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Benefits of HemoHIM Plus • Strengthen the immune system's natural functioning to fight various chronic diseases • increase stamina as well as to improve general health for everybody • NK cell activation - An immune cell which is generated in the human bone marrow to destruct harmful substances to the human body. NK cells can eat cancer cells • produce more white blood cell, produce more red blood cell • Immunity enhancement - Enhances immunity to maintain health • Immune cell activation - Improves human body defense capacity
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RESEARCH ARTICLE OPEN ACCESS OPEN PEER REVIEW
Enhanced antitumor efficacy of cisplatin in combination with HemoHIM in tumor-bearing mice
Hae-Ran Park, Eun-Jin Ju, Sung-Kee JoEmail author, Uhee Jung, Sung-Ho Kim and Sung-Tae Yee
BMC Cancer20099:85
DOI: 10.1186/1471-2407-9-85© Park et al; licensee BioMed Central Ltd. 2009
Received: 23 July 2008Accepted: 17 March 2009Published: 17 March 2009
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Abstract
Background
Although cisplatin is one of the most effective chemotherapeutic agents, cisplatin alone does not achieve a satisfactory therapeutic outcome. Also cisplatin accumulation shows toxicity to normal tissues. In this study, we examined the possibility of HemoHIM both to enhance anticancer effect with cisplatin and to reduce the side effects of cisplatin in melanoma-bearing mice.
Methods
HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of 3 edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Anticancer effects of HemoHIM with cisplatin were evaluated in melanoma-bearing mice. We used a Cr51-release assay to measure the activity of NK/Tc cell and ELISA to evaluate the production of cytokines.
Results
In melanoma-bearing mice, cisplatin (4 mg/kg B.W.) reduced the size and weight of the solid tumors, and HemoHIM supplementation with cisplatin enhanced the decrease of both the tumor size (p < 0.1) and weight (p < 0.1). HemoHIM itself did not inhibit melanoma cell growth in vitro, and did not disturb the effects of cisplatin in vitro. However HemoHIM administration enhanced both NK cell and Tc cell activity in mice. Interestingly, HemoHIM increased the proportion of NK cells in the spleen. In melanoma-bearing mice treated with cisplatin, HemoHIM administration also increased the activity of NK cells and Tc cells and the IL-2 and IFN-γ secretion from splenocytes, which seemed to contribute to the enhanced efficacy of cisplatin by HemoHIM. Also, HemoHIM reduced nephrotoxicity as seen by tubular cell of kidney destruction.
Conclusion
HemoHIM may be a beneficial supplement during cisplatin chemotherapy for enhancing the anti-tumor efficacy and reducing the toxicity of cisplatin.
Background
Chemotherapy has been one of the major therapeutic modalities commonly used for the treatment for a variety of cancer patients. However, in many cases, chemotherapy or radiotherapy alone cannot achieve a satisfactory therapeutic outcome, namely the complete remission of tumors, and induces severe side effects at therapeutically effective doses.
Cisplatin (cis-diaminedichloroplatinum (II) or CDDP), a platinum-containing anticancer drug, is one of the most commonly used cytotoxic agents for the treatment of a variety of solid malignant tumors. Despite its excellent anticancer activity, the clinical use of cisplatin is often limited by its undesirable side effects, such as severe nephrotoxicity and hepatotoxicity [1, 2]. Although the precise mechanism for the cisplatin-induced toxicity is not well understood, cisplatin is preferentially taken up and accumulated in the liver and kidney cells [3], resulting in the enhanced production of reactive oxygen species (ROS) and the decrease in antioxidant enzymes [4, 5, 6, 7]. Therefore, antioxidants have been administered before cisplatin treatment to protect against nephrotoxicity [8, 9, 10].
Complementary and alternative medicine defined by the National Center as a group of diverse medical and health care systems is not normally considered to be conventional medicine [11]. Complementary and alternative medicine does not inhibit tumor growth. These treatments might be undertaken adjuvant to, or instead of, conventional treatments. Numerous herbal medical products are promoted as complementary and alternative medicines. In addition, scientific and medical studies in Korea, China, and Japan, and more recently in the United States, have increasingly shown that plant-derived polysaccharides have potent immunotherapeutic properties with respect to the prevention and treatment of cancer [12, 13, 14, 15, 16, 17, 18, 19].
