Feihua Wu

Astilbin selectively induces dysfunction of liver-infiltrating cells — novel protection from liver damage

The present study aimed to examine the effect of astilbin, a flavanoid, on liver injury. When administered during the effector but not induction phase, astilbin significantly decreased the liver injury induced by delayed-type hypersensitivity to picryl chloride in mice. The pretreatment of nonparenchymal cells but not hepatocytes with astilbin in vitro caused a concentration- and time-dependent inhibition against the damage. Nonparenchymal cells isolated from astilbin-administered mice also showed a significant incompetence of hepatotoxicity, correlated with the inhibition of serum transaminase elevation. However, astilbin did not protect from CCl4-induced liver damage. Furthermore, the flavanoid markedly promoted the apoptosis of nonparenchymal cells from liver-injured mice, whereas did not influence those from naive mice. These results suggest that astilbin provides improvement against liver injury through a selective dysfunction of liver-infiltrating cells rather than by protecting the hepatocyte membrane. Such characteristics will be of significance to pave a new way for treating immunologically related liver diseases and for developing new drugs.

Ruscogenin glycoside (Lm‐3) isolated from Liriope muscari improves liver injury by dysfunctioning liver‐infiltrating lymphocytes

The effects of ruscogenin 1‐O‐[β‐d‐glucopyranosyl(1 → 2)] [β‐d‐xylopyranosyl(1 → 3)]‐β‐d‐fucopyranoside (Lm‐3) and its aglycone, ruscogenin, on liver injury induced in mice by delayed‐type hypersensitivity to picryl chloride have been investigated. Lm‐3 and ruscogenin significantly decreased liver injury when given during the effector phase of the delayed‐type hypersensitivity reaction. The pretreatment of nonparenchymal cells, but not hepatocytes, with Lm‐3 or ruscogenin in‐vitro caused a concentration‐ and time‐dependent inhibition against the damage. Lm‐3 showed a stronger inhibition against the damage than ruscogenin (IC50: Lm‐3 6.3 times 10−10 m, ruscogenin 3.9 times 10−7 m). However, neither Lm‐3 nor ruscogenin blocked the hepatotoxic potential of CCl4, when used to pretreat hepatocytes. Moreover, Lm‐3 and ruscogenin inhibited concanavalin A‐induced lymphocyte proliferation only at high concentrations. These results suggested that Lm‐3 and ruscogenin improved the immunological liver injury by selectively causing dysfunction of the liver‐infiltrating cells rather than by protecting hepatocyte membranes. Such characteristics would be significant for treating immunologically related liver diseases as well as for developing new drugs.

Apigenin and naringenin regulate glucose and lipid metabolism, and ameliorate vascular dysfunction in type 2 diabetic rats.

Vascular endothelial dysfunction is regarded as the initial step of vascular complications in diabetes mellitus. This study investigated the amelioration of apigenin and naringenin in type 2 diabetic (T2D) rats induced by high-fat diet and streptozotocin and explored the underlying mechanism. Apigenin or naringenin was intragastrically administered at 50 or 100mg/kg once a day for 6 weeks. Biochemical parameters including blood glucose, glycated serum protein, serum lipid, insulin, superoxide dismutase (SOD), malonaldehyde and intercellular adhesion molecule-1 (ICAM-1) were measured. Vascular reactivity in isolated thoracic aortic rings was examined. Pathological features of the thoracic aorta were further observed through optical microscopy and transmission electron microscopy. Lastly, we evaluated their effects on insulin resistance of palmitic acid (PA)-induced endothelial cells. Compared with diabetic control group, apigenin and naringenin significantly decreased the levels of blood glucose, serum lipid, malonaldehyde, ICAM-1 and insulin resistance index, increased SOD activity and improved impaired glucose tolerance. Apigenin and naringenin restored phenylephrine-mediated contractions and acetylcholine or insulin-induced relaxations in aortic tissues. Furthermore, pathological damage in the thoracic aorta of apigenin and naringenin groups was more remissive than diabetic control group. In vitro, apigenin and naringenin inhibited NF-κB activation and ICAM-1 mRNA expression in PA-treated endothelial cells and improved nitric oxide production in the presence of insulin. In conclusion, both apigenin and naringenin can ameliorate glucose and lipid metabolism, as well as endothelial dysfunction in T2D rats at least in part by down-regulating oxidative stress and inflammation. In general, apigenin showed greater potency than naringenin equivalent.

