|Year : 2014 | Volume
| Issue : 3 | Page : 623-630
Solanum muricatum Ait. Inhibits inflammation and cancer by modulating the immune system
Kittappa Shathish, Chandrasekaran Guruvayoorappan
Department of Biotechnology, Karunya University, Coimbatore, Tamilnadu, India
|Date of Web Publication||14-Oct-2014|
Department of Biotechnology, Karunya University, Coimbatore, Tamilnadu
Source of Support: None, Conflict of Interest: None
Context: The pepino fruit Solanum muricatum Ait. (Solanaceae) is commonly known as melon pear and sweet cucumber grown in South America, New Zealand, and India. Traditionally, the fruits are used in the treatment of diabetes and cancer.
Aim: The objective of present study is to explore the immunomodulatory, anticancer, and anti-inflammatory activities of the methanol extract of S. muricatum fruits in experimental mice models.
Materials and Methods: Immunomodulatory activity of S. muricatum fruits was evaluated by assessing the relative organ weight, bone marrow cellularity, α-esterase activity, and by studying the phagocytic activity by carbon clearance test. The anti-tumor activity of the fruit extract was studied against Dalton's lymphoma ascites (DLA) cell line induced solid and ascites tumor models. The anti-inflammatory activity of the fruit extract was evaluated using carrageenan and formaldehyde models.
Statistical Analysis: The results were expressed as mean (±SD). Statistical analyses were performed using a one-way analysis of variance (ANOVA) followed by Dunnett's test using GraphPad Instat software. P values less than 0.05 were considered statistically significant.
Results: S. muricatum treatment could not only stimulate the immune system but also significantly (P < 0.01) inhibit the growth of transplantable tumor. The serum glutathione and γ-glutamyl transpeptidase (GGT) levels were found to be significantly decreased compared with tumor-bearing control animals. The increased tumor necrosis factor (TNF)-α level in tumor control (802.6 ± 12.0) was significantly (P < 0.01) decreased to 175.2 ± 16.5 after S. muricatum treatment. The TNF-α level in normal animals was found to be 21.0 ± 3.5 pg/ml. An increase in life span was observed after S. muricatum treatment. The extract also inhibited the edema induced by carrageenan and formaldehyde, respectively.
Conclusion: The results showed that the S. muricatum fruit extract has potent immunomodulatory, anticancer, and anti-inflammatory activities.
Keywords: Anti-inflammatory, anti-tumor, Dalton′s lymphoma ascites, immunomodulation, Solanum muricatum
|How to cite this article:|
Shathish K, Guruvayoorappan C. Solanum muricatum Ait. Inhibits inflammation and cancer by modulating the immune system. J Can Res Ther 2014;10:623-30
| > Introduction|| |
Malignancy is one of the most serious diseases that damage human health in the modern world and the second largest deadly disease just after heart disease. Cancer-related deaths will rank first in the industrialized countries in 2015.  There exists a close relationship between the occurrence, growth, and decline of tumor and the immune status.  The weak immune function of an organism may not only result in the generation and development of tumor, but also is one of the most important factors that prevent the recovery of the patients. Immunomodulation using synthetic or natural substances may be considered as an alternative for the prevention and cure of cancer.  The enhancement of host immune response has been recognized as a possible means of inhibiting tumor growth without harming the host.  Hence, it is very important to investigate novel antitumor substances with the potential to improve immunity.
Natural products remain a precious and largely unexplored reservoir from which novel anticancer compounds can be identified. , Wild fruits have captured the attention of some investigators on account of the exploitable bioactive constituents that they contain. The pepino fruit (Solanum muricatum Ait.) (Family Solanaceae), which is an exotic fruit, is also known as melon pear and sweet cucumber. The fruits are low in calories, very rich in minerals such as calcium, phosphorous, and potassium, and contain vitamins such as thiamin, niacin, riboflavin, and ascorbic acid, which are ideal for a number of metabolic and antioxidant reactions.  The ripened fruit can also be consumed as a dessert fruit, and as an ingredient of fruit salads, in juices, or in ice cream.  S. muricatum has long been recognized as an edible fruit with various medicinal uses owing to its antioxidant, antidiabetic, and hypotensive properties, and induction of apoptosis in tumor cell lines. ,, However, information on its effect on immune system, inflammation, and solid as well as ascitis tumor is limited. In this paper, therefore, we report the immunomodulatory, antitumor, and anti-inflammatory activities of S. muricatum methanol extract on experimental mice models.
