Mn(III) ortho-N-alkyl- and N-alkoxyalkyl porphyrins (MnPs) were initially developed as superoxide dismutase (SOD) mimics. These compounds were later shown to react with numerous reactive species (such as ONOO-, H2O2, H2S, CO3•-, ascorbate, and GSH). Moreover, the ability of MnPs to oxidatively modify activities of numerous proteins has emerged as their major mechanism of action both in normal and in cancer cells. Among those proteins are transcription factors (NF-κB and Nrf2), mitogen-activated protein kinases, MAPKs, antiapoptotic bcl-2, and endogenous antioxidative defenses. The lead Mn porphyrins, namely, MnTE-2-PyP5+ (BMX-010, AEOL10113), MnTnBuOE-2-PyP5+ (BMX-001), and MnTnHex-2-PyP5+, were tested in numerous injuries of normal tissue and cellular and animal cancer models. The wealth of the data led to the progression of MnTnBuOE-2-PyP5+ into four Phase II clinical trials on glioma, head and neck cancer, anal cancer, and multiple brain metastases, while MnTE-2-PyP5+ is in Phase II clinical trial on atopic dermatitis and itch.

Ginsenoside Rb1 (RB1), the most clinically effective constituent of ginseng, possesses a variety of biological activities. The objectives of this study were to investigate the protective effects of RB1 and its underlying mechanism on renal injury induced by intestinal ischemia-reperfusion (IIR) in mice. RB1 was administered prior to inducing IIR achieved by occluding the superior mesenteric artery for 45 min followed by 120 min of reperfusion. All-trans-retinoic acid (ATRA) was used as an inhibitor of NF-E2-related factor-2 (Nrf2) signaling. Adult male C57BL/6J mice were randomly divided into six groups: (1) sham group, (2) IIR group, (3) RB1 group, (4) sham + ATRA group, (5) IIR + ATRA group, and (6) RB1 + ATRA group. Intestinal histology and pathological injury score were observed. Intestinal mucosal injury was also evaluated by measuring serum diamine oxidase (DAO). Renal injury induced by IIR was characterized by increased levels of histological severity score, blood urea nitrogen (BUN), serum creatinine (Scr) and neutrophil gelatinase-associated lipocalin (NGAL), which was accompanied with elevated renal TUNEL-positive cells and the Bcl-2/Bax expression ratio. RB1 significantly reduced renal injury and apoptosis as compared with IIR group, which was reversed by ATRA treatment. Immunohistochemistry and Western blot analysis demonstrated that RB1 significantly upregulated the protein expression of heme oxygenase-1 (HO-1) and Nrf2, which were attenuated by ATRA treatment. Taken together, these results suggest that the protective effects of RB1 pretreatment against renal injury induced by IIR are associated with activation of the Nrf2/ anti-oxidant response element (ARE) pathway.

Previous studies have suggested that the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway is involved in hyperglycemia-induced lung injury. The present study aimed to investigate the roles of suppressor of cytokine signaling3 (SOCS3) in the regulation of JAK2/STAT3 activation following high glucose (HG) treatment in A549 human pulmonary epithelial cells. Cell viability was evaluated using Cell Counting Kit-8 and lactate dehydrogenase assays. HG-induced inflammatory injury in A549 cells was assessed through the evaluation of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels using ELISA. The protein expression levels of SOCS3, JAK2, STAT3, phosphorylated (p)-JAK2 and p-STAT3 were determined using western blot analysis. Cellular viability was significantly decreased, whereas IL-6 and TNF-α levels were significantly increased, following HG stimulation of A549 cells. In addition, the protein levels of SOCS3, p-JAK2 and p-STAT3 were significantly increased in HG-treated cells. Treatment with the JAK2/STAT3 inhibitor tyrphostin AG490, or SOCS3 overexpression, appeared to prevent the HG-induced alterations in protein expression. Furthermore, cellular viability was enhanced, whereas the levels of proinflammatory cytokines were suppressed. These finding suggested the involvement of the SOCS3/JAK2/STAT3 signaling pathway in HG-induced responses in lung cells. Therefore, it may be hypothesized that the inhibition of the JAK2/STAT3 pathway through SOCS3 overexpression may prevent hyperglycemia-induced lung injury, and may have therapeutic potential for the treatment of patients with diabetic lung injury.

