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In our previous laboratory findings, Cyathocalyx pruniferus extracts exhibited platelet-activating factor inhibition, suggesting their anti-inflammatory potential. Hence, this study was designed with the aim to isolate phyto-constituents from C. pruniferus with potent anti-inflammatory activities. Column and volume liquid chromatography were used for isolation of phyto-constituents. The structure elucidation was carried out using spectroscopic analysis (HRESI-MS, 1H and 13C-NMR) and compared with published literature. For cytotoxicity analysis, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide assay was performed on peripheral blood mononuclear cells. Anti-inflammatory activities were evaluated against the levels of inflammatory cytokines (IL-1ß and IL-6), prostaglandin-E2 (PGE2) and cyclooxegenase-2 (COX-2), in lipopolysaccharide (LPS)-induced human plasma using ELISA and radioimmunoassay (RIA). The chromatographic purification of methanol leaves extract afforded 13 (1-13) secondary metabolites. Additionally, cytotoxicity analysis suggested that isolates were non-cytotoxic at 100 µM. In anti-inflammatory evaluation, 2-octaprenyl-1, 4-benzoquinone (5) produced strong (≥ 70%) inhibition of PGE2, COX-2, IL-1ß and IL-6 at 50 µM. Moreover, 2-octaprenyl-1,4-benzoquinone (5) exhibited concentration-dependent inhibition with IC50 values (µM) of 11.21, 6.61, 2.20 and 3.56 as compared to controls; indomethacin for PGE2 (11.84) and dexamethasone in COX-2 (5.19), IL-1ß (1.83) and IL-6 (3.76) analysis, respectively. In conclusion, two new compounds including 2-octaprenyl-1, 4-benzoquinone (5) and 14-methyloctadec-1-ene (6) are reported for the first time from plant species. Additionally, 2-octaprenyl-1, 4-benzoquinone (5) dose-dependently suppressed the production of pro-inflammatory mediators involved in acute and chronic inflammation at non-cytotoxic concentrations.
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Annonaceae , Benzoquinonas/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Citocinas/antagonistas & inibidores , Dinoprostona/antagonistas & inibidores , Mediadores da Inflamação/antagonistas & inibidores , Extratos Vegetais/farmacologia , Benzoquinonas/isolamento & purificação , Benzoquinonas/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Inibidores de Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Dinoprostona/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/toxicidade , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/metabolismo , Prenilação/fisiologiaRESUMO
Lycopene is a well-known compound found commonly in tomatoes which brings wide range of health benefits against cardiovascular diseases and cancers. From an anti-cancer perspective, lycopene is often associated with reduced risk of prostate cancer and people often look for it as a dietary supplement which may help to prevent cancer. Previous scientific evidence exhibited that the anti-cancer activity of lycopene relies on its ability to suppress oncogene expressions and induce proapoptotic pathways. To further explore the real potential of lycopene in cancer prevention, this review discusses the new insights and perspectives on the anti-cancer activities of lycopene which could help to drive new direction for research. The relationship between inflammation and cancer is being highlighted, whereby lycopene suppresses cancer via resolution of inflammation are also discussed herein. The immune system was found to be a part of the anti-cancer system of lycopene as it modulates immune cells to suppress tumor growth and progression. Lycopene, which is under the family of carotenoids, was found to play special role in suppressing lung cancer.
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Antineoplásicos Fitogênicos/uso terapêutico , Suplementos Nutricionais , Licopeno/uso terapêutico , Neoplasias da Próstata/prevenção & controle , Solanum lycopersicum/química , Antineoplásicos Fitogênicos/química , Humanos , Licopeno/química , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologiaRESUMO
The therapeutic efficacy of the contemporary anti-inflammatory drugs are well established; however, prolonged use of such can often lead to serious and life-threatening side effects. Natural product-based anti-inflammatory compounds with superior efficacy and minimum toxicity can serve as possible therapeutic alternatives in this scenario. Genus Uvaria is a part of Annonaceae family, while the majority of its species are widely distributed in tropical rain forest regions of South East Asia. Uvaria species have been used extensively used as traditional medicine for treating all sorts of inflammatory diseases including catarrhal inflammation, rheumatism, acute allergic reactions, hemorrhoids, inflammatory liver disease and inflamed joints. Phytochemical analysis of Uvaria species has revealed flavones, flavonoids, tannins, saponins, polyoxygenated cyclohexene and phenolic compounds as major phyto-constituents. This review is an attempt to highlight the anti-inflammatory activity of Uvaria species by conducting a critical appraisal of the published literature. The ethnopharmacological relevance of Uvaria species in the light of toxicological studies is also discussed herein. An extensive and relevant literature on anti-inflammatory activity of Uvaria species was collected from available books, journals and electronic databases including PubMed, ScienceDirect, Scopus, Proquest and Ovid. Extracts and isolates of Uvaria species exhibited significant anti-inflammatory activity through various mechanisms of action. 6,7-di-O-Methyl-baicalein, flexuvarol B, chrysin, (-)-zeylenol, 6-hydroxy-5,7-dimethoxy-flavone, and pinocembrin were the most potent anti-inflammatory compounds with comparable IC50 with positive controls. Therefore, it is suggested that further research should be carried out to determine the pharmacokinetics, pharmacodynamics and toxicity of these therapeutically significant compounds, to convert the pre-clinical results into clinical data for drug development and design.
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Inflamação/tratamento farmacológico , Extratos Vegetais/farmacologia , Uvaria/química , Animais , Anti-Inflamatórios/farmacologia , Humanos , Medