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Background Glabridin (Glab) is a bioactive component of licorice that can ameliorate diabetes, but its role in diabetic nephropathy (DN) has seldom been reported. Herein, we explored the effect and underlying mechanism of Glab on DN. Methods The bioactive component-target network of licorice against DN was by a network pharmacology approach. The protective effect of Glab on the kidney was investigated by a high-fat diet with streptozotocin induced-diabetic rat model. High glucose-induced NRK-52E cells were used for in vitro studies. The effects of Glab on ferroptosis and VEGF/Akt/ERK pathways in DN were investigated in vivo and in vitro using qRT-PCR, WB, and IHC experiments. Results Bioinformatics analysis constructed a network comprising of 10 bioactive components of licorice and 40 targets for DN. 13 matching targets of Glab were mainly involved in the VEGF signaling pathway. Glab treatment ameliorated general states and reduced FBG, HOMA-β, and HOMA-insulin index of diabetic rats. The renal pathological changes and the impaired renal function (the increased levels of Scr, BUN, UREA, KIM-1, NGAL, and TIMP-1) were also improved by Glab. Moreover, Glab repressed ferroptosis by increasing SOD and GSH activity, and GPX4, SLC7A11, and SLC3A2 expression, and decreasing MDA and iron concentrations, and TFR1 expression, in vivo and in vitro. Mechanically, Glab significantly suppressed VEGF, p-AKT, p-ERK1/2 expression in both diabetic rats and HG-induced NRK-52E cells. Conclusions This study revealed protective effects of Glab on the kidney of diabetic rats, which might exert by suppressing ferroptosis and the VEGF/Akt/ERK pathway.

Respiratory diseases like chronic obstructive pulmonary disease (COPD) are associated with the presence of particulate matter 2.5 (PM2.5) in the air. In the present study, the effect of synthesized ursolic acid derivatives on mice model of PM2.5-induced COPD was investigated in vivo. The mice model of COPD was established by the administration of 25 μL of PM2.5 suspension through intranasal route daily for 1 week. The levels of oxidative stress markers and inflammatory cytokines like tumor necrosis factors-α and interleukin-6 in the mice bronchoalveolar fluids increased markedly on administration with PM2.5. However, treatment with ursolic acid derivative caused a significant suppression in PM2.5-induced increase in oxidative stress markers and inflammatory cytokines in dose-dependent manner. Hematoxylin and eosin staining showed excessive inflammatory cell infiltration in pulmonary tissues in mice with COPD. The inflammatory cell infiltration was inhibited on treatment of the mice with ursolic acid derivative. The ursolic acid derivative treatment increased level of superoxide dismutase in mice with COPD. The lung injury induced by PM2.5 in mice was also prevented on treatment with ursolic acid derivative. Thus, ursolic acid derivative inhibits pulmonary tissues damage in mice through suppression of inflammatory cytokine and oxidative enzymes. Therefore, ursolic acid derivative can be of therapeutic importance for treatment of PM2.5-induced COPD.

Acute pancreatitis (AP) is a leading cause of death and is commonly accompanied by systemic manifestations that are generally associated with a poor prognosis. Many cytokines contribute to pancreatic tissue damage and cause systemic injury. Interleukin-17 (IL-17) is a cytokine that may play a vital role in AP. Specifically, IL-17 has important effects on the immune response and causes interactions between different inflammatory mediators in the AP-related microenvironment. In this literature review, we will discuss the existing academic understanding of IL-17 and the impacts of IL-17 in different cells (especially in acinar cells and immune system cells) in AP pathogenesis. The clinical significance and potential mechanisms of IL-17 on AP deterioration are emphasized. The evidence suggests that inhibiting the IL-17 cytokine family could alleviate the pathogenic process of AP, and we highlight therapeutic strategies that directly or indirectly target IL-17 cytokines in acute pancreatitis.