| > Materials and methods|| |
Carrageenan and formaldehyde were purchased from Sigma (St Louis, MO, USA). Gum acacia was purchased from HiMedia, Mumbai, India. p-Rosaniline and Harris Hematoxylin were purchased from Loba Chemie, Mumbai, India. Standard drug methotrexate was purchased from Cipla, Mumbai, India. g-Glutamyl transpeptidase kit was purchased from Ecoline® , Merck, Mumbai. Tumor necrosis factor (TNF)-α kit was purchased from Biovision, California, USA. All the reagents used were of analytical reagent grade.
Male BALB/c mice (20-25 g) were procured from Small Animals Breeding Station, Veterinary College, Mannuthy, Trichur, India. The animals were fed with standard diet (Sai Durga Feeds, Bangalore, India) and water ad libitum. All the animal experiments were performed with the approval of Institutional Animal Ethics Committee (IAEC).
Dalton's lymphoma ascites (DLA) cells were obtained from Amala Cancer Research Centre, Trichur, India and were maintained in the laboratory animals as ascites tumor.
S. muricatum Ait. fruits were collected from Ooty. A specimen was deposited in the Department of Botany, MES Kalladi College, Mannarkkad. The fruits were shade-dried and powdered using pulverizer and were used for the extraction procedure.
The fruits were shade-dried, powdered (100 g), and extracted with 70% methanol at room temperature for 24 h using Soxhlet apparatus. Solvent was evaporated by rotary evaporation at 35°C.  The residue was lyophilized and the resulting dry powder was stored at 4°C. The yield of the extract was found to be 8% (w/w) relative to the dry starting material.
Gas chromatography (GC)/mass spectrometry (MS) analysis of the S. muricatum methanolic extract was performed using a GC-Trace Ultra VER: 5.0 (Thermo Scientific, Bremen, Germany). For MS detection, a Thermo MS DSQ II electron ionization mode with ionization energy of 70 eV and a mass range at m/z 50-650 was employed. A TR-5MS capillary standard column (30 m × 0.25 mm, film thickness 0.25 μm) was used for the GC/MS. The column temperature was programmed from 80°C to 250°C (rate = 8°C/min), with the lower and upper temperatures being held for 3 and 10 min, respectively. The GC injector and MS transfer line temperatures were set at 280°C and 290°C, respectively. All analyses were done in the split-less mode. An injection volume of 1 μl was used for analysis. Major and essential compounds were identified by their retention times and mass fragmentation patterns using the data of standards from the National Institute of Standards and Technology (NIST) Wiley 9.0 library (Ringoes, NJ, USA).
Male BALB/c mice were divided into two groups of six animals each. Group I served as normal untreated control. Group II was injected with S. muricatum (10 mg/kg b.wt.) for 10 consecutive days. Three animals from each group were sacrificed by cervical dislocation on day 10 and day 15, respectively. The spleen, thymus, lungs, liver, and kidney were dissected out and the relative organ weight was calculated using the equation R = (organ weight/body weight) × 100.
Male BALB/c mice were divided into two groups of six animals each. Group I served as normal untreated control. Group II were injected with S. muricatum (10 mg/kg b.wt.) for 10 consecutive days. Three animals from each group were sacrificed on day 10 and day 15, respectively. Bone marrow cells were flushed and collected from the femur bone of the animals using RPMI 1640 supplemented with 10% fetal calf serum. The bone marrow cellularity was estimated using hemocytometer counting. A smear of bone marrow cells were prepared on a clean microscopic slide and stained with p-rosaniline and Harris Hematoxylin to determine the α-esterase positive cells by the azodye coupling method. 
Phagocytic index was determined by carbon clearance test. BALB/c mice were divided into two groups of six animals each. Group I was kept as normal untreated control. Group II was injected with S. muricatum (10 mg/kg b.wt.) for 10 consecutive days. After 48 h of the last dose of the extract, all the animals were injected with 0.1 ml of Indian ink via the tail vein. Blood samples were withdrawn from the orbital vein at 0 and 15 min after injection. A 50 μl blood sample was mixed with 0.1% sodium carbonate (4 ml) and the absorbance of this solution was determined at 660 nm. The phagocytic index K was calculated using the equation K = ( In OD 1 - In OD 2 )/(t2 - t1 ), where OD 1 and OD 2 are the optical densities at time t1 and t2 , respectively.
