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Hepatocellular carcinoma (HCC) is often recognized as an inflammation-linked cancer, which possesses an immunosuppressive tumor microenvironment. Curative treatments such as surgical resection, liver transplantation, and percutaneous ablation are mainly applicable in the early stage and demonstrate significant improvement of survival rate in most patients. However, 70-80% of patients report HCC recurrence within 5 years of curative treatment, representing an important clinical issue. However, there is no effective recurrence marker after surgical and locoregional therapies, thus, tumor size, number, and histological features such as cancer cell differentiation are often considered as risk factors for HCC recurrence. Host immunity plays a critical role in regulating carcinogenesis, and the immune microenvironment characterized by its composition, functional status, and density undergoes significant alterations in each stage of cancer progression. Recent studies reported that analysis of immune contexture could yield valuable information regarding the treatment response, prognosis and recurrence. This review emphasizes the prognostic value of tumors associated with immune factors in HCC recurrence after curative treatment. In particular, we review the immune landscape and immunological factors contributing to early-stage HCC recurrence, and discuss the immunotherapeutic interventions to prevent tumor recurrence following curative treatments.

The survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts, and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also regulated AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression., Significance: Mutant HRAS drives metastasis of head and neck cancer by switching off the Hippo pathway to activate the YAP1-AXL axis and to stimulate lymphovascular angiogenesis., (©2023 American Association for Cancer Research.)

Melanoma is the most aggressive among all types of skin cancers. The current strategies against melanoma utilize BRAF V600E , as a focal point for targeted therapy. However, therapy resistance developed in melanoma patients against the conventional anti-melanoma drugs hinders the ultimate benefits of targeted therapies. A major mechanism by which melanoma cells attain therapy resistance is via the activation of microphthalmia-associated transcription factor-M (MITF-M), the key transcription factor and oncogene aiding the survival of melanoma cells. We demonstrate that tryptanthrin (Tpn), an indole quinazoline alkaloid, which we isolated and characterized from Wrightia tinctoria, exhibits remarkable anti-tumor activity towards human melanoma through the down-regulation of MITF-M. Microarray analysis of Tpn-treated melanoma cells followed by a STRING protein association network analysis revealed that differential expression of genes in melanoma converges at MITF-M. Furthermore, in vitro and in vivo studies conducted using melanoma cells with differential MITF-M expression status, endogenously or ectopically, demonstrated that the anti-melanoma activity of Tpn is decisively contingent on its efficacy in down-regulating MITF-M expression. Tpn potentiates the degradation of MITF-M via the modulation of MEK1/2-ERK1/2-MITF-M signaling cascades. Murine models demonstrate the efficacy of Tpn in attenuating the migration and metastasis of melanoma cells, while remaining pharmacologically safe. In addition, Tpn suppresses the expression of mutated BRAF V600E and inhibits Casein Kinase 2α, a pro-survival enzyme that regulates ERK1/2 homeostasis in many tumor types, including melanoma. Together, we point to a promising anti-melanoma drug in Tpn, by virtue of its attributes to impede melanoma invasion and metastasis by attenuating MITF-M., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The ethnomedicinal plant from the Cucurbitaceae family, Corallocarpus epigaeus , or its bioactive derivatives have been widely utilized in traditional medicine owing to their distinct applications against various human ailments and have lured the interest of ethnobotanists and biochemists. Here, we report for the first time, the anti-cancer potential of a bio-active fraction isolated from the dried rhizome of C. epigaeus , and the bioactive principle identified as cucurbitacin B (Cu-B). The purification processes involving the utilization of multiple organic extracts of C. epigaeus rhizome powder, yielded Cu-B from the Ethyl acetate Cytotoxic Fraction (ECF), obtained by the chromatographic separation of the ethyl acetate extract. Amongst the various cancer lines tested, melanoma cells exhibit maximal sensitivity towards the Cu-B-containing ECF fraction. Cu-B induces an apoptotic mode of cell death initiated intrinsically as well as extrinsically in A375 melanoma cells whilst remaining comparatively less toxic to normal skin fibroblasts. In vivo studies involving a NOD-SCID murine model of human melanoma demonstrate the ability of Cu-B to attenuate tumor growth, while being pharmacologically safe in vivo , as assessed in Swiss albino mice. Furthermore, Cu-B inhibits MEK 1/2 as well as the constitutive and EGF-induced ERK 1/2 activation, indicating a definitive involvement of MAPK signal transducers in regulating Cu-B-mediated anti-melanoma activity. Together, our study demonstrates the anti-melanoma potential of C. epigaeus -derived Cu-B, which indicates the Cucurbitaceae succulent as a prospective source for deriving potent and pharmacologically safe anti-cancer compounds., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Aiswarya, Vikas, Haritha, Liju, Shabna, Swetha, Rayginia, Keerthana, Nath, Reshma, Sundaram, Anto, Lankalapalli, Anto and Bava.)

