Combinatorial Herbal Extracts Alleviate Alcohol-Induced Hepatic Disorders.

Plant-derived compounds can be useful for the management of liver disease. Traditionally, hepatic disorders have been treated with herbal extracts. Although many herbal extracts in Eastern medicine have been shown to possess hepatoprotective activities, single-origin herbal extracts primarily demonstrate either antioxidant or anti-inflammatory activities. The current study investigated the effects of combinatorial herbal extracts on alcohol-induced hepatic disorders in an ethanol-fed mouse model. Sixteen herbal combinations were evaluated as hepatoprotective formulations; the active constituents in these herbal extracts were daidzin, peonidin-3-glucoside, hesperidin, glycyrrhizin, and phosphatidylcholine. RNA sequencing analysis showed that exposure to ethanol altered hepatic gene expression profiles (compared to those of the non-alcohol-fed group), resulting in 79 differentially expressed genes. A majority of the differentially expressed genes in alcohol-induced hepatic disorders were associated with dysfunction of the normal cellular homeostasis in the liver; however, these genes were repressed by treatment with herbal extracts. Moreover, following treatment with herbal extracts, there were neither acute inflammatory responses in the liver tissue nor abnormalities in the cholesterol profile. These results suggest that combinatorial herbal extracts may alleviate alcohol-induced hepatic disorders by modulating the inflammatory response and lipid metabolism in the liver.

Ligularia fischeri extract attenuates liver damage induced by chronic alcohol intake.

Context Ligularia fischeri (Ledebour) Turcz. (Compositae) has been used as a leafy vegetable and in traditional medicine to treat hepatic disorder in East Asia. Objective The present study explores the antioxidant activity of LF aqueous extract on EtOH-induced oxidative stress accompanied by hepatotoxicity both in vitro and in vivo. Materials and methods In vitro study using the mouse liver NCTC-1469 cell line was conducted to estimate the cytotoxicity as well as the inhibitory effect of LF extract against alcohol-treated cell damage. In vivo study used an alcohol-fed Wister rat model orally administered EtOH (3.95 g/kg of body weight/d) with or without LF extract (100 or 200 mg/kg body weight) for 6 weeks. Serum and liver tissue were collected to evaluate hepatic injury and antioxidant-related enzyme activity. Results The EC50 value for the DPPH radical scavenging capacity of LF extract was 451.5 µg/mL, whereas the IC50 value of LF extract in terms of EtOH-induced reactive oxygen species (ROS) generation was 98.3 µg/mL without cell cytotoxicity. LF extract (200 mg/kg body weight) significantly reduced the triglyceride content of serum (33%) as well as hepatic lipid peroxidation (36%), whereas SOD activity was elevated three-fold. LF extract suppressed expression of CYP2E1 and TNF-α, and attenuated alcohol-induced abnormal morphological changes. Discussion and conclusion LF extract attenuated liver damage induced by alcoholic oxidative stress through inhibition of ROS generation, down-regulation of CYP2E1, and activation of hepatic antioxidative enzymes. Homeostasis of the antioxidative defence system in the liver by LF extract mitigated hepatic disorder following chronic alcohol intake.

Diabetic conditions downregulate the expression of CD2AP in podocytes via PI3-K/Akt signalling.

BACKGROUND: Proteinuria is typically accompanied by structural and compositional changes of the foot processes and of the slit diaphragms between podocytes. CD2-associated protein (CD2AP) in podocytes serves as an adaptor protein binding to nephrin and podocin, anchoring these slit diaphragm proteins to actin filaments of podocyte cytoskeleton and sending signals inward or outward. METHODS: In the present study, we prepared streptozotocin-induced diabetic renal tissues and cultured podocytes in diabetic conditions to investigate podocyte phenotypical changes, including quantitative and distributional changes of CD2AP protein and search for the signalling mechanisms in diabetic conditions. We prepared cultured rat glomerular epithelial cells and mouse podocytes to study how high glucose and advanced glycosylation end products (AGE) induce phenotypical changes of cultured podocyte, under (1) normal glucose (5 mM, = control), (2) high glucose (30 mM), (3) AGE-added or (4) high glucose plus AGE-added conditions. RESULTS: According to diabetic duration, density of CD2AP in renal tissue of experimental diabetic nephropathy became conglomerulated and diminished. In cultured podocytes, CD2AP co-localized with nephrin and zonula occludens-1 by confocal imaging. High glucose and high glucose plus AGE induced the relocalization and concentration of CD2AP at internal cytoplasmic and perinuclear areas of podocytes. High glucose plus AGE-added condition also decreased CD2AP protein amount and its mRNA expression compared with normal glucose or osmotic control conditions. In addition, LY294002, a phosphoinositide 3-kinase inhibitor, prevented the quantitative and distributional changes of CD2AP induced by high glucose and AGE. CONCLUSIONS: These findings suggest that diabetic conditions induce the phenotypical changes of podocyte CD2AP possibly via phosphoinositide 3-kinase/Akt signalling.