A new herbal composition, HemoHIM, was designed by adding its polysaccharide fraction into a hot water extract of an herb mixture consisting of Angelica Radix, Cnidium Rhizoma and Paeonia Radix. This composition was designed to protect the self-renewal tissues and to promote a recovery of the immune system against oxidative stresses, such as irradiation [20, 21]. The general composition of HemoHIM were 60.4% carbohydrate, 6% protein and 33.6% other (Data not shown). The immune modulating components in HemoHIM were the ethanol-insoluble fraction [21], and the polysaccharide content in this fraction was 40.9% (± 3.8) (Data not shown). In addition, the functional components included in the ethanol-soluble fraction of HemoHIM were Gallic acid [0.2% (± 0.06)], chlorogenic acid [0.33% (± 0.05)], paeoniflorin [1.32% (± 0.15)], nodakenin [0.58% (± 0.04)] and benzoic acid [0.17% (± 0.05)] (Data not shown). Especially, these 3 herbs are listed as raw materials in the Korea Food Code. Finally, HemoHIM has been proven to be safe for long-term administration (data not shown).
Surveillance capacity to tumor cells was mediated nonspecifically by dendritic cells, macrophages and natural killer cells and was mediated specifically by T cells including cytotoxic T (Tc) cells. Both T and NK cells have been shown to be anticancer effector cells [22, 23]. Also, IFN-γ and IL-2 have been shown to have anticancer activity in animals [24, 25].
In this study, the possibility of HemoHIM increasing the immune surveillance capacity to tumor cells through both NK cells and Tc cells in melanoma-bearing mice treated with cisplatin was assessed. Also, we examined its protective effect against cisplatin-induced nephrotoxicity in melanoma-bearing mice. Our results suggest that HemoHIM may be a beneficial supplement during cisplatin chemotherapy by enhancing the anti-tumor efficacy and reducing the toxicity of cisplatin.
Methods
Animals
Research was approved and conducted according to the principles enunciated in the 'Animal Care Act', prepared by the Ministry of Agriculture and Forestry, Republic of Korea. 8-week-old female C57BL/6 (H-2b) mice were used (The Orient Inc.; Charles River Technology; Seoul, Korea). The mice were housed in polycarbonate cages under a specific pathogen-free condition, and were fed with a standard animal diet and water ad libitum.
Preparation of HemoHIM
A mixture of 3 edible medicinal herbs, Angelica Radix (root of Angelica gigas Nakai), Cnidii Rhizoma (rhizome of Cnidium officinale Makino), and Paeonia Radix (root of Paeonia japonica Miyabe), was decocted for 4 hours in boiling water to obtain a total extract (HIM-I). One half of HIM-I was fractionated into an ethanol-soluble fraction and into an ethanol-insoluble polysaccharide fraction by a precipitation in 80% ethanol. HemoHIM was prepared by adding the ethanol-insoluble polysaccharide fraction to the other half of HIM-I.
Cell culture
B16F0 (Melanoma cell line; CRL-6322) and YAC-1 (Molony virus induced leukemia; TIB-160) were purchased from ATCC (Rockville, MD, USA) and cultured in RPMI 1640 supplemented with 10% fetal bovine serum (FBS, GIBCO BRL, Grand Island, USA)), 2 × 10-2 M HEPES buffer, 2 × 10-3 M L-glutamine, 100 U/ml penicillin and 50 μg/ml streptomycin (GIBCO BRL). All cells were grown at 37°C in a humidified atmosphere containing 5% CO2.
Cisplatin injection and HemoHIM administration in tumor-bearing mice model
Mice were divided randomly into three groups (Control, Cisplatin and Cisplatin+HemoHIM), and each group consisted of twenty mice. B16F0 melanoma (5 × 105 cells/mouse) was inoculated into subcutaneous femoral left region of mice at 3 days before an initial injection of cisplatin. Cisplatin was injected intraperitoneally at 4 mg/kg body weight (B.W.) on day 0, 7 and 14 (total three injections). Experimental group was intubated with HemoHIM at a final concentration of 100 mg/kgB.W. by everyday from day -1 to day 16, while the control group received only water. The scheme of the administration procedure is summarized in Fig. 1. On day 17 after initial injection of cisplatin, all mice of each group were experimented, respectively, to evaluate tumor weight or tumor size. The tumor size was calculated as follows: tumor size = ab2/2, where a and b are the larger and smaller diameters, respectively.