Approximately 40% of human messenger RNAs (mRNAs) contain upstream open reading frames (uORFs) in their 5' untranslated regions. Some of these uORF sequences, thought to attenuate scanning ribosomes or lead to mRNA degradation, were recently shown to be translated, although the function of the encoded peptides remains unknown. Here, we show a uORF-encoded peptide that exhibits kinase inhibitory functions. This uORF, upstream of the protein kinase C-eta (PKC-η) main ORF, encodes a peptide (uPEP2) containing the typical PKC pseudosubstrate motif present in all PKCs that autoinhibits their kinase activity. We show that uPEP2 directly binds to and selectively inhibits the catalytic activity of novel PKCs but not of classical or atypical PKCs. The endogenous deletion of uORF2 or its overexpression in MCF-7 cells revealed that the endogenously translated uPEP2 reduces the protein levels of PKC-η and other novel PKCs and restricts cell proliferation. Functionally, treatment of breast cancer cells with uPEP2 diminished cell survival and their migration and synergized with chemotherapy by interfering with the response to DNA damage. Furthermore, in a xenograft of MDA-MB-231 breast cancer tumor in mice models, uPEP2 suppressed tumor progression, invasion, and metastasis. Tumor histology showed reduced proliferation, enhanced cell death, and lower protein expression levels of novel PKCs along with diminished phosphorylation of PKC substrates. Hence, our study demonstrates that uORFs may encode biologically active peptides beyond their role as translation regulators of their downstream ORFs. Together, we point to a unique function of a uORF-encoded peptide as a kinase inhibitor, pertinent to cancer therapy., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Background: The ongoing treatment modalities for breast cancer (BC) primarily rely on the expression status of ER, PR and HER-2 receptors in BC tissues. Our strategy of chemosensitization provides new insights to counter chemoresistance, a major obstacle that limits the benefits of chemotherapy of mammary cancers., Methods: By utilizing a murine breast cancer model employing NSG mice bearing orthotopic triple-negative breast cancer (TNBC) xenografts, we have evaluated the ability of phytochemical curcumin in chemosensitizing BC to 5-Fluorouracil (5-FU) chemotherapy and the differential modulations of cellular events in response to this strategy, independent of their receptor status., Results: A significant synergistic antitumor potential was observed in the murine model with a sub-optimal dose treatment of 5-FU plus curcumin, as evaluated by a reduction in the tumor-related parameters. We authenticated the pivotal role of thymidylate synthase (TS) in regulating the 5-FU-curcumin synergism using the TNBC pre-clinical model. Our study also confirmed the pharmacological safety of this chemotherapeutic plus phytoactive combination using acute and chronic toxicity studies in Swiss albino mice. Subsequently, the molecular docking analysis of curcumin binding to TS demonstrated the affinity of curcumin towards the cofactor-binding site of TS, rather than the substrate-binding site, where 5-FU binds. Our concomitant in vivo and in silico evidence substantiates the superior therapeutic index of this combination., Conclusion: This is the first-ever pre-clinical study portraying TS as the critical target of combinatorial therapy for mammary carcinomas and therefore we recommend its clinical validation, especially in TNBC patients, who currently have limited therapeutic options., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Haritha, Nawab, Vijayakurup, Anto, Liju, Alex, Amrutha, Aiswarya, Swetha, Vinod, Sundaram, Guijarro, Herlevich, Krishna, Nestory, Bava, Sadasivan, Zajac-Kaye and Anto.)