Geranyl derivative of phloroacetophenone induces cancer cell-specific apoptosis through Bax-mediated mitochondrial pathway in MCF-7 human breast cancer cells.

Plant-derived polyhenols inhibit cancer cell proliferation and induce apoptosis. Recently, prenylflavonoids and alkyl-phloroacetophenones have been reported for their in vitro antitumor activity. In the present study, we examined the cytotoxic activity of prenyl (3-PAP) and geranyl (3-GAP) derivatives of phloroacetophenone, and xanthohumol (XN), a prenyl-chalcone, in human breast cancer (MCF-7) and human sarcoma (HT1080) cell lines in vitro. 3-GAP showed the strongest cytotoxicity in these cell lines with IC(50) values of less than 10 µM. In addition, we report that 3-GAP is a more potent anti-cancer agent for breast cancer than XN which is a well-known anticancer flavonoid. Moreover, 3-GAP did not induce cytotoxicity in the normal cell line, TCMK-1, whereas 3-PAP and XN significantly reduced TCMK-1 cell viability. In 3-GAP-treated MCF-7 cells, nuclear accumulation and transcriptional activity of p53 were increased. In addition, pro-apoptotic Bax but not B-cell lymphoma 2 (Bcl-2) expression was increased by 3-GAP. In accordance with the Bax increase, 3-GAP induced mitochondrial cytochrome c release and activated caspase-9, an initiator of the caspase cascade. In the MCF-7 cell line which does not express caspase-3, activation of caspase-7, a member of the caspase-3 subfamily, was increased by 3-GAP. The present results indicate that synthetic 3-GAP is a safe and effective anti-cancer agent, and the Bax-mediated mitochondrial pathway is the main apoptosis signaling pathway of 3-GAP in MCF-7 cells.

Neurexin-1, a presynaptic adhesion molecule, localizes at the slit diaphragm of the glomerular podocytes in kidneys.

The slit diaphragm connecting the adjacent foot processes of glomerular epithelial cells (podocytes) is the final barrier of the glomerular capillary wall and serves to prevent proteinuria. Podocytes are understood to be terminally differentiated cells and share some common features with neurons. Neurexin is a presynaptic adhesion molecule that plays a role in synaptic differentiation. Although neurexin has been understood to be specifically expressed in neuronal tissues, we found that neurexin was expressed in several organs. Several forms of splice variants of neurexin-1α were detected in the cerebrum, but only one form of neurexin-1α was detected in glomeruli. Immunohistochemical study showed that neurexin restrictedly expressed in the podocytes in kidneys. Dual-labeling analyses showed that neurexin was colocalized with CD2AP, an intracellular component of the slit diaphragm. Immunoprecipitation assay using glomerular lysate showed that neurexin interacted with CD2AP and CASK. These observations indicated that neurexin localized at the slit diaphragm area. The staining intensity of neurexin in podocytes was clearly lowered, and their staining pattern shifted to a more discontinuous patchy pattern in the disease models showing severe proteinuria. The expression and localization of neurexin in these models altered more clearly and rapidly than that of other slit diaphragm components. We propose that neurexin is available as an early diagnostic marker to detect podocyte injury. Neurexin coincided with nephrin, a key molecule of the slit diaphragm detected in a presumptive podocyte of the developing glomeruli and in the glomeruli for which the slit diaphragm is repairing injury. These observations suggest that neurexin is involved in the formation of the slit diaphragm and the maintenance of its function.

Ameliorating effects of fermented rice bran extract on oxidative stress induced by high glucose and hydrogen peroxide in 3T3-L1 adipocytes.