Diabetic nephropathy (DN) is one of the most common chronic complications of diabetes, which is associated with an increased oxidative stress induced by hyperglycemia and alterations in DJ-1/NF-E2-related factor-2 (Nrf2) pathway. In the present study, we investigated the role and the proper time nodes of DJ-1/Nrf2 pathway in the pathogenesis of DN. Diabetes mellitus (DM) model of rats was induced by intraperitoneal injection of streptozotocin (STZ) on male Sprague-Dawley (SD) rats. Then, the diabetic rats were divided into 4, 8 and 12 weeks groups. As early at 4 weeks of diabetes, renal histologic evaluation score, cystatin C (Cys C), b2-microglobulin (b2-MG) and malondialdehyde (MDA) levels were increased, and total antioxidative capacity (T-AOC) level was decreased as compared with that in the control group. The protein expressions of DJ-1, NF-E2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) were upregulated compared with the control group from 4 weeks and further increased with the progression of DM. The protein expressions of DJ-1, Nrf2 and HO-1 in renal tissues have good line correlations with renal histologic evaluation score, respectively. Taken together, these results suggested that the activation of DJ-1/Nrf2 pathway was involved in the pathogenesis of diabetic nephropathy in rats.ARTICLE HISTORY

The aim of the present study was to examine the protective effect of caveolin-1 (Cav-1) in the penehyclidine hydrochloride (PHC)-based inhibition of lipopolysaccharide (LPS)-induced acute lung injury (ALI) in vivo and in vitro , in addition to the potential underlying mechanisms. In vivo , an ALI rat model was established via intratracheal administration of LPS (5 mg/kg), and PHC (2 mg/kg) was administered 30 min following LPS treatment. In vitro , the Cav-1 gene was knocked down by small interfering (si)RNA in J774A.1 cells. Cells were incubated with LPS (1 µ g/ml) for 2 h, and subsequently incubated with PHC (2 µ g/ml) for an additional 2 h. Lung injury was assessed by lung histology and the ratio of polymorphonuclear leukocytes (PMNs) to total cells was assessed in bronchoalveolar lavage fluid (BALF), myeloperoxidase (MPO) activity, BALF protein content and lung wet/dry (W/D) ratio. The levels of pro-inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β, in the sera of rats and cell culture supernatant were determined by ELISA. The protein expression levels of Cav-1, toll-like receptor 4 (TLR4), phosphorylated (p)-p38 mitogen activated protein kinases (p38 MAPKs) and nuclear factor kappa-light-chain-enhancer of activated B cells transcription factor p65 subunit (NF-κB p65) in lung tissues and J774A.1 cells were analyzed by western blot analysis. The results indicated that PHC effectively alleviated lung injury by decreasing neutrophil infiltration and protein concentration in BALF, and the lung W/D ratio and MPO activity and pro-inflammatory cytokine production induced by LPS. Furthermore, PHC significantly decreased the degrees of histopathological changes and pulmonary dysfunction. In vitro , treatment with PHC inhibited pro-inflammatory cytokine levels and MPO activity in LPS-stimulated J774A.1 cells. However, the results in the J774A.1 cells with Cav-1 gene knockdown were contrary. In addition, PHC decreased TLR4, p-p38 MAPKs and nuclear NF-κB p65 expression levels and upregulated the expression level of Cav-1, in vivo and in vitro . These data demonstrated that PHC exhibited a protective effect against LPS-induced ALI in rats and LPS-stimulated J774A.1 cells, which may be due to the inhibition of p38 MAPKs phosphorylation and TLR4/NF-κB signaling pathway by Cav-1 upregulation.