• IMMUNE NETWORK
• /
• v.21 no.3
• /
• pp.23.1-23.16
• /
• 2021

Chemokines are key factors that influence the migration and maintenance of relevant immune cells into an infected tissue or a tumor microenvironment. Therefore, it is believed that the controlled administration of chemokines in the tumor microenvironment may be an effective immunotherapy against cancer. Previous studies have shown that CCL3, also known as macrophage inflammatory protein 1-alpha, facilitates the recruitment of dendritic cells (DCs) for the presentation of tumor Ags and promotes T cell activation. Here, we investigated the role of CCL3 in regulating the tumor microenvironment using a syngeneic mouse tumor model. We observed that MC38 tumors overexpressing CCL3 (CCL3-OE) showed rapid regression compared with the wild type MC38 tumors. Additionally, these CCL3-OE tumors showed an increase in the proliferative and functional tumor-infiltrating T cells. Furthermore, PD-1 immune checkpoint blockade accelerated tumor regression in the CCL3-OE tumor microenvironment. Next, we generated a modified CCL3 protein for pre-clinical use by fusing recombinant CCL3 (rCCL3) with a non-cytolytic hybrid Fc (HyFc). Administering a controlled dose of rCCL3-HyFc via subcutaneous injections near tumors was effective in tumor regression and improved survival along with activated myeloid cells and augmented T cell responses. Furthermore, combination therapy of rCCL3-HyFc with PD-1 blockade exhibited prominent effect to tumor regression. Collectively, our findings demonstrate that appropriate concentrations of CCL3 in the tumor microenvironment would be an effective adjuvant to promote anti-tumor immune responses, and suggest that administering a long-lasting form of CCL3 in combination with PD-1 blockers can have clinical applications in cancer immunotherapy.

• Journal of Sasang Constitutional Medicine
• /
• v.16 no.3
• /
• pp.96-107
• /
• 2004

1. Objectives This study was carried out to investigate the effects of Gunyuljejo-tang on the $CCl_4$-induced Liver Damage in Rats. 2. Methods Sprague-Dawley rats were devided into 5 experimental groups : Normal, $NS+CCl_4$(Solid extract of $CCl_4$ injection group after Normal Saline feed), $GYJJT+CCl_4$(Solid extract of $CCl_4$ injection group after Gunyuljejo-tang feed), $CCl_4+NS$(Normal Saline feed group after $CCl_4$ injection), $CCl_4+GYJJT$(Solid extract of Gunyuljejo-tang feed group after $CCl_4$ injection). Biochemical assays for serum enzyme activities such as AST, ALT, ALP, BUN, Creatinine, Uric Acid, Total Protein, Albumin, Total Cholesterol, Triglyceride, Glucose, and mRNA Revelation of Cytochrome p450 and activities such as LPO, GSH, GST, Glutathione Reductase, Glutathione Peroxidase, SOD, Catalase, Hydroxyproline, and ${\beta}$-Glucuronidase were performed. 3. Results (1) $GYJJT+CCl_4$ showed lower revelation of Cytochrome p450. (2) $GYJJT+CCl_4$ showed higher GSH activity than $NS+CCl_4$, $CCl_4+GYJJT$ showed higher GSH activity than $CCl_4+NS$ injection significantly. (3) $GYJJT+CCl_4$ showed higher GST activity than $NS+CCl_4$. $CCl_4+GYJJT$ showed higher GST activity than $CCl_4+NS$ significantly. (4) $GYJJT+CCl_4$ showed higher Glutathione Peroxidase activity than $NS+CCl_4$, $CCl_4+GYJJT$ showed higher Glutathione Peroxidase activity than $CCl_4+NS$ significantly. (5) $CCl_4+GYJJT$ showed higher SOD activity than $CCl_4+NS$ significantly. (6) $CCl_4+GYJJT$ showed higher Catalase activity than $CCl_4+NS$ significantly. (7) $GYJJT+CCl_4$ showed lower Hydroxyproline than $NS+CCl_4$ significantly, $CCl_4+GYJJT$ showed higher Hydroxyproline than $CCl_4+NS$ significantly. (8) $GYJJT+CCl_4$ showed higher ${\beta}$-Glucuronidase activity than $NS+CCl_4$, $CCl_4+GYJJT$ showed higher ${\beta}$-Glucuronidase activity than $CCl_4+NS$ significantly. 4. Conclusions Gunyuljejo-tang has the recovering effects on the $CCl_4$-induced Liver Damage significantly.