In this study, we investigated whether fermented rice bran (FRB) can ameliorate the oxidative stress induced by high glucose and hydrogen peroxide (H(2)O(2)) in 3T3-L1 adipocytes by analyzing reactive oxygen species (ROS), oil red O staining, as well as the expression of mRNAs related to glucose homeostasis and adipogenesis. It was first confirmed that rice bran fermented by Issatchenkia orientalis MFST1 extract increased free phenolic content compared to non-fermented rice bran. The FRB extract strongly inhibited ROS generation and upregulated the expression of PPAR-γ and adiponectin. Moreover, FRB upregulated GLUT4 related to glucose transportation and insulin sensitivity. Taken together, FRB extract ameliorated oxidative stress-induced insulin resistance by neutralizing free radicals and upregulating adiponectin in adipocytes. Our results provide information toward understanding the beneficial effects of FRB on oxidative stress.

The effect of sigumjang (Korean fermented barley bran) marination on the physicochemical properties of pork loin.

Sigumjang is a traditional Korean fermented barley bran consumed in the Gyungsang-do area. In this study, pork loin was marinated with sigumjang, and its physicochemical and textural properties were investigated. Sigumjang-marinated pork loin (SMPL) displayed an attractive yellowish-brown overall color. SMPL's pH marginally increased during storage and finally equilibrated to the pH of sigumjang, 5.5, on day 14. The amino-type nitrogen content of SMPL increased linearly during the marination period. Due to the lower extractability and higher pH compared to the control, the volume of myofibrillar fragments in SMPL decreased during the marination period. SMPL showed an increase in free amino acids related to umami (Asp and Glu) and sweet (Ser, Thr, Ala and Gly) tastes compared to the control. These may indicate improvement of sensory qualities of SMPL. The results also provide valuable information for the use of sigumjang in the development of novel meat products.

Induction of apoptosis by L-carnitine through regulation of two main pathways in Hepa1c1c 7 cells.

This study shows the effects of L-carnitine treatment on cell proliferation with hepa1c1c7 mouse cancer cells and NCTC 1469 normal cells. In an MTT assay, L-carnitine increased the number of dead hepa1c1c7 cells, while there was no difference in the number of NCTC 1469 cells. mRNA and protein levels of TNF-alpha, Fas, and caspase-8, which are closely related to cell apoptosis by a death ligand/receptor-dependent apoptosis pathway, were increased by L-carnitine treatment. In addition, L-carnitine treatment regulated mitochondria-dependent apoptosis pathways by inducing the up-regulation of caspase-9 and caspase-3 and the down-regulation of Bcl-2 in hepa1c1c 7 cells. Taken together, the findings of this study have demonstrated that L-carnitine could induce apoptosis in hepa1c1c7 cells by regulating Fas ligands and inhibiting the expression of Bcl-2. These results suggest that L: -carnitine treatment could be related to both a mitochondrion-dependent and a death ligand/receptor-dependent apoptosis pathway in hepa1c1c7 cells. Our results could give information for understanding the L-carnitine-induced apoptosis mechanism in some cancer cells.

Therapeutic targets in the podocyte: findings in anti-slit diaphragm antibody-induced nephropathy.

Recent studies have demonstrated that the slit diaphragm of the glomerular epithelial cell (podocyte) is the structure likely to be the barrier in the glomerular capillary wall. Murine monoclonal antibody against nephrin, a molecule constituting the extracellular site of the slit diaphragm, caused severe proteinuria if injected into rats, in a complement- or inflammatory cell-independent manner. In this proteinuric state, not only nephrin but also other slit diaphragm-associated molecules are down-regulated. These observations suggest that the antibody alters the molecular composition of the slit diaphragm and, thereby, affects the glomerular permeability barrier. Recently, it was found that IP-10, SV2B, ephrin B1 and the receptors of angiotensin II were expressed in the podocyte, and that their expressions were clearly altered in anti-nephrin antibody-induced nephropathy. It is conceivable that these molecules are involved in the development of proteinuria in this model. IP-10 is assumed to play a role in maintaining the slit diaphragm function by regulating the cell cycle balance of the podocyte. SV2B and ephrin B1 play pivotal roles in the proper localization of the slit diaphragm component. In vivo and in vitro studies demonstrated that angiotensin II type 2 receptor-mediated action enhanced the expression of nephrin. We propose that these molecules could be novel therapeutic targets for proteinuria.

Changes in ginsenoside patterns of red ginseng extracts according to manufacturing and storage conditions.