Figure 1
The experimental schedule used for assessing the efficacy of HemoHIM in melanoma-bearing mice which were injected with cisplatin. B16F0 melanoma cells (5 × 105/mouse) were inoculated into subcutaneous femoral left region of mice 3 days before an initial injection of cisplatin. Cisplatin was intraperitoneally injected at 4 mg/kg B.W., and HemoHIM was daily given at 100 mg/kg B.W. from day -1 to day 16. On day 17 after initial injection of cisplatin, all mice of each group were experimented, respectively, to evaluate various parameters.
Melanoma cell growth assay in vitro
The effect of cisplatin and HemoHIM on the number of viable melanoma cells was assessed by CCK-8 (WST-8; Dojindo Lab, Kumamoto, Japan). The principle underlying the cell viability assessment by CCK-8 is based on the dehydrogenase activity detection in viable cells, similar with the principle of MTT. Briefly, the melanoma cells were seeded on to 96-well plates at a density of 7 × 103 cells per well in 100 μl of media. After incubation for 24 hours, cells were treated with various concentration of cisplatin and with HemoHIM 100 μg/ml for 24 hours. After incubation, a CCK-8 solution was added to each well. Cells were incubated at 37°C for two hours and the optical density was measured using microplate reader (Molecular Devices) at 450 nm (-Ref. 570 nm).
Preparation of lymphocyte in the spleen
Spleens were removed aseptically from the mice and a single cell suspension was prepared by mincing the spleen. The spleen lymphocytes were prepared by a density gradient centrifugation on a Ficoll-Hypaque solution (Sigma-Aldrich Co., St. Louis, MO, USA). All the cell suspensions were maintained in the RPMI 1640 media supplemented with 10% fetal bovine serum (FBS), 2 × 10-2 M HEPES buffer, 2 × 10-3 M L-glutamine, 1 × 10-3 M pyruvate, 100 U/ml penicillin, 50 μg/ml streptomycin, 5 × 10-5 M of 2-mercaptoethanol and 1% nonessential amino acid. All the supplements were purchased from GIBCO BRL (Grand Island, USA).
HemoHIM administration in MMC-treated tumor-bearing mice model
Firstly, harvested B16F0 melanoma was inactivated by mitomicin C (MMC) treatment (50 μg/ml, incubation for 40 minutes at 37°C water bath). MMC-treated B16F0 melanoma were inoculated intraperitoneally with 1 × 106 cells/mouse 3 days after an initial administration of HemoHIM. Experimental group was intubated with HemoHIM at a final concentration of 100 mg/kgB.W. by everyday from day -3 to day 4, while the control group was received only water. Ten days after cancer cell inoculation, spleen lymphocytes were prepared as effector cells to measure the activity of NK cells and Tc cells through Cr51-release assay.
Assay for NK cell and cytotoxic T (Tc) cell mediated cancer cell killing activity
YAC-1 tumor targets or B16F0 tumor targets were labeled with 51Cr-sodium chromate (Amersham Pharmacia Biotech, Kangnam-ku, Seoul, Korea) at a dose of 40 μCi/106 cells for 60 min to measured NK cell activity or Tc cell activity, respectively. The cells were washed three times in HBSS (Hank's Balanced Salt Solution; Sigma-Aldrich Co.) and resuspended to a final concentration of 2 × 105 cells/ml. Twenty thousand target cells and 106 or 2 × 106 spleen effector cells were plated into the wells of a 96-well U bottom plate. The plates were then incubated at 37°C for 4 hr in humidified air containing 5% CO2. Following a centrifugation at 350 g for 10 min, 100 μl of the supernatant was harvested from each well and counted for 1 min in a gamma counter (Wallac, Wellesley, MA, USA). The percent lysis was calculated as follows: % lysis = {[CPM (experimental) - CPM (spontaneous)]/[CPM (maximum) - CPM (sponstaneous)]} × 100.
Flow cytometry analysis of NK and Tc cells in spleen lymphocytes
The spleen lymphocytes were stained with fluorescent-labeled antibodies or isotype control antibodies in phosphate buffered saline (PBS). After staining for 30 minutes, the lymphocytes were washed three times with a fresh FACS media and then analyzed by flow cytometry (Backman Coulter, Miami, Florida, USA). A fluorescence histogram of at least 50,000 counts was analyzed in each sample. The following reagents from BD PharMingen (San Diego, CA, USA) were used: PE-conjugated anti-NK1.1 and FITC-conjugated anti-CD8.