• The Korean Journal of Pain
• /
• v.21 no.3
• /
• pp.187-196
• /
• 2008

Background: Upregulation of one type of the pro-inflammatory chemokine (CCL2) and its receptor (CCR2) following peripheral nerve injury contributes to the induction of neuropathic pain. Here, we examined whether another type of chemokine (CCL3) is involved in neuropathic pain. Methods: We measured changes in mechanical and thermal sensitivity in the hind paws of naïve rats or rats with an L5 spinal nerve ligation (SNL) after intra-plantar injection of CCL3 or met-RANTES, an antagonist of the CCL3 receptor, CCR1. We also measured CCL3 levels in the sciatic nerve and the hind paw skin as well as CCR1 expression in dorsal root ganglion (DRG) cells from the lumbar spinal segments. Results: Intra-plantar injection of CCL3 into the hind paw of naive rats mimicked L5 SNL-produced hyperalgesia. Intra-plantar injection of met-RANTES into the hind paw of rats with L5 SNL attenuated hyperalgesia. L5 SNL increased CCL3 levels in the sciatic nerve and the hind paw skin on the affected side. The number of CCR1-positive DRG cells in the lumbar segments was not changed following L5 SNL. Conclusions: Partial peripheral nerve injury increases local CCL3 levels along the degenerating axons during Wallerian degeneration. This CCL3 binds to its receptor, CCR1, located on adjacent uninjured afferents, presumably nociceptors, to induce hyperalgesia in the neuropathic pain state.

• Biomolecules & Therapeutics
• /
• v.19 no.3
• /
• pp.302-307
• /
• 2011

Peptidoglycan (PGN) is detected in inflammatory cell-rich regions of human atheromatous plaques. The present study investigated the effects of PGN on CC chemokine ligand 3 (CCL3) expression, which is elevated in the atherosclerotic arteries, and determined cellular factors involved in PGN-mediated CCL3 up-regulation in mononuclear cells, with the goal of understanding the molecular mechanisms of inflammatory responses to bacterial pathogen-associated molecular patterns in diseased arteries. Exposure of human monocytic leukemia THP-1 cells to PGN resulted in enhanced secretion of CCL3 and profound induction of the CCL3 gene transcript. Both events were abrogated by oxidized 1-palmitoyl-2-arachidonosyl-sn-phosphatidylcholine, an inhibitor of Toll-like receptors 2/4. Pharmacological inhibitors such as U0126, SP6001250, Akt inhibitor IV, rapamycin, RO318220, diphenyleneiodonium chloride, and N-acetylcysteine also significantly attenuated PGN-mediated CCL3 up-regulation. However, polymyxin B, LY294002, and SB202190 did not influence CCL3 expression. We propose that PGN contributes to enhanced CCL3 expression in atherosclerotic plaques and that Toll-like receptors (TLR2), Akt, mTOR, mitogen-activated protein kinase, and reactive oxygen species are involved in that process.