BALB/c mice were divided into three groups (n = 6). Group I served as normal untreated control. Group II and group III BALB/c mice were injected with DLA cells (1 × 10 6 cells/mouse) into the right hind limb (intramuscular). Group I served as tumor control, whereas group II and group II were treated with methotrexate (3.5 mg/kg b.wt.) and S. muricatum (10 mg/kg b.wt.) [intraperitoneal (i.p.)], respectively, for 10 consecutive days starting from the same day of tumor implantation. The radii of the developing tumor were subsequently measured using vernier calipers at 3-day intervals for 1 month. Tumor volume was calculated using the equation V = [4/3]ßr 1 2r2 .  At the end of the experiment, the animals were sacrificed by cervical dislocation and the tumor was recovered and fixed in 10% formaldehyde for histopathologic studies.
BALB/c mice were divided into three groups (n = 6). Group I served as normal untreated control. Group II and group III BALB/c mice were injected with DLA cells (1 × 10 6 cells/mouse) into the peritoneal cavity (i.p.). Group II mice served as tumor control, whereas group III mice were treated with S. muricatum (10 mg/kg b.wt.) for 10 consecutive days starting from the same day of tumor implantation. Survival rate was observed and the percentage of increased life span (ILS%) was calculated according to the formula: ILS% = (T - C)/C × 100, where T represents the mean survival time of the treated animals and C represents the mean survival time of the control group. Based on the UN National Cancer Institute criteria, ILS exceeding 25% indicates that the drug has significant antitumor activity. 
Blood was collected from the tail vein on day 10 and day 15, respectively. Total WBC count (hemocytometer) and hemoglobin level (cyanmethemoglobin method) were estimated. The serum was separated by centrifugation and used for the estimation of nitric oxide,  glutathione,  and g-glutamyl transpeptidase (GGT) and TNF-α.
BALB/c animals were divided into two groups (n = 6/group). Group I was kept as normal untreated control, and mice in group II received the S. muricatum extract (10 mg/kg b.wt.) for 10 consecutive days (i.p.). The last dose was administered 60 min before the induction of inflammation. Subsequently, all mice received a subcutaneous injection of 0.1 ml of 1% (w/v) carrageenan solution in the plantar region of the right hind paw to induce edema. The paw volume was measured initially and then at 30 min intervals for up to 8 h after the injection, using a vernier caliper.
An additional set of BALB/c animals was divided into two groups (n = 6/group). Group I was kept as normal untreated control, and mice in group II received the S. muricatum extract (10 mg/kg b.wt.) for 10 consecutive days (i.p.). The last dose was administered 60 min before the induction of inflammation. Subsequently, all mice received a subcutaneous injection of 0.1 ml of a 2% (v/v) formaldehyde solution in the dorsal surface of their right hind paw. Diameters of the hind paw were first measured to obtain the baseline value before the injection; thereafter, measurement of dorsal plantar foot thickness (at metatarsal level) was performed on five consecutive days using a vernier caliper.
The results were expressed as mean (±SD). Statistical analyses were performed using a one-way analysis of variance (ANOVA) followed by Dunnett's test using GraphPad Instat (Version 3.0 for Windows 95; GraphPad Software, San Diego, CA, USA). P values less than 0.05 were considered statistically significant.
| > Results|| |
The GC/MS chromatogram of the methanolic extract of S. muricatum is shown in [Figure 1]. Relative retention times (R t ) and mass spectra of the extract components were compared with those of authenticated samples and with the mass spectra from a data library. As shown in [Table 1], analysis of the extract at Rt = 14.92 min resulted in the identification of 20 different compounds (with more similarity with the standard mass spectra in the library) representing 19.83% of the relative area in the methanolic extract. The extract was primarily characterized by the presence of 20 compounds [Table 1] such as methyl trans-2-(cyanomethyl) cyclobutylcarbamate, (2E)-4-hydroxy-3-methylbut-2enyl acetate, cyclohexanemethanol, 2-amino-, trans-, etc., [Figure 2].