Transcatheter arterial embolization (TAE) is a well-established technique for unresectable hepatic malignancies. However, TAE can temporally halt the growth of hepatic tumors by blocking their arterial supply, but often tumors rapidly develop collateral blood vessels via angiogenesis. We have previously demonstrated that intraportal delivery of adeno-associated viral particles expressing angiostatin leads to long-term expression of angiostatin capable of inhibiting angiogenesis and suppressing the outgrowth of tumors in the liver. Thus, we hypothesize that adeno-associated virus (AAV)-mediated antiangiogenic therapy could enhance the efficacy of TAE to combat liver cancers. To achieve this objective, we engineered a recombinant AAV vector encoding rat angiostatin. Intraportal delivery of this vector led to long term and stable transgenic expression of angiostatin locally in rat hepatocytes and suppressed the growth of CBRH7919 hepatocellular carcinomas established in rat livers by inhibiting formation of neovessels. Although TAE therapy led to necrosis of liver tumors and suppressed their growth, the neovessels of tumors were rapidly reformed 3 weeks after TAE. However, intraportal injection of AAV-angiostatin inhibited the angiogenesis stimulated by TAE, synergized with TAE in suppressing growth of tumors established in livers and prolonged the survival of rats. In conclusion, these encouraging results warrant future investigation of the use of antiangiogenic therapy for enhancing the therapeutic efficacy of TAE to treat unresectable liver cancers.

Transcatheter arterial embolization (TAE) is a standard treatment for unresectable hepatic malignancies. It blocks the arterial blood supply to the tumor, but blockade of the blood supply can be short-lived as collateral blood vessels develop, leading to the failure of TAE. Here we report that intraportal delivery of adeno-associated viral (AAV) vectors expressing antisense hypoxia-inducible factor-1alpha (HIF-1alpha) (AAV-ASHIF) augments TAE to combat hepatocellular carcinoma (HCC). Intraportal delivery of AAV-ASHIF led to long-term localized expression of transgenic ASHIF in rat liver, and suppressed the growth of CBRH7919 HCC tumors established in rat liver by inhibiting the formation of neovessels and tumor cell proliferation. TAE therapy caused the necrosis and shrinkage of liver tumors; however, neovessels quickly formed and the residual tumors underwent rapid expansion. TAE enhanced tumor and liver hypoxia, which in turn upregulated expression of HIF-1alpha, vascular endothelial growth factor, glucose transporter-1, lactate dehydrogenase A, and proliferating cell nuclear antigen. Intraportal injection of AAV-ASHIF augmented the therapeutic effects of TAE and diminished its undesirable effects, resulting in extensive tumor cell death and suppression of the growth of liver tumors. In conclusion, this study has revealed that HIF-1 impedes the response of liver tumors to TAE. Antisense HIF-1alpha therapy is warranted as an approach for enhancing the efficacy of TAE to treat unresectable liver cancers.

Background Apoptotic cells have immunosuppressive activity, whereas necrotic cells activate immune response, indicating they might have different effects on immune rejection against splenic allografts. The aim of this study was to determine whether administration of apoptotic or necrotic splenocytes of donor origin could impact the acute rejection of splenic allografts. Materials and methods Apoptotic or necrotic splenocytes derived from donor rats were induced by irradiation or freeze thaw, respectively. Heterotopic vascularized spleen transplantation was performed from Wistar-Furth (donor) to Sprague-Dawley (recipient) rats, and splenocytes were intravenously injected into the recipients. At different time points, the recipients were sacrificed and the splenic allografts underwent histological examination. The interferon-γ (IFN-γ) and transforming growth factor-β1 (TGF-β1) in sera, spleens of recipients, and donor splenocytes before administration were measured. Mixed leukocyte reaction (MLR) was detected with recipient splenocytes as effectors and donor splenocytes as stimulators. Results Exposure to γ-irradiation at dose of 10,000 rad caused over 80% splenocytes to become apoptotic. The levels of TGF-β1 released by apoptotic splenocytes in vitro were significantly higher than that by untreated splenocytes, whereas there was almost no TGF-β1 detected in necrotic splenocytes culture medium. Administration of apoptotic splenocytes significantly attenuated acute rejection of splenic allografts, evidenced by less severe splenic histological alteration and reduction of histological scores compared with control; whereas necrotic splenocytes exacerbated the acute rejection. Apoptotic splenocytes inhibited production of IFN-γ but increased the levels of TGF-β1, whereas necrotic splenocytes showed opposite activity in production of those cytokines. Administration of apoptotic splenocytes inhibited MLR, and necrotic splenocytes promoted MLR. Conclusions The apoptotic and necrotic splenocytes exhibited opposite effects on acute rejection against splenic allografts, and IFN-γ and TGF-β1 have been involved in the effects.