Effects of (±)-praeruptorin A on airway inflammation, airway hyperresponsiveness and NF-κB signaling pathway in a mouse model of allergic airway disease

The root of Peucedanum praeruptorum Dunn is a traditional Chinese medicine commonly used to treat asthma in China. (±)-praeruptorin A (PA) is the most abundant constituent of P. praeruptorum Dunn, the effects of which on asthma were investigated using a murine model of allergic airway disease. BALB/c mice were sensitized and challenged by ovalbumin to induce airway inflammation. PA was administered intragastrically before every OVA challenge. Airway responsiveness was measured by a lung function analysis system. The number of total leukocytes in bronchoalveolar lavage fluid was counted using a hemocytometer, and differential cell counts were determined using Diff-Quick-stained smears. Histopathology of lung tissue was analyzed by hematoxylin-eosin and Congo red staining. Levels of inflammatory mediators in bronchoalveolar lavage fluid and immunoglobulins in serum were measured by enzyme-linked immunosorbent assay. The expression of pulmonary eotaxin was detected by immunohistochemistry and reverse transcription polymerase chain reaction. The activation of NF-κB was evaluated by electrophoretic mobility shift assay and western blot analysis. Compared with model group, PA significantly reduced airway hyperresponsiveness and airway eosinophilic inflammation, improved pathologic lesion of the lungs, reduced levels of interleukin (IL)-4, IL-5, IL-13 and LTC₄ in bronchoalveolar lavage fluid and immunoglobulin (Ig) E in serum, and inhibited eotaxin protein and mRNA expression, IκBα degradation, NF-κB nuclear translocation, NF-κB DNA-binding activity and RelA/p65 phosphorylation in lung, which suggested that PA can significantly suppress OVA-induced airway inflammation and airway hyperresponsiveness in mice, showing great therapeutic potential for the treatment of allergic asthma.

LFA-1/ICAM-1 interaction is essentially involved in the pathogenesis of delayed-type hypersensitivity-induced liver injury to picryl chloride

The kinetics of lymphocyte function associated antigen 1 (LFA-1) expression on spleen cells (SPC) and liver non-parenchymal cells (NPC), and intercellular adhesion molecule 1 (ICAM-1) expression on hepatocytes (HC) was examined in acute liver injury mice induced by a DTH reaction to picryl chloride (PCl). The peak expression of LFA-1 on SPC was seen at 6 hr after eliciting liver injury, and then that of LFA-1 on NPC and ICAM-1 on HC appeared at 12 hr. Thereafter, the serum ALT elevation reached to a peak at 18 hr. A splenectomy before the PCl elicitation significantly reduced the ALT elevation. Both SPC and NPC from liver injury mice induced a remarkable release of ALT from HC in vitro, in parallel with their LFA-1 expression. The pre-treatment of NPC or SPC with anti-LFA-1 mAb, irrespective of the presence of complement, completely blocked the ALT release. Also, when HC was prebound with anti-ICAM-1 mAb, neither NPC nor SPC showed a cytotoxicity against the HC. Furthermore, the treatment of NPC with either anti-Thy1.2 or anti-CD4 mAb in the presence but not absence of complement, showed a complete abolishment of ALT release. Anti-CD8 mAb plus complement also tended to inhibit ALT release. The twofold increase in CD4+ LFA-1+ and mild increase in CD8+ LFA-1+ populations were also confirmed in NPC at 12 hr. These results suggest that PCl elicitation in liver may trigger an increased expression of LFA-1 on SPC and NPC and ICAM-1 on HC. LFA-1/ICAM-1 interaction between liver-infiltrating NPC, mainly including CD4+ and CD8+ T cells, and HC may be an essential step for the hepatocyte damage in PCl-DTH liver injury.