|Figure 1: GC/MS chromatogram of the methanolic extract of S. muricatum using a Thermo GC Trace Ultra VER:5.0|
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|Figure 2: The chemical formula of methyl trans-2-(cyanomethyl) cyclobutylcarbamate, (2E)-4-hydroxy-3-methylbut-2enyl acetate, and cyclohexanemethanol, 2-amino-, trans|
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|Table 1: GC/MS analysis of the methanolic extract of S. muricatum at Rt=14.92 min (representing 19.83% of the relative area)|
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The effect of S. muricatum on body weight and relative organ weight is shown in [Table 2]. Treatment with the extract did not significantly affect the body weight throughout the experiment compared to the normal group. However, there was a marked increase in the relative organ weight of spleen, thymus, liver, lungs, and kidney to 22.80%, 25.92%, 4.25%, 8.57%, and 15.38%, respectively, after S. muricatum treatment, compared to normal animals.
The effect of S. muricatum on bone marrow cellularity and α-esterase-positive cells is shown in [Table 3]. Administration of S. muricatum showed a significant increase in bone marrow cellularity (31.4 × 10 6 cells/femur) (54.23%) compared to normal animals (14.37 × 10 6 cells/femur). Moreover, the number of α-esterase-positive cells was also found to be increased significantly in the extract-treated animals (1242 cells/4000 bone marrow cells) (32.85%) compared to the normal animals (834 cells/4000 bone marrow cells).
|Table 2: Effects of Solanum muricatum on body weight and relative organ weight on experimental animals|
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|Table 3: Effect of Solanum muricatumon bone marrow cellularity and ƒ¿-esterase activity of experimental animals|
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Effect of S. muricatum on the phagocytic activity determined by the carbon clearance test is shown in [Table 4]. The phagocytic activity of the reticuloendothelial system (RES) is generally measured by the rate of removal of carbon particles from the blood stream. In carbon clearance test, S. muricatum treated animals exhibited significantly high phagocytic index. The phagocytic index of S. muricatum treated animals showed significant (P < 0.01) increase in the phagocytic index (45%) compared to the animals in the control group. This indicates the stimulation of RES.
Tumor volume of solid tumor-bearing mice treated with the extract was found to be significantly decreased (P < 0.01) compared to tumor-bearing control animals [Figure 3]. Tumor volume of control animals was 2.52 mm 3 on day 30, whereas S. muricatum treatment could significantly decrease the volume to 0.78 mm 3 on the same day. The standard drug methotrexate also showed a significant (P < 0.01) reduction in tumor volume (0.88 mm 3 ) compared to control animals.
|Figure 3: Effect of S. muricatum on solid tumor development. Solid tumor was induced by injecting B16F-10 cells (1 × 106 cells) into the right hind limb (intramuscular) of the animals (six animals/group). Group I served as tumor control. Group II and group III animals were treated i.p. with 10 consecutive doses of methotrexate (3.5 mg/kg b.wt.) and S. muricatum (10 mg/kg b.wt.), respectively. Tumor volume was measured using vernier calipers every 3rd day starting from day 1 of tumor transplantation. Values are expressed as Mean ± SD of six animals per group. **P < 0.01 compared to tumor-bearing control animals|
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|Table 4: Effect of Solanum muricatum on phagocytic activity by carbon clearance test|
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The effect of S. muricatum on the survival time and increase in life span during ascitis tumor development is shown in [Table 5]. Treatment with the extract significantly increased the survival time from 16.66 to 30.42 days. The increase in life span was found to be 82.59%. The standard drug methotrexate increased the life span to 79.05%. A decrease in total WBC count and hemoglobin level was observed during tumor progression, compared to normal animals [Table 6]. On day 15, S. muricatum treatment significantly (P < 0.01 increased the total WBC count and hemoglobin level to 12,150 ± 530 cells/mm 3 and 15.20 ± 0.95 g/dl, respectively, compared with the tumor-bearing animals. The serum nitric oxide, glutathione, GGT, and TNF-α levels during ascites tumor development are shown in [Table 7]. The increased levels of serum nitric oxide (32.04 μM), glutathione (15.10 nmol/mg protein), GGT (27.40 U/l), and TNF-α (802.6 pg/ml) observed on day 15 were significantly decreased by S. muricatum treatment to 29.11 μM, 8.30 nmol/mg protein, 16.40 U/l, and 175.2 pg/ml, respectively.