Condition for a cytokine production in vitro
The spleen lymphocytes (2 × 106 cells/well) obtained from the mice were stimulated with concanavalin A (ConA) at 1 μg/ml for 1 or 2 days to measure IL-2 and IFN-γ level in supernatant.
Antibodies and the enzyme-linked immunosorbent assay (ELISA)
For the IL-2, clone JES6-1A12 was used as the capture Ab, and biotin-labelled JES6-5H4 was the detecting Ab. For the IFN-γ measurements, clone R4-6A2 was used as the capture Ab, and biotin-labeled XMG1.2 was the detecting Ab. All the antibodies as well as the recombinant IFN-γ and IL-2 were purchased from BD PharMingen (San Diego, CA, USA). Cytokines were determined by previously described ELISA method [26].
Histopathological examination of kidney by hematoxylin and eosin staining
Kidney from mice of each group on day 17 after initial injection of cisplatin was removed and fixed in 10% buffered formalin for 2 days. The paraffin-embedded sections (5 μm thick) were stained with hematoxylin and eosin (H&E) for histolpathological examination and observed under light microscope at × 200 magnifications.
Statistical analysis
Data were expressed as mean ± S.D. and a statistical significance was analyzed by using a Student's t-test. Differences with a p value of less than 0.05 were taken as significant, and considerable with a p value of less than 0.1.
Results
HemoHIM enhances the antitumor efficacy of cisplatin in tumor-bearing mice
To assess the effect of HemoHIM on tumor growth inhibition in cisplatin treated B16F0 melanoma-bearing mice, we used a tumor-bearing mice model that was summarized in Fig. 1. As shown in Fig. 2A and 2B, at 20 days after melanoma inoculation, the tumor weight and size of the control group without cisplatin and HemoHIM treatment were 6.093 g (± 2.28) and 12.6 mm3 (± 5.65), respectively. However, in the cisplatin-injected group, tumor weight (2.97 g (± 1.29)) and size (6.3 mm3 (± 2.32)) were reduced significantly in comparison to the control group. HemoHIM supplementation with cisplatin resulted in a further reduction in both the tumor weight (2.22 g (± 1.24)) and size (4.7 mm3 (± 2.93)). Only HemoHIM supplementation without cisplatin showed no reduction in tumor weight [6.15 g (± 1.238)] when compared with the control group (Data not shown). This suggests that HemoHIM itself did not show a reduction effect of tumor growth. Photographs are shown in Fig. 2C.
Figure 2
The inhibition of tumor growth was enhanced by HemoHIM administration in melanoma-bearing mice which were injected with cisplatin. All mice performed as described in figure 3 were sacrificed at 17 days after initial injection of cisplatin. Tumor weight (A) and size (B) were measured. (C) Photographs of melanoma solid tumor taken from all mice of each group. There were twenty mice in each group. Data show the Mean ± SD. *p < 0.1 compared with only cisplatin treated group.
HemoHIM enhances the activity of NK and Tc cells rather than directly killing cancer cells
The anticancer effect of cisplatin mainly depends on its DNA-damaging activity, via its direct interaction with DNA to form DNA adducts [27]. As shown in Fig. 3, cisplatin inhibited melanoma cell growth in a dose-dependent manner, with IC50 at about 15 μg/ml. However, HemoHIM itself did not inhibit melanoma growth in vitro (Data not shown), nor did it disturb the working of cisplatin in vitro (Fig. 3).
Figure 3
Growth inhibition effect of cisplatin and HemoHIM on melanoma cells in vitro. The melanoma cells were seeded at a density of 7 × 103 cells per well. After incubation for 24 hours, cells were treated with various concentration of cisplatin and with HemoHIM 100 μg/ml for 24 hours. After incubation, a CCK-8 solution was added to each well for 1 hour and then the optical density was measured.
Because HemoHIM did not directly kill cancer cells, we thought that the activity of immune cells which were in charge of tumor surveillance may be enhanced by HemoHIM. We investigated the cancer cell-killing activity of NK and Tc cells, as they are in charge of innate and adaptive immunity against tumor, respectively. To investigate the activity of Tc cell, we used the mice which were immunized with mitomycin C (MMC)-treated melanoma cells. As shown in Fig. 4A and 4B, HemoHIM administration enhanced cancer cell-killing activity of NK cells and Tc cells in MMC-treated melanoma cell-bearing mice (p < 0.05 and p = 0.06, respectively). Also, the proportion of NK cell in spleen lymphocytes was increased by HemoHIM administration (p < 0.05), but not the proportion of Tc cells. Specially, these results were important because NK cells take part in both innate and adaptive immunity, and are regarded as interfaces between the innate and adaptive immune systems [28].