Purpose: The present study investigated the role of free curcuminoids bioavailability on the relative radioprotective efficacy of natural unformulated curcuminoids., Materials and Methods: A food-grade bioavailable formulation of curcuminoids as curcumagalactomannosides (CGM) and unformulated curcuminoids (UC) were employed for the study. Swiss albino mice were randomized into Normal control, Radiation control, Radiation + UC, and Radiation + CGM groups and irradiated with γ-radiation of 6, 8, 10 and 12 Gy. Survival rate, hematological and biochemical parameters, bone marrow cellularity, chromosomal aberrations and histopathology of intestine were followed as a measure of the relative efficacy. Results and Discussion: Oral administration with both UC and CGM at 100 mg/kg. b.wt. produced significant radioprotective effect over the untreated control group of animals. However, CGM treatment was found to provide better clastogenic and genotoxic potential as compared to UC. Further, the histopathology analysis of intestine confirmed the better protective effect of CGM over UC-treated animals., Conclusion: The present study demonstrated the positive role of the bioavailability of curcuminoids in the amelioration of radiation-induced damages in mice since CGM treatment exerted better survival rate and radioprotective effect as compared with UC, despite the relatively low concentrations of curcuminoids in CGM (39% w/w).

The rate of lung cancer incidence is alarmingly mounting, despite the decline of smoking and tobacco consumption. Recent reports indicate a very high correlation between the growing fast food culture and lung cancer incidence. Benzo[a]pyrene (B[a]P) is a potent carcinogen abundantly present in grilled and deep-fried food and in tobacco smoke. Our previous studies have proved the efficacy of curcumin in curbing B[a]P-induced lung carcinogenesis. However, the poor pharmacokinetic profile of the compound considerably hampers its potential as an effective chemopreventive. This study was intended to evaluate whether encapsulation of curcumin in chitosan nanoparticles can improve the cellular uptake and prolong the tissue retention of curcumin yielding better chemoprevention. The curcumin-loaded chitosan nanoparticles (chitosan nanocurcumin) exhibited a size of 170-200 nm in transmission electron microscopy. In vitro drug release studies showed sustained release of curcumin over a period of approximately 180 hours and excellent intracellular uptake and cytotoxicity in lung cancer cells. Bioavailability studies using healthy Swiss albino mice demonstrated drastic enhancement in lung localization of chitosan nanocurcumin compared with free curcumin. Toxicologic evaluation using chronic toxicity model in Swiss albino mice confirmed the pharmacologic safety of the formulation. Moreover, the formulation, even at a dose equivalent to one fourth that of free curcumin, exhibits better efficacy in reducing tumor incidence and multiplicity than free curcumin, thereby hampering development of B[a]P-induced lung adenocarcinomas in Swiss albino mice. Hence, our study underscores the supremacy of the formulation over free curcumin and establishes it as a potential chemopreventive and oral supplement against environmental carcinogenesis., (©2019 American Association for Cancer Research.)