Although the pharmacological action of red ginseng is mostly generated by ginsenosides, contents of ginsenosides in manufactured extracts are still varying according to processing and storage conditions. Rg1, Rb1, and Rh1 levels significantly decreased overtime under pH adjustment and thermal treatment during storage, and these changes were exacerbated at lower pH and higher storage temperature. However, Rg3 level showed the opposite pattern compared to other ginsenosides. Rg3 level linearly increased at higher temperature and pH while significantly decreased at pH 2. Furthermore, Rg3 level constantly increased during storage. This is the first combined study on the effects of manufacturing and storage conditions on ginsenoside contents of red-ginseng-extract products. To minimize loss of major marker and bioactive compounds of red ginseng products during manufacturing processes and storage, it is recommended that red-ginseng-extracts be maintained at pH 6-8, sterilized at below 105 °C, and stored at below 25 °C.

Sigumjang (fermented barley bran) water-soluble extracts inhibit the expression of adipogenic and lipogenic regulators in 3T3-L1 adipocytes.

Sigumjang prepared from fermented barley bran is a traditional fermented food found only in the Gyeongsang-do area of South Korea. There have been no studies reported to date despite the potential bioactivities of sigumjang. In this study, the anti-obesity activities of sigumjang extracts (SEs) during 3T3-L1 differentiation into adipocytes were investigated. SEs inhibited adipocyte differentiation by suppressing the CCAAT/enhancer binding protein-ß and sterol regulatory element binding protein-1c expression in the early stage of differentiation, followed by the suppression of the peroxisome proliferator-activated receptor-γ, CCAAT/enhancer binding protein-α, and adiponectin. These changes in adipogenic markers induced inhibition of lipogenesis via down-regulation of mainly fatty acid synthase, acetyl-CoA carboxylase, fatty acid binding protein 4, and perilipin. These results were more significant in the extract of sigumjang fermented with isolated Bacillus amyloliquefaciens MFST compared to naturally fermented sigumjang group. SEs can be considered as a useful material for developing food with health benefits and anti-obesity properties.

Alanine-scanning mutagenesis of HM-1 killer toxin and the essential residues for killing activity.

Each of the aromatic, acidic and basic amino acid residues in HM-1 were separately substituted with alanine by site-directed mutagenesis. The mutant genes were successfully expressed in HM-1 resistant Saccharomyces cerevisiae. HM-1 gene analogues corresponding to the aromatic substitutions resulted in lower production of HM-1 analogues. In the case of the acidic amino acid residue and basic amino acid residue substitutions, some analogues were produced in the same amount as and exhibited similar killing activity to that of the wild type HM-1. But the H35A HM-1 analogue had completely lost the killing activity, and D44A, K21A, K46A, R82A, R85A and R86A HM-1 showed highly decreased killing activities. These results strongly indicate the importance of histidine-35, aspartic acid-44, lysine-21, lysine-46, and C-terminal arginine residues in HM-1 for the killing activity.

Multi-glycoside of Tripterygium wilfordii Hook f. ameliorates proteinuria and acute mesangial injury induced by anti-Thy1.1 monoclonal antibody.

BACKGROUND/AIMS: Multi-glycoside from Tripterygium wilfordii Hook f. (GTW) is used for various immune and inflammatory diseases including renal diseases represented by mesangial proliferative glomerulonephritis (MsPGN) in China. However, there have been no fundamental studies on the operating mechanism of GTW on MsPGN. The aim of this study is to examine as the first step the effects of GTW on acute injurious process such as mesangial injury and proteinuria in an acute and reversible Thy.1.1 glomerulonephritis (Thy1.1GN) model and then to clarify the action mechanism of GTW at molecular level by examining its effects on various injurious factors in this model. METHODS: Thy1.1 GN was induced in rats by a single intravenous injection with 500 microg of anti-Thy1.1 mAb 1-22-3. Daily oral administration of GTW and vehicle as a control was started from 3 days before injection of mAb to the day of sacrifice in each experiment. Fourteen rats were randomly divided into 2 groups, GTW-treated and vehicle-treated groups, and sacrificed on day 14 in experiment 1 or on day 7 in experiment 2 after induction of Thy1.1 GN. Proteinuria was determined on days 1, 3, 5, 7, 10 and 14 in experiment 1 or on 1, 3, 5 and 7 in experiment 2. From blood and kidneys taken at sacrifice, blood biochemical parameters, mesangial morphological changes, glomerular macrophage infiltration, and glomerular mRNA expression of cytokines were examined. RESULTS: In experiment 1, proteinuria and mesangial matrix expansion were significantly attenuated by GTW treatment. In experiment 2, GTW treatment significantly ameliorated proteinuria, mesangial lesions and macrophage accumulation in glomerulus. In addition, it significantly reduced the glomerular expression of mRNA for PDGF, MCP-1 and IL-2. CONCLUSION: GTW ameliorated not only proteinuria but also mesangial alterations in Thy1.1 GN most likely by reducing expression of injurious cytokines, indicating that GTW has suppressive effects on acute inflammatory changes in glomeruli.