Figure 4
Effect of HemoHIM on cancer cell killing activity of NK cells and Tc cells. C57BL/6 mice were orally administrated with HemoHIM (100 mg/kg B.W.) and injected with MMC-treated B16F0 melanoma (1 × 106cell/mouse) into peritoneal cavity. 10 days after cancer cell inoculation, the cancer cell killing activity of NK cells or Tc cells was determined by 51Cr release assay as described in Materials and Methods. There were six mice in each group. Data show the Mean ± SD. * p = 0.06 and ** p < 0.05 compared with mice administrated water.
The enhanced efficacy of cisplatin with HemoHIM in melanoma-bearing mice was due to increasing IL-2 and IFN-γ secretion and enhancing the activity of NK and Tc cells
As the mechanisms for an enhanced anticancer efficacy of cisplatin in combination with HemoHIM in melanoma cell-bearing mice (Fig. 1), we concentrated on the activity of NK and Tc cells because these cells play an important role on cancer surveillance. As shown Fig. 5A and 5B, cisplatin injection alone in melanoma-bearing mice did not enhance or decrease the activity of NK cells and Tc cells. However, HemoHIM administration enhanced the activity of NK cells in melanoma-bearing mice which were treated with cisplatin (p = 0.1; Fig. 5A). In addition, the activity of Tc cells was enhanced significantly by HemoHIM administration (p < 0.05; Fig. 5B). These data suggested that the enhanced anticancer efficacy of cisplatin in combination with HemoHIM administration was due to the increase in the activity of NK and Tc cells that are in charge of tumor surveillance.
Figure 5
HemoHIM administration promotes immune responses for tumor surveillance in melanoma-bearing mice which were injected with cisplatin. All mice performed as described in figure 3 were sacrificed at 17 days after initial injection of cisplatin. (A)(B) The cancer cell killing activity of NK cells or Tc cells was determined by 51Cr release assay as described in Materials and Methods. (C)(D) Spleen lymphocytes were cultured with ConA (1 μg/ml). After 1 or 2 days, IL-2 and IFN-γ in culture supernatants were measured by ELISA as described in Materials and Methods. There were twenty one mice in each group. The spleens of three mice were pooled. Bars show the means ± SD of the septuple experiments. * p = 0.1, **p < 0.05 and ***p < 0.001 compared with only cisplatin treated group.
Macrophages, dendritic cells, NK cells and Tc cells that are able to recognize, bind and subsequently kill tumor cells, were activated by cytokines such as IL-2 and IFN-γ. In our previous study, lymphocytes treated with HemoHIM alone enhanced the expression of IL-2 and IFN-γ in vitro (data not shown). Truly, IL-2 and IFN-γ are potent activators of NK cell and Tc cell effector functions. We therefore ascertained whether HemoHIM administration enhanced the production of IL-2 and IFN-γ in melanoma-bearing mice treated with cisplatin. HemoHIM administration significantly enhanced IL-2 (p < 0.001; Fig. 5C) and IFN-γ (p < 0.05; Fig. 5D) production in melanoma-bearing mice treated with cisplatin.
HemoHIM decreases the cisplatin-induced nephrotoxicity in tumor-bearing mice
Undesirable side effects of cisplatin appear in the kidney and liver, due to cisplatin accumulation in these organs [3]. As one of the mechanisms for cisplatin-induced toxicity is the enhanced production of ROS in these organs, we thought that HemoHIM may have a radical scavenging activity [20, 21], reducing cisplatin-induced damage. Experimental studies in animals have shown that a minimum dose of cisplatin (5 mg/kg body weight, i.p.) was sufficient to induce nephrotoxicity in rats [29, 30]. In this study, the cisplatin was injected at 4 mg/kg body weight three times once weekly. The nephrotoxicity was assessed using kidneys removed from mice on day 17 after an initial injection of cisplatin, and the representative result of each group is shown in Fig. 6. In the histopathological examination of the kidney, cisplatin destroyed renal tubular cells (Fig. 6). However HemoHIM administration reduced the destruction of renal tubular cells by cisplatin.