Radioprotective effects of ginger essential oil (GEO) on mortality, body weight alteration, hematological parameters, antioxidant status and chromosomal damage were studied in irradiated mice. Regression analysis of survival data in mice exposed to radiation yielded LD50/30 as 7.12 and 10.14 Gy for control (irradiation alone) and experimental (GEO-treated irradiated) mice, respectively, with a dose reduction factor (DRF) of 1.42. In mice exposed to whole-body gamma-irradiation (6 Gy), GEO pre-treatment at 100 and 500 mg/kg b.wt (orally) significantly ameliorated decreased hematological and immunological parameters. Radiation induced reduction in intestinal tissue antioxidant enzyme levels such as superoxide dismutase, catalase, glutathione peroxidase and glutathione was also reversed following administration of GEO. Tissue architecture of small intestine which was damaged following irradiation was improved upon administration of GEO. Anticlastogenic effects of GEO were studied by micronuclei assay, chromosomal aberration and alkaline gel electrophoresis assay. GEO significantly decreased the formation of micronuclei, increased the P/N ratio, inhibited the formation of chromosomal aberrations and protected agaisnt cellular DNA damage in bone marrow cells as revealed by comet assay. These results are supportive of use of GEO as a potential radioprotective compound.

Background: Turmeric (Curcuma longa) and ginger (Zingiber officianale) are widely used in Asian countries as traditional medicine and food ingredients. In the present study, we have evaluated the gastroprotective activity of turmeric essential oil (TEO) and ginger essential oil (GEO) in rats., Methods: Turmeric and ginger were evaluated for their antiulcer activity against ethanol-induced ulcers in male Wistar rats at different doses: 100, 500 and 1000 mg/kg body weight. Ethanol was used to induce gastric ulcer in Wistar rats. Parameters such as ulcer index, histopathology and levels of antioxidant enzymes such as glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase and glutathione (GSH) levels were measured to assess the degree of protection produced by the essential oils., Results: TEO and GEO inhibited ulcer by 84.7% and 85.1%, respectively, as seen from the ulcer index. Reduced antioxidant enzymes such as GPx, SOD, catalase and GSH produced by alcohol administration were significantly (p<0.001) increased by simultaneous administration of TEO and GEO. Histopathological examination showed that ethanol-induced lesions such as necrosis, erosion and hemorrhage of the stomach wall were significantly reduced after oral administration of essential oils., Conclusions: RESULTS suggest that TEO and GEO could reduce the gastric ulcer in rat stomach as seen from the ulcer index and histopathology of the stomach. Moreover, oxidative stress produced by ethanol was found to be significantly reduced by TEO and GEO.

In spite of the various bioavailable formulations of curcumin for pharma and dietary supplement applications, food grade formulations suitable as a dietary ingredient, and capable of providing significant levels of plasma curcumin, are limited. The present contribution describes the safety and oral bioavailability of a novel water soluble formulation of curcumin, curcumagalactomannosides (CGM), when used as a dietary ingredient in selected food items. CGM was prepared using a food grade hydrocolloid (galactomannans) derived from the kitchen spice fenugreek (Trigonella foenum graccum), without using any synthetic excipients. The safety of the formulation was assessed through acute and subchronic toxicity studies on Wistar rats and genotoxicity studies. The efficacy of CGM as a bioavailable dietary ingredient was assessed by successfully preparing various food items and by measuring the post-blood plasma curcumin levels at various time intervals after the consumption of food items. High performance liquid chromatography coupled with a photodiode array detector (HPLC-PDA) and electrospray ionization tandem mass spectrometer (ESI-MS/MS) was employed for the quantification of plasma curcuminoids. It was observed that CGM is safe and suitable for further development and clinical studies, with a no observable adverse effect level (NOAEL) up to 2.0 g kg⁻¹ per day b.wt. CGM was found to offer seven to ten times higher bioavailability of curcumin in humans, when incorporated into various food/beverage items at 100 mg CGM per serving size, as compared to the standard unformulated curcumin.