Diabetic conditions modulate the adenosine monophosphate-activated protein kinase of podocytes.

BACKGROUND: Adenosine monophosphate-activated protein kinases (AMPKs), as a sensor of cellular energy status, have been known to play an important role in the pathophysiology of diabetes and its complications. Because AMPKs are known to be expressed in podocytes, it is possible that podocyte AMPKs could be an important contributing factor in the development of diabetic proteinuria. We investigated the roles of AMPKs in the pathological changes in podocytes induced by high-glucose (HG) and advanced glycosylation end products (AGEs) in diabetic proteinuria. METHODS: We prepared streptozotocin-induced diabetic renal tissues and cultured rat and mouse podocytes under diabetic conditions with AMPK-modulating agents. The changes in AMPKα were analyzed with confocal imaging and Western blotting under the following conditions: (1) normal glucose (5mM, =control); (2) HG (30mM); (3) AGE-added; or (4) HG plus AGE-added. RESULTS: The density of glomerularphospho-AMPKα in experimental diabetic nephropathy decreased as a function of the diabetic duration. Diabetic conditions including HG and AGE changed the localization of phospho-AMPKα from peripheral cytoplasm to internal cytoplasm and peri- and intranuclear areas in podocytes. HG reduced the AMPKα (Thr172) phosphorylation of rat podocytes, and similarly, AGEs reduced the AMPKα (Thr172) phosphorylation of mouse podocytes. The distributional and quantitative changes in phospho-AMPKα caused by diabetic conditions were preventable using AMPK activators, metformin, and 5-aminoimidazole-4-carboxamide-1ß-riboside. CONCLUSION: We suggest that diabetic conditions induce the relocation and suppression of podocyte AMPKα, which would be a suggestive mechanism in diabetic podocyte injury.

Bioavailability of nanoemulsified conjugated linoleic acid for an antiobesity effect.

BACKGROUND: The aim of this study was to enhance the bioavailability of conjugated linoleic acid (CLA), which has low water solubility, using nanoemulsion technology and to evaluate the effects of its improved bioavailability as an antiobesity agent. METHODS: The antiobesity effect of nanoemulsified water-soluble conjugated linoleic acid (N-CLA) was evaluated using in vitro and in vivo studies. Differentiated 3T3-L1 adipocytes were treated with CLA and N-CLA to assess their lipolytic effect. Further, to confirm the antiobesity effect of N-CLA, male Sprague-Dawley rats were randomly separated into four groups, ie, a group fed a normal diet, a group fed a high-fat diet (obesity rat model), a CLA-treated group, and an N-CLA-treated group. RESULTS: N-CLA showed a greater lipolytic effect on differentiated 3T3-L1 adipocytes compared with normal CLA. N-CLA enhanced the release of glycerol from triglycerides, which accumulated in differentiated 3T3-L1 adipocytes. Further, N-CLA enhanced leptin secretion to an extent similar to that of orlistat, an antiobesity agent. In an animal obesity model fed a high-fat diet, N-CLA attenuated accumulation of triglycerides, total cholesterol, and low-density lipoprotein cholesterol in serum, and also significantly decreased the volume of triglycerides and cholesterol in liver tissue. CONCLUSION: These results indicate that N-CLA has a greater antiobesity effect than CLA as a result of its improved bioavailability.

Changes of podocyte p130Cas in diabetic conditions.

BACKGROUND: Proteinuria results from increased glomerular permeability and is associated with retraction and effacement of the highly specialized interdigitating podocyte foot processes. In podocytes (glomerular epithelial cells [GECs]), p130Cas localizes diffusely to the cytoplasm and connects focal adhesion proteins and kinases to the glomerular basement membrane and adapter proteins of slit diaphragm insertion sites. METHODS: To investigate whether high-glucose (HG) and advanced glycosylation end products (AGEs) induce quantitative and distributional changes of podocyte p130Cas protein, a docking protein connecting F-actin fibers to the glomerular basement membrane and adapter proteins, we cultured rat GECs (r-GECs) and mouse GECs (m-GECs) under (i) normal glucose (5 mM = control), (ii) HG (30 mM), (iii) AGE-added or (iv) HG plus AGE-added conditions. We also prepared streptozotocin-induced diabetic renal tissues. RESULTS: We found that p130Cas stainings were located in peripheral cytoplasm of r-GECs and m-GECs as dots in linear alignment, partially colocalized with actin-binding proteins such as synaptopodin and alpha-actinin, and locally connected to the ends of actin filaments. In diabetic conditions, the intensities of p130Cas stainings were diminished in more pathological HG plus AGE-added condition of r-GECs and m-GECs and in chronic diabetic renal tissues. p130Cas protein was decreased significantly by HG, AGE and HG plus AGE in both cells compared with normal glucose or osmotic control conditions. p130Cas mRNA expression levels were also suppressed similarly in diabetic conditions. CONCLUSION: We suggest that diabetic conditions modulate the quantitative and distributional changes of podocyte p130Cas and therefore affect the filtration function of podocytes.