Figure 6
HemoHIM reduces the cisplatin-induce damage of kidney. Kidney from mice of each group on day 17 after initial injection of cisplatin was removed and fixed in 10% buffered formalin for 2 days. The paraffin-embedded sections (5 μm thick) were stained with hematoxylin and eosin (H&E) for histolpathological examination and observed under light microscope at × 200 magnifications. The result shown here is representative cortex from each group. (A) Control, cortex (× 200), (B) Cisplatin control, cortex (× 200), renal tubule cell destruction (marked by arrows), (C) Cisplatin+HemoHIM, cortex (× 200).
Discussion
HemoHIM is an herbal composition designed to protect the self-renewal tissues and to promote the recovery of the immune system against an oxidative stresses such as an irradiation. In this study, we examined the possibility of HemoHIM both to enhance the anticancer effect of cisplatin and to reduce its side effects in melanoma-bearing mice. In our previous studies, HemoHIM was tested for its efficacy as a radioprotective agent [20, 21]. Also, we investigated the effect of HemoHIM on a restoration of the immune functions which had been impaired in aged mice [31]. Besides, in our previous study, we showed that HemoHIM accelerated the recovery of immune cells in mice treated with cyclophosphamide, which is a well-known anticancer agent [32]. In this study, unlike cisplatin, HemoHIM alone did not directly kill the cancer cells. Nevertheless, our results showed that HemoHIM administration enhanced antitumor efficacy of cisplatin in melanoma-bearing mice.
Immune responses that are capable of killing tumor cells consist of dendritic cells, macrophages, NK cells and Tc cells. Tc cells may perform a surveillance function by recognizing and killing potentially malignant cells that express peptides derived from mutant cellular proteins or oncogenic viral proteins and presented in association with class I MHC molecules. NK cells kill many types of tumor cells, especially cells that have reduced class I MHC expression and can escape killing by Tc cells [33]. In vitro studies using cells from humans and several other mammalian species, as well as in vivo studies in mice and rats, have long suggested that tumor cells are recognized as NK cell targets [34]. Also, NK cells act as regulatory cells to influence various other cell types, such as dendritic cells, helper T (Th) cells, Tc cells and B cells [35]. Many studies for immuno-cancer therapy were focused on enhancing the activity of NK cells as well as Tc cells against tumor cells. In our data, cisplatin alone decreased tumor size, but did not enhance the activity of NK cells and Tc cells (Fig. 5). Also, HemoHIM alone without cisplatin did not enhance the activity of these cells (data not shown). However, HemoHIM administration with cisplatin injection increases the activity of NK cells and Tc cells in melanoma-bearing mice (Fig. 5A and 5B), while the tumor size was decreased by cisplatin. Thus, we suggest that the mechanism of action of cisplatin and HemoHIM in tumor-bearing mice differ.
IL-2 and IFN-γ are potent activators of NK cell and Tc cell effecter functions. For these reasons, cytokine therapies of malignant tumors using IL-2, IL-12, and IFN-γ have been investigated extensively in experimental and clinical studies [34]. It is also well known that IL-2 and IFN-γ promote tumor-reactive lymphocyte proliferation, cytotoxicity and, to some extent, cytokine secretion [36, 37, 38, 39, 40, 41]. IFN-γ is a pleiotropic immunoregulatory cytokine that has been used for clinical treatment of certain tumors [42, 43]. However, the clinical application of such cytokines has been hampered largely due to their undesirable side effects [44, 45]. In our data, HemoHIM administration with cisplatin injection increased the secretion of IL-2 and IFN-γ in melanoma-bearing mice.
Although cisplatin is an anticancer drug highly effective against several cancers, cisplatin is toxic to liver and kidney cells through producing ROS [1, 2, 3, 4, 30]. However, many studies to counter nephrotoxicity through the administration of antioxidants have been performed [8, 9, 10]. As HemoHIM was designed to protect the self-renewal tissues and to promote a recovery of the immune system against oxidative stresses [20, 21], we thought it may be able to decrease cisplatin-induced kidney damage. As expected, HemoHIM administration reduced nephrotoxicity as seen by tubular cell destruction of kidney.
Based on the overall these results, the possibility of HemoHIM both to enhance anticancer effect of cisplatin and to reduce its side effects in melanoma-bearing mice were ascertained. However, the protective efficacy of HemoHIM on cisplatin-induce damage in the kidney needs to be investigated further.
Conclusion
In conclusion, although the manner in which HemoHIM administration decreases cisplatin-induced kidney damage remains unknown, our results indicate that HemoHIM may be a useful complementary agent during cisplatin chemotherapy by enhancing the anti-tumor efficacy and reducing the toxicity of cisplatin.