Essential oil extracted from ginger (GEO) was evaluated for its mutagenicity to Salmonella typhimurium TA 98, TA 100, TA 102, and TA 1535 strains with and without microsomal activation. GEO was found to be non-mutagenic up to a concentration of 3 mg/plate. It was also assessed for antimutagenic potential against direct acting mutagens such as sodium azide, 4-nitro-o-phenylenediamine, N-methyl-N'-nitro-N-nitrosoguanidine, tobacco extract, and 2-acetamidoflourene, which needs microsomal activation. GEO significantly inhibited (p < 0.001) the mutagenicity induced by these agents in a concentration-dependent manner. The effect of GEO to modulate the action of phase I carcinogen-metabolizing enzymes was investigated by studying its effect on various isoforms of microsomal cytochrome P450 enzymes. Significant inhibition of CYP1A1, CYP1A2, and CYP2B1/2, aniline hydroxylase (an indicator of CYP2E1 activity), and aminopyrine-N-demethylase (indicator of CYP1A, 2A, 2B, 2D, and 3A activity) was shown by GEO both in vitro and in vivo. GEO gave an IC50 value of 30, 57.5, and 40 µg for CYP1A1, CYP1A2, and CYP2B1/2, respectively, 55 µg for aniline hydroxylase, and 37.5 µg for aminopyrene-N-demethylase. GEO also significantly increased the levels of phase II carcinogen-metabolizing enzymes uridine 5'-diphospho-glucuronyl transferase and glutathione-S-transferase in vivo indicating the use of GEO as an antimutagen and as a potential chemopreventive agent., (Copyright © 2013 John Wiley & Sons, Ltd.)

This study aimed to evaluate the antimutagenic and anticarcinogenic activity of turmeric essential oil as well as to establish biochemical mechanisms of action. Antimutagenicity testing was accomplished using strains and known mutagens with and without microsomal activation. Anticarcinogenic activity was assessed by topical application of 7, 12 - dimethylbenz[a]anthracene (DMBA) as initiator and 1% croton oil as promoter for the induction of skin papillomas in mice. Inhibition of p450 enzymes by TEO was studied using various resorufins and aminopyrene as substrate. Turmeric essential oil (TEO) showed significant antimutagenic activity (p<0.001) against direct acting mutagens such as sodium azide (NaN3), 4-nitro-O-phenylenediamine (NPD) and N-methyl- N-nitro N'nitrosoguanine (MNNG). TEO was found to have significant antimutagenic effect (>90%) against mutagen needing metabolic activation such as 2-acetamidoflourene (2-AAF). The study also revealed that TEO significantly inhibited (p<0.001) the mutagenicity induced by tobacco extract to Salmonella TA 102 strain. DMBA and croton oil induced papilloma development in mice was found to be delayed and prevented significantly by TEO application. Moreover TEO significantly (P<0.001) inhibited isoforms of cytochrome p450 (CYP1A1, CYP1A2, CYP2B1/2, CYP2A, CYP2B and CYP3A) enzymes in vitro, which are involved in the activation of carcinogens. Results indicated that TEO is antimutagenic and anticarcinogenic and inhibition of enzymes (p450) involved in the activation of carcinogen is one of its mechanisms of action.