• Journal of Veterinary Clinics
• /
• v.28 no.1
• /
• pp.20-27
• /
• 2011

Hovenia dulcis Thunb (HDT) has been known folk medicine and has been used as therapeutic drug in the treatment of liver disease. Also it has been used as a detoxifying agents for alcoholic poisoning and promoting diuresis. However, there has not been any study on therapeutic effect of Hovenia dulcis extract on $CCl_4$ induced liver and kidney damage in rats. In this study, we report on therapeutic effects of Hovenia dulcis extract on $CCl_4$ induced liver and kidney damage in rats. Rats were divided into four groups of eighteen animals. Control group (DW) was administrated with distilled water 2.5 mL/kg per peritonial administration and then $CCl_4$ group (CCl) was administrated $CCl_4$ 2.5 mL/kg per peritonial administration, $CCl_4$+HDT extract group ($CCl_4$+HDT) was administrated HDT extrat (100 mg/kg) after $CCl_4$ 2.5 mL/kg administration, $CCl_4$+Silymarin group ($CCl_4$+Sily) was administrated Silymarin (50 mg/kg) after $CCl_4$ 2.5 mL/kg administration. The complete blood cell (CBC) count of RBC, WBC, PCV, Hb, MCH, MCV, MCHC and blood chemistry profile of AST, ALT, GGT, ALP, Total choloesterol, Tryglyceride, Total bilirubin, Amylase, Glucose, BUN, Creatinine, Lipase and pathologic changes were observed for 7 days after administration of D.W., $CCl_4$, $CCl_4$+HDT extract, $CCl_4$+Silymarin. The results are as follows : 1. RBC and PCV were significantly (p < 0.01) increased in all groups compared to D.W. but hemoglobin, MCH, MCV and MCHC were not showed significant difference during experimental periods. 2. AST, ALT, T-cholesterol, T-bilirubin, TG were significantly (p < 0.05) increased in all groups on day 3 compared to D.W. and were normal on day 7. 3. ALP was significantly (p < 0.05) decreased in $CCl_4$+HDT group on day 3 but Amylase was not showed significant difference during experimental periods. 4. BUN was significantly (p < 0.05) increased in $CCl_4$ group on day 7, but $CCl_4$+HDT group and $CCl_4$+Sily group were normal. Creatninie was significantly (p < 0.05) increased in $CCl_4$ group on day 3 and normal on day 7 but $CCl_4$+HDT group and $CCl_4$+Sily group were not showed significant difference during experimental periods.

• IMMUNE NETWORK
• /
• v.5 no.4
• /
• pp.237-246
• /
• 2005

Background: Little information is available on the identification and characterization of the upstream regulators of the signal transduction cascades for Mycobacterium tuberculosis (M. tbc)-induced ERK 1/2 activation and chemokine expression. We investigated the signaling mechanisms involved in expression of CCL3 /MIP-1 and CCL4/MIP-1 in human primary monocytes infected with M. tbc. Methods: MAP kinase phosphorylation was determined using western blot analysis with specific primary antibodies (ERK 1/2, and phospho-ERK1/2), and the upstream signaling pathways were further investigated using specific inhibitors. Results: An avirulent strain, M. tbc H37Ra, induced greater and more sustained ERK 1/2 phosphorylation, and higher CCL3 and CCL4 production, than did M. tbc H37Rv. Specific inhibitors for mitogen-activated protein kinase (MAPK) kinase (MEK; U0126 and PD98059) significantly inhibited the expression of CCL3 and CCL4 in human monocytes. Mycobactetia-mediated expression of CCL3 and CCL4 was not inhibited by the Ras inhibitor manumycin A or the Raf-1 inhibitor GW 5074. On the other hand, phospholipase C (PLC) inhibitor (U73122) and protein kinase C (PKC)specific inhibitors ($G\ddot{o}6976$ and Ro31-8220) significantly reduced M. tbc-induced activation of ERK 1/2 and chemokine synthesis. Conclusion: These results are the first to demonstrate that the PLC-PKC-MEK-ERK, not the Ras-Raf-MEK-ERK, pathway is the major signaling pathway inducing M. tbc-mediated CCL3 and CCL4 expression in human primary monocytes.

• Journal of the Korean Chemical Society
• /
• v.48 no.4
• /
• pp.339-350
• /
• 2004

The simplified cumulant method was applied to diffraction data of $CClF_3$ to study the equilibrium molecular parameters over a range of temperatures. The molecular parameters of $CClF_3$ by the simplified cumulant method were compared with those from the traditional method. Also the instrumentation of picosecond time resolved electron diffraction (TRED) and the experimental details are described. The total experimental temporal resolution was discussed in terms of the electron pulse width. The TRED system was applied to study the molecular structures for $CClF_3$ at room temperature. The molecular structural parameters $CClF_3$ from TRED are compared with those from GED/RT. The molecular parameters ($r_e$)of bonded C-F and C-Cl for $CClF_3$ by simplified CA are 132.00(2) pm and 175.20(3) pm, respectively, by using GED/RT. From the results of TRED experiments $r_a$ for bonded C-F and C-Cl are 132.23(13) pm and 177.23(19) pm.