Declarations
Acknowledgements
This work was conducted under a grant (M-2007-008) from Daedeok Innopolis R&BD Program and under a grant (2007-00091) from the Nuclear R&D program by Ministry of Education, Science & Technology of Korea.
Authors' original submitted files for images
Below are the links to the authors’ original submitted files for images.
12885_2008_1419_MOESM1_ESM.pdf Authors’ original file for figure 1
12885_2008_1419_MOESM2_ESM.pdf Authors’ original file for figure 2
12885_2008_1419_MOESM3_ESM.pdf Authors’ original file for figure 3
12885_2008_1419_MOESM4_ESM.pdf Authors’ original file for figure 4
12885_2008_1419_MOESM5_ESM.pdf Authors’ original file for figure 5
12885_2008_1419_MOESM6_ESM.pdf Authors’ original file for figure 6
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
HRP carried out making HemoHIM, the cell culture, Cr51-relaeas assay, animal experiments, and draft out the manuscript. EJJ performed the cell culture, ELISA analysis and histopathological examination. UHJ, SHK and STY participated in the design of study. SKJ conceived of the study, and participated in its design. All authors have read and approved the manuscript.
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Sunday, June 18, 2017
healthline
15 Ways to Avoid Depression
Depression can be severe and life-altering, affecting the quality of life and the happiness of those who live with it. It’s also a common condition. According to the Anxiety and Depression Association of America, it affects around 15 million Americans every year.
In some cases, it’s possible to prevent depression, even if you’ve already had a previous episode.
There are many lifestyle changes and stress management techniques you can use to prevent or avoid depression. There are certain triggers that can cause us to experience depressive episodes. While triggers may be different for everyone, these are some of the best techniques you can use to prevent or avoid depression relapse.
1. Exercise regularly
Exercising regularly is one of the best things you can do for your mental health. According to the Mayo Clinic, exercise can help in the treatment and prevention of depression in several key ways:
It increases your body temperature, which can have a calming effect on the central nervous system.
It releases chemicals like endorphins, which can boost mood.
It reduces immune system chemicals that may worsen depression.
All types of physical exercise can help treat depression, but it’s best to exercise regularly. To get more exercise, you can:
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Join a sports team or studio (like yoga or kickboxing), where you’ll be part of a community in addition to being active.
Take the stairs instead of the elevator.
Make it a habit: This is the best way to maintain the fitness level that is most effective in preventing depression.
Learn more about exercise, depression, and the brain »
2. Cut back on social media time
Research has shown that increased social media usage can cause or contribute to depression and low self-esteem. Social media can be addicting, and it’s a necessity to stay connected with family, friends, and even coworkers. It’s how we plan and invite each other to events and share big news.
However, limiting social media time can help prevent depression. You can do this by:
deleting all social apps from your phone
using website-blocking extensions that only let you use certain sites for a preset amount of time
only going to social media with a purpose and avoiding logging on several times a day just for something to do
3. Build strong relationships
Having a strong support system and an active social life is important for our mental health. Research has shown that having even “adequate” social support can protect against depression.
Make sure that you’re regularly connecting with friends and family, even when your lives are busy. Attending social events when you can and finding new hobbies that could help you meet new people can all help you build new relationships too.
4. Minimize your daily choices
Have you ever walked into a theme park and been overwhelmed at what you want to do first? Researchers think that having too many choices can actually cause significant stress that can lead to depression.
Psychologist Barry Schwartz, author of the book “The Paradox of Choice,” describes research that shows that when faced with too many choices, those who aim to make the best possible choice — “maximizers” — face higher rates of depression.
For many of us, our lives are filled with choices. Which outfit do we wear, and should we buy yogurt or eggs or bagels or English muffins or sausage for breakfast? The pressure of making the right — or wrong — choice is thought to contribute to depression.
If making choices stresses you out, simplify things. You can:
Learn to be decisive more quickly.
Reduce the decisions you’ll have to make during the work week: Plan out your outfits, and have your meals prepped and ready to go.
5. Reduce stress
Chronic stress is one of the most avoidable common causes of depression. Learning how to manage and cope with stress is essential for optimal mental health.
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To manage stress, you can:
Avoid overcommitting to things.
Practice mindfulness or meditation.
Learn to let things go that you can’t control.