The present study investigated the acute, subchronic and genotoxicity of turmeric essential oil (TEO) from Curcuma longa L. Acute administration of TEO was done as single dose up to 5 g of TEO per kg body weight and subchronic toxicity study for thirteen weeks was done by daily oral administration of TEO at doses 0.1, 0.25 and 0.5 g/kg b.wt. in Wistar rats. There were no mortality, adverse clinical signs or changes in body weight; water and food consumption during acute as well as subchronic toxicity studies. Indicators of hepatic function such as aspartate aminotransferase (AST), alanine amino transferase (ALT) and alkaline phosphatase (ALP) were unchanged in treated animals compared to untreated animals. Oral administration of TEO for 13 weeks did not alter total cholesterol, triglycerides, markers of renal function, serum electrolyte parameters and histopathology of tissues. TEO did not produce any mutagenicity to Salmonella typhimurium TA-98, TA-100, TA-102 and TA-1535 with or without metabolic activation. Administration of TEO to rats (1 g/kg b.wt.) for 14 days did not produce any chromosome aberration or micronuclei in rat bone marrow cells and did not produce any DNA damage as seen by comet assay confirming the non toxicity of TEO., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Chemical compositions of ginger oil as well as its antioxidant, anti-inflammatory and antinociceptive potential were evaluated in the present study. The main constituents as detected by GC/MS analysis was alpha-zingiberene which constituted 31% of the total area, ar-curcumene (15.4%) and a -sesquiphellandrene (14.02%). Ginger oil scavenged superoxide, DPPH, hydroxyl radicals and inhibited tissue lipid peroxidation in vitro. Intraperitoneal administration of ginger oil was found to inhibit phorbol-12-myristate-13-acetate induced superoxide radicals elicited by macrophages. Oral administration of ginger oil for one month, significantly increased superoxide dismutase, glutathione and glutathione reductase enzymes level (P < 0.001) in blood of mice and glutathione-S-transferase, glutathione peroxidase and superoxide dismutase enzymes in liver. Ginger oil produced significant reduction in acute inflammation produced by carrageenan and dextran and formalin induced chronic inflammation (P < 0.001). It also exhibited significant reduction in acetic acid induced writhing movements (P < 0.001). The present report revealed that ginger oil possesses antioxidant activity as well as significant anti-inflammatory and antinociceptive property.

Zingiber officinale Roscoe, ginger, is a major spice extensively used in traditional medicine. The toxicity profile of ginger oil was studied by subchronic oral administration for 13 weeks at doses of 100, 250, and 500 mg/kg per day to 6 groups of Wistar rats (5/sex per dose). Separate groups of rats (5/sex per group) received either paraffin oil (vehicle) or were untreated and served as comparative control groups. There was no mortality and no decrease in body weight or food consumption as well as selective organ weights during the study period. Administration of ginger oil to rats did not produce any treatment-related changes in hematological parameters, hepatic, renal functions, serum electrolytes, or in histopathology of selected organs. The major component of ginger oil was found to be zingiberene (31.08%), and initial studies indicated the presence of zingiberene in the serum after oral dosing. These results confirmed that ginger oil is not toxic to male and female rats following subchronic oral administrations of up to 500 mg/kg per day (no observed adverse effect level [NOAEL]).

Objectives: This study was aimed to evaluate the chemical composition, antioxidant potential in vitro and in vivo, anti-inflammatory, and antinociceptive activity of turmeric oil., Materials and Methods: Chemical analysis of turmeric oil was done by gas chromatography/mass spectrometry. Antioxidant activities in vitro was done by six different methods and in vivo antioxidant activity was determined by measuring superoxide generation from macrophages treated with phorbol-12-myristate-13-acetate (PMA) as well as determining antioxidant level after feeding the oil orally for one month. Anti-inflammatory activity was studied in mice using carrageenan, dextran, and formalin. Antinociceptive activity was evaluated by using acetic acid-induced writhing movement in mice., Results: The main constituent of essential oil of turmeric was found to be ar-turmerone (61.79%), curlone (12.48%), and ar-curcumene (6.11%). Turmeric oil was found to have in vitro antioxidant activity and IC(50) for scavenging superoxides, hydroxyl radicals, and lipid peroxidation were 135 μg/ml, 200 μg/ml, and 400 μg/ml, respectively. The ferric-reducing activity for 50 μg of turmeric essential oil was found to be 5 mM. Intraperitoneal administration of oil was found to inhibit PMA-induced superoxide radicals elicited by macrophages. Oral administration of turmeric oil for one month to mice significantly increased superoxide dismutase, glutathione, and glutathione reductase enzyme levels in blood and glutathione-S-transferase and superoxide dismutase enzymes in liver. Turmeric oil showed significant reduction in paw thickness in carrageenan, dextran-induced acute inflammation, and formalin-induced chronic inflammation. The drug produced significant antinociceptive activity (P < 0.001) at all doses studied., Conclusions: These results demonstrated that turmeric oil has potential health benefits as it can scavenge the free radicals and produce significant anti-inflammatory and antinociceptive activities.