|Table 5: Effect of Solanum muricatum on survival time and increase in life span during ascites tumor development|
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|Table 6: Effect of Solanum muricatum on total WBC count and hemoglobin levels during ascites tumor development|
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|Table 7: Effect of Solanum muricatum on serum nitric oxide, glutathione, γ-glutamyl transpeptidase, and TNF-α levels during ascites tumor development|
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The effect of S. muricatum on carrageenan- and formaldehyde-induced paw edema is shown in [Figure 4] and [Figure 5], respectively. Treatment with the extract showed marked reduction in the paw edema compared with control animals. The paw edema of control animals was found to be 0.37 mm after 1 h of carrageenan administration, which gradually increased to a peak of 0.50 mm by 3 rd hour followed by gradual reduction to 0.22 mm by 48 h. Treatment with S. muricatum did not show marked reduction in the early phase (1 h), but the paw edema was significantly decreased during the late phase. At the end of the experimental study (24 h), the paw edema in S. muricatum treated group was found to be 0.18 mm. Similarly, S. muricatum treated animals also showed significant reduction in paw edema induced by formaldehyde. On day 5, the paw edema in control group was found to be 0.42 mm, whereas S. muricatum treatment could significantly reduce the paw edema to 0.31 mm.
|Figure 4: Effect of S. muricatum on carrageenan-induced paw edema. Treated animals received 10 doses of S. muricatum methanol extract (10 mg/kg b.wt.). Subsequently, the normal untreated (control) and extract-treated hosts received subcutaneous injection (0.1 ml) of 1% (w/v) carrageenan solution in the right paw. Paw volumes were then measured initially and at 30 min intervals thereafter using a vernier caliper. Values shown are mean (±SD) of six mice per treatment group|
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|Figure 5: Effect of S. muricatum on formaldehyde-induced paw edema. Treated animals received 10 doses of S. muricatum methanol extract (10 mg/kg b.wt.). Subsequently, the normal untreated (control) and extract-treated hosts received subcutaneous injection (0.1 ml) of 2% (v/v) formaldehyde solution in the right paw. Paw volumes were then measured initially and for 5 consecutive days thereafter using a vernier caliper. Values shown are mean (±SD) of six mice per treatment group|
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| > Discussion|| |
The immune system is involved in the etiology as well as pathopysiologic mechanisms of several diseases. Modulation of immune responses has been shown to alleviate various diseases like cancer, atherosclerosis, arthritis, etc. , The present study shows that S. muricatum could stimulate the immune response, as evidenced by increased body weight, relative organ weight, bone marrow cellularity, and α-esterase activity. An increase in the phagocytic activity by carbon clearance test was also observed after S. muricatum treatment. The S. muricatum treated animals showed enhanced levels of bone marrow cellularity, which indicate that S. muricatum could stimulate the hematopoietic system. This observation is further supported by the increased number of α-esterase-positive cells, a marker of maturing monocytes. All the stem cells possess nonspecific esterase activity. During α-esterase staining, α-napthyl acetate is hydrolyzed to α-napthol by the esterase present in the monocytes. Sodium nitrate present in the stain acts as the coupler. The enzyme-substrate complex formed is stained using hematoxylin, and hence can be observed. It can be identified by the red-brown azo dye reaction product that is developed by the simultaneous coupling of hexazonium pararosaniline to α-naphthol. The increase in the number of bone marrow cells and differentiating stem cells with α-esterase activity in S. muricatum treated animals also shows the effect of S. muricatum on enhancing the immunological response. Moreover, the extract was found to increase the weight of spleen and thymus, indicating that S. muricatum could stimulate the production of immune cells.
Phagocytosis represents an important innate defense mechanism against ingested foreign materials.  Phagocytosis by macrophages is important against the smaller parasites, and its effectiveness is markedly enhanced by opsonization of parasites with antibodies and complement C3b, leading to more rapid clearance of the parasite from blood.  The term clearance has been employed for studies that measure the disappearance of a particle or immune complex from the circulation, depending upon the formation of intravascular complexes following the injection of an antigen, which are then more rapidly removed by the RES. Cells of the RES play important role in the clearance of particles from the blood stream. In carbon clearance test, the rate of clearance of carbon from blood by the phagocytic cells is governed by phagocytic index (K). Phagocytic index increases whenever there is an increase in the immune response.  In this study, the increase in phagocytic index as seen from the carbon clearance test after treatment with S. muricatum advocates its effect on macrophages and, therefore, on the subsequent stimulation of the immune system.