Keep reading: The best meditation apps of the year »
6. Maintain your treatment plan
If you’ve already experienced one depressive episode, there’s a decent chance you’ll experience another. That’s why maintaining your treatment plan is so important.
This includes:
continuing prescription medications, and never stopping them abruptly
having “maintenance” visits with your therapist every so often when in remission
consistently practicing the strategies and coping mechanisms your therapist taught you
7. Get plenty of sleep
Getting plenty of high-quality sleep is necessary for both mental and physical health. According to the National Sleep Foundation, people with insomnia have a tenfold risk of developing depression compared to those who sleep well.
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To get better sleep, you can:
not look at any screens for two hours before bed (including your phone!)
meditate before bed
have a comfortable mattress
avoid caffeine after noon
8. Stay away from toxic people
We’ve all met that person who just makes us feel bad about ourselves. Sometimes they’re an outright bully, and other times they subtly put us down to make themselves feel better. They may even be someone who takes advantage of us. Regardless of the specific situation, toxic people should be avoided at all costs. They can lower our self-esteem.
One study from 2012 found that negative social interactions were linked to higher levels of two proteins known as cytokines. These two proteins are associated with inflammation as well as depression.
To avoid toxic people, you should:
Stay away from anyone who makes you feel worse about yourself.
Cut people out of your life who take advantage of you.
Know the signs. If someone spreads rumors or talks badly about someone as soon as they leave the room, they’re likely to do the same for you.
9. Eat well
Recent research has shown that regularly consuming a high-fat diet can have similar effects as chronic stress in terms of causing depression. In addition, an unhealthy diet can also deprive your body of vital nutrients it needs to maintain physical and mental health.
To prevent depression with your diet, you should:
Eat balanced meals with lean protein, and lots of fruits and vegetables.
Reduce high-sugar and high-fat foods.
Eliminate processed foods from your diet as much as possible.
Incorporate more omega-3s into your diet, with foods like salmon or nuts.
10. Maintain a healthy weight
Obesity can result in low self-esteem, especially once you start adding in the judgements and criticisms of other people. According to the Centers for Disease Control and Prevention, there is a clear correlation between being obese and experiencing depression. A national survey found that 43 percent of adults with depression were obese. Additionally, adults with depression were more likely to be obese than those without it.
If you’re exercising regularly, getting enough sleep, and eating well, maintaining a healthy weight should fall into place.
11. Manage chronic conditions
People with other chronic conditions have a higher risk of developing depression. Chronic conditions aren’t something that can be avoided, but in many cases, they can be managed.
You should:
Consult your doctor if your condition or symptoms get worse.
Follow your treatment plan carefully.
Take your medications and make lifestyle changes as recommended.
12. Read prescription medication side effects carefully
However, a number of different prescription medications can cause depression as a side effect. Read prescription labels carefully before taking them. You can talk to your doctor and see if other medications or treatments can resolve your condition without depression as a side effect.
A few medications that can cause depression include:
hormonal medications, like birth control pills
beta-blockers
corticosteroids
anticonvulsants
13. Reduce alcohol and drug use
The excessive use of alcohol and any drug use not only is associated with higher risks of depression, but also high risks of depression relapse. Limit alcohol intake, and eliminate any drug use as safely as possible.
Because limiting alcohol can be difficult in some social situations, you can:
Order an appetizer instead of a drink at happy hour.
Plan and invite friends to events where alcohol isn’t central.
Order cranberry juice; you don’t have to tell anyone it doesn’t have vodka in it.
Learn more about depression relapse »
14. Get off nicotine
Smoking and depression can perpetuate each other, though any type of nicotine can act as a depression trigger.
To stop smoking, you can:
Focus on your reason for quitting and remind yourself of this every time you’re tempted.
Know what to expect ahead of time.
Tell your friends and ask them to help hold you accountable.
Quit at the same time as a friend.
15 tips for quitting smoking »
15. Plan for unavoidable known triggers
There are some depression triggers, but if you know about them, you can plan for them. And that can help you cope preemptively. Examples of unavoidable depression triggers could be the anniversary of a death or a divorce, or knowing that you’ll see your ex and their new partner at your child’s school function.
To plan for these triggers, you can:
know that it’s coming up, and know what it will entail
have plans with a friend, or ask someone to check in with you
remind yourself that you will get through it
If you’re concerned, you can also make an appointment with your therapist for more tips to help manage it ahead of time.
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Medically Reviewed by Timothy J. Legg, PhD, CRNP on June 2, 2017 — Written by Ana Gotter
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