Ameliorating effects of L-carnitine on diabetic podocyte injury.

High glucose levels can change podocyte gene expression and subsequently induce podocyte damage through altered glucose metabolism. l-Carnitine is known to play a beneficial role in diabetes; however, there are no studies on the effects of l-carnitine on podocyte alteration under high glucose conditions. This study investigated whether l-carnitine can attenuate diabetic podocyte injury through the prevention of loss of slit diaphragm proteins. The l-carnitine treatment group showed increased glucose uptakes compared to the control group, suggesting that glucose utilization in the podocytes was increased by l-carnitine. l-Carnitine treatment also prevented decreased mRNA expressions of nephrin and podocin in the high glucose-stimulated podocytes. However, mRNA expressions of CD2AP and α-actinin-4 were not significantly changed by the high glucose conditions. When these data are taken together, l-carnitine can increase glucose uptake in podocytes under high glucose conditions, and its mechanism may be at least partly related to the up-regulation of nephrin and podocin. Our results help clarify the beneficial effects of l-carnitine in diabetic nephropathy.

Angiotensin II type 1 and type 2 receptors play opposite roles in regulating the barrier function of kidney glomerular capillary wall.

Although angiotensin II (Ang II) type 1 receptor antagonist ameliorates proteinuria, its pharmacological mechanism and the differential roles of Ang II type 1 receptor (AT1R) and type 2 receptor (AT2R) are not well understood. We analyzed the effect of Ang II type 1 receptor antagonist on proteinuria caused by antibody against nephrin, a functional molecule of glomerular slit diaphragm and dysfunction of which is involved in the development of proteinuria in several glomerular diseases. We show here that AT1R antagonist ameliorated proteinuria by preventing a reduction in the functional molecules of the slit diaphragm. We also analyzed the role of AT1R- or AT2R-mediated actions on the expression of the slit diaphragm molecules in an in vivo study of normal rat and in an in vitro study of cultured podocytes. AT1R-mediated action hampered the mRNA expression of the slit diaphragm molecules, whereas AT2R-mediated action enhanced it. These findings indicate that Ang II receptor subtypes play opposite roles in regulating the barrier function of glomerular capillary wall and that the enhancement of AT2R stimulation may serve as a potential therapeutic strategy for proteinuria.

Blockade of interferon-gamma-inducible protein-10 attenuates chronic experimental colitis by blocking cellular trafficking and protecting intestinal epithelial cells.

The role of chemokines, especially CXCL10/interferon-gamma-inducible protein 10 kDa (IP-10), a chemokine to attract CXCR3(+) T-helper 1-type CD4(+) T cells, is largely unknown in the pathophysiology of inflammatory bowel disease; ulcerative colitis and Crohn's disease. The authors have earlier shown that IP-10 neutralization protected mice from acute colitis by protecting crypt epithelial cells of the colon. To investigate the therapeutic effect of neutralization of IP-10 on chronic colitis, an anti-IP-10 antibody was injected into mice with newly established murine AIDS (MAIDS) colitis. Anti-IP-10 antibody treatment reduced the number of colon infiltrating cells when compared to those mice given a control antibody. The treatment made the length of the crypt of the colon greater than control antibody. The number of Ki67(+) proliferating epithelial cells was increased by the anti-IP-10 antibody treatment. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)(+) apoptotic cells were observed in the epithelial cells of the luminal tops of crypts in control MAIDS colitis, whereas TUNEL(+) apoptotic epithelial cells were rarely observed with anti-IP-10 antibody treatment. In conclusion, blockade of IP-10 attenuated MAIDS colitis through blocking cellular trafficking and protecting intestinal epithelial cells, suggesting that IP-10 plays a key role in the development of inflammatory bowel disease as well as in chronic experimental colitis.