In DLA-bearing mice, a regular rapid increase in the ascites tumor volume was noticed. Ascites fluid is the direct nutritional source of the tumor cells, and a rapid increase in the ascetic fluid with tumor growth would be a means to meet the nutritional requirement for these cells.  The most reliable criterion for judging the value of any antitumor drug is the prolongation of the life span of the animals.  S. muricatum administration increased the percentage of life span (ILS%) of the ascites tumor-bearing animals. Similarly, administration of S. muricatum could also significantly inhibit the growth of solid tumor.
It has been reported, for instance, that many tumors can be considered glutathione (GSH) dependent, and it is suspected that cancer cells use GSH for protection against oxidative damage. Increased levels of GSH in tumors are related to chemotherapeutic effects and multidrug resistance.  Data obtained on the fluid of the DLA-inoculated mice revealed that the administration of S. muricatum decreased the GSH levels compared to non-treated tumor control mice. If we accept that the efficiency of chemotherapy is associated with a reduction of ascetic GSH content, it is reasonable to suppose that S. muricatum has an antiproliferative effect. Administration of S. muricatum reduced the serum GGT, an enzyme that catalyzes the transfer of g-glutamyl moieties from GSH to other aminoacids and dipeptides. 
The role of nitric oxide in tumor biology is ambiguous. Nitric oxide may induce vasodialation or, as a second messenger of other growth factors, give rise to enhanced permeability in tumor vasculature. In such cases, the blood flow in the tumor will be increased.  The enhanced nitric oxide levels act as a tumor promoter. S. muricatum significantly reduced the over-production of nitic oxide during tumor progression; hence, it can be considered an anti-tumor agent. The major sources of TNF-α are macrophages or tumor-associated macrophages and, to a lesser extent, T-lymphocytes, proliferating B cells, and natural killer (NK) cells.  TNF-α was found to be involved in the up-regulation of nitric oxide synthesis. , Administration of S. muricatum significantly reduced the dramatically enhanced TNF-α level on induction with DLA cells. Thus, the elevation of nitric oxide and TNF-α from normal levels is strictly pro-tumorigenic and the extract which could down-regulate these pro-tumorigenic factors can act as an anticancer agent.
It was reported that the anti-inflammatory effects of several agents result in the partial inhibition of inflammation-mediator release.  Subcutaneous injection of carrageenan into the mice paw produces plasma extravazation  and inflammation characterized by increased tissue water and plasma protein exudation with neutrophil extravasation and metabolism of arachidonic acid by both cyclooxygenase and lipoxygenase enzyme pathways.  The first phase begins immediately after injection and diminishes in 1 h. The second phase begins at 1 h and remains through 3 h.  It is suggested that early hyperemia of carrageenan-induced edema results due to the release of histamine and serotonin.  On the other hand, the delayed phase of carrageenan-induced edema results mainly from the potentiating effect of prostaglandins on mediator release, especially of bradykinin. This leads to a dilation of the arterioles and venules and to an increased vascular permeability. Hydrocortisone and some nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit strongly the second phase of carrageenan-induced edema, but some others are effective against both phases. , In the light of these data, S. muricatum extract seems more effective in the second phase of acute inflammation than in the first phase. Therefore, S. muricatum extract may block prostaglandin and/or bradykinin release better than histamine and/or serotonin release, and further studies on this are in progress in our laboratory.
Chronic inflammation is a long-lasting type of change that may persist for weeks, months, or even years, and is brought on by acute inflammation or may be the result of an autoimmune disease.  It is a pathological condition characterized by concurrent active inflammation, tissue destruction, and attempts at repair. In chronic inflammatory model, inhibition of formalin-induced paw edema in rats is considered as one of the most suitable test procedures to screen chronic anti-inflammatory agents, as it closely resembles rheumatoid arthritis.  It was also observed that S. muricatum could significantly inhibit formaldehyde-induced chronic inflammation. The results of the present study show that S. muricatum serves as a potent inhibitor for acute and chronic inflammation. The mechanism may depend upon inhibition of the formation of inflammatory mediators. Detailed studies are needed to clarify the mechanism of the anti-inflammatory effect of S. muricatum.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]