescein (DCF), respectively. Costimulation of PA-treated cells with the H O scavenger catalase abolished the PA-induced DCF fluorescence. Only PA induced mitochondrial damage as shown by electron microscopy. The AMPK activity was determined by immunoblotting, measuring the ratio of phosphorylated AMPK (p-AMPK) to total AMPK. Only PA significantly increased the p-AMPK levels compared with controls. Addition of catalase to PA-treated cells did not affect the PA-stimulated p-AMPK levels. Collectively, our results indicate that PA induces mitochondrial superoxide and H O generation in cultured podocytes, which may not be directly linked to AMPK activation. Given that, PA seems to play an important role in the pathogenesis of DN through lipotoxicity initiated by mitochondrial superoxide overproduction.

PurposePain in terminal cancer patients may be refractory to systemic analgesics or associated with adverse drug reactions to analgesics. Epidural analgesia has been effectively used in such patients for pain control. However, this method does not provide pain relief to all patients. The efficacy and complications of continuous epidural analgesia were evaluated for expanding efficacy in terminal cancer patients.Materials and MethodsThe charts of patients who received epidural analgesia for over 5 years for the control of terminal cancer pain were reviewed retrospectively.ResultsNinety-six patients received 127 epidural catheters. The mean duration for epidural catheterization was 31.5±55.6 (5-509) days. The dose of epidural morphine increased by 3.5% per day. The efficacy of epidural analgesia at 2 weeks follow up revealed improved pain control (n=56), as the morphine equivalent drug dose dropped from 213.4 mg/day to 94.1 mg/day (p<0.05) at 2 weeks follow up. Accordingly, after 2 weeks institution of epidural analgesia, there was a significant reduction in the proportion of patients with severe pain, from 78.1% to 19.6% (p<0.05).ConclusionEpidural analgesia was an effective pain control method in patients with terminal cancer pain, however, a systematized algorithm for the control of cancer-related pain in needed.