• Environmental Analysis Health and Toxicology
• /
• v.23 no.4
• /
• pp.325-335
• /
• 2008

The protective effects of the Naringin, on carbon tetrachloride ($CCl_4$)-induced hepatotoxicity and the possible mechanisms involved in this protection were investigated in mice. Pretreatment with Naringin prior to the administration of $CCl_4$ significantly prevented an increase in serum alanine, aspartate aminotransferase activity and hepatic lipid peroxidation in a dose-dependent manner. In addition, pretreatment with Naringin also significantly prevented the depletion of glutathione (GSH) content in the livers of $CCl_4$-induced mice. However, reduced hepatic glutathione levels was unaffected by treatment with Naringin alone. In addition, Naringin prevented $CCl_4$-induced apoptosis and necrosis, as indicated by a liver DNA laddering. To determine whether caspase-8,-3 pathway involved in $CCl_4$-induced acute liver injury, caspase-8, -3 activities were tested by ELISA. Naringin attenuated $CCl_4$induced caspase-8, -3 activities in mouse livers. $CCl_4$-induced hepatotoxicity was also prevented, as indicated by a liver histopathologic study. The effects of Naringin on the cytochrome P450 (CYP) 2E1, the major isozyme involved in $CCl_4$ were also investigated. Treatment of mice with Naringin resulted in a significant decrease of the CYP2E1-dependent hydroxyl at ion and aniline in a dose-dependent manner. These findings suggest that protective effects of Naringin against the $CCl_4$-induced hepatotoxicity may be due to its ability to block CYP2E1-mediated $CCl_4$ bioactivation and that is also protects against caspase-8, -3 pathway mediated apoptosis.

• Journal of Life Science
• /
• v.27 no.8
• /
• pp.896-901
• /
• 2017

This study was performed to investigate the protective effects of succinic acid of Succiniter against carbon tetrachloride ($CCl_4$)-induced hepatotoxicity in rats. After an adaptation period of one week, Sprague-Dawley rats were administered succinic acid of Succiniter at 200 mg/kg every day for 21 days. Then $CCl_4$ (3.3 ml/kg) was intraperitoneally injected into rats of the other groups except the normal group, five hours after the last treatment of succinic acid of Succiniter on day 21. The succinic acid-treated group showed 93.20% and 88.76% of inhibitory effects in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, respectively, compared with the $CCl_4-treated$ group. The succinic acid-treated group showed inhibition of malonedialdehyde (MDA) by 85.17% compared with the $CCl_4-treated$ group. The succinic acid-treated group in liver homogenate promoted effects of 38.65% and 47.99% in superoxide dismutase (SOD) and catalase (CAT), respectively, compared with the $CCl_4-treated$ group. In conclusion, the AST and ALT activities of the succinic acid-treated group were both decreased compared with the $CCl_4-treated$ group. The MDA level of the succinic acid-treated group was decreased compared with the $CCl_4-treated$ group. However, the SOD and CAT levels of the succinic acid-treated group in liver homogenate were both increased compared with the $CCl_4-treated$ group. Also, histological examinations showed that the liver cell necrosis and centrilobular congestion aggregation induced by $CCl_4$ were clearly eliminated by treatment with succinic acid of Succiniter. These results suggest that succinic acid of Succiniter has a protective effect against liver damage and could be used in the development of the appropriate drug.

• Journal of Life Science
• /
• v.9 no.3
• /
• pp.300-307
• /
• 1999

The enzyme activities and antioxidative of tocopherol and ascorbate were investigated at the levels of liver, kidney homogenates and sera of SD-rats intoxicated with tetrachlorocarbon$CCl_4$. GOT and GPT activities of sera in the $CCl_4$ group were 3, 6 times increased compared to normal group. But they tended to decrease significantly in tocopherol and ascorbate administered group. As for BUN and total cholesterol they were the same. HDL-cholesterol in the $CCl_4$group was 42% decreased compared to normal group. HDL-cholesterol was about 26% increased in the tocopherol group and tocopherol ascorbate group compared to $CCl_4$ group. MDA and SOD activities in the liver and the kidney tissue homogenates were significantly increased in $CCl_4$ group compared to normal group. But they were decreased significantly in the tocopherol group and tocopherol-ascorbate group compared to $CCl_4$ group. In view of this study tocopherol and ascorbated were ascorbate were effective on the detoxication of liver and kidney injury.