ONE-SHOT DELAYED-TYPE HYPERSENSITIVITY REACTION IN THE MOUSE LIVER CAUSES A SUSTAINED LIVER INJURY TO PICRYL CHLORIDE

The developmental characteristics of liver injury induced by a delayed-type hypersensitivity (DTH) mechanism against picryl chloride were examined for 9 consecutive weeks in 3 mouse strains, BALB/c, Kunming and ICR mice. The changes of most biochemical parameters were similar in these three strains, namely, the activities of serum transaminases, lactic dehydrogenase, and prolidase were elevated significantly on day 1, during the first several weeks, and almost throughout the duration, respectively, of liver injury. The content of liver hydroxyproline was also increased after 1-9 weeks of liver injury. In addition, a significant decrease of liver weight, serum alkaline phosphatase and albumin level was observed in BALB/c and Kunming mice. Similar changes in liver histology were also found in the three strains. The hepatocellular necrosis and inflammatory infiltration into the portal area were the predominant features on day 1 and were still distinct during the subsequent several weeks. The mild or moderate hepatocellular degeneration, regeneration and connective tissue hyperplasia were observed after 1 or 3 weeks. A bridging necrosis between portal and portal was observed in several BALB/c and ICR mice, reflecting the possibility of exacerbation of liver injury. These results suggest that the liver injury could be caused and sustained by a one-shot DTH reaction to picryl chloride. The chronicity of the biochemical and histopathological characteristics may be helpful in elucidating the mechanisms of chronic development of liver injury.

A new triterpenoid saponin from Clinopodium chinense (Benth.) O. Kuntze

Abstract A new triterpene saponin, 3β,16β,23α,28β,30β-pentahydroxyl-olean-11,13(18)-dien-3β-yl-[β-d-glucopyranosyl-(1→2)]-[β-d-glucopyranosyl-(1→3)]-β-d-fucopyranoside, was named Clinoposaponin D (1), together with six known triterpene saponins, buddlejasaponin IVb (2), buddlejasaponin IVa (3), buddlejasaponin IV (4), clinopodisides D (5), 11α,16β,23,28-Tetrahydroxyolean-12-en-3β-yl-[β-d-glucopyranosyl-(1→2)]-[β-d-glucopyranosyl-(1→3)]-β-d-fucopyranoside (6) and prosaikogenin A (7), and two known triterpenes, saikogenin A (8) and saikogenin F (9) were isolated from Clinopodium chinense (Benth.) O. Kuntze. Their structures were elucidated on the basis of 1D, 2D NMR and MS analysis. Meanwhile, the effects of all compounds on rabbit platelet aggregation and thrombin time (TT) were investigated in vitro. Compounds 4 and 7 had significant promoting effects on platelet aggregation with EC50 value at 53.4 and 12.2 μM, respectively. In addition, the highest concentration (200 μM) of compounds 2 and 9 shortened TT by 20.6 and 25.1%, respectively. Graphical abstract

Aqueous Extract from Rhizoma Smilacis Glabrae Alleviates Immunological Liver Damage by Selectively Facilitating the Dysfunction of Liver‐infiltrating Lymphocytes

The effect of an aqueous extract from Rhizoma Smilacis Glabrae (RSG) on liver injury induced by delayed-type hypersensitivity to picryl chloride in mice has been studied. In in-vitro co-culture of non-parenchymal cells (NPC) and hepatocytes isolated from liver-injured mice, pretreatment of NPC, but not parenchymal hepatocytes, with the extract resulted in concentration- and time-dependent inhibition of NPC-induced hepatocyte damage. A significant reduction of in-vitro hepatotoxicity, as measured by inhibition of serum transaminase elevation, was also observed in NPC isolated from mice treated with RSG extract. RSG extract facilitated apoptosis in NPC from liver-injured mice but not in parenchymal hepatocytes. The results suggest that RSG extract protects against liver injury by selective induction of apoptosis in liver-infiltrating cells, mainly activated T lymphocytes. Such characteristics will help provide a novel strategy not only for treatment of liver diseases, but also for regulation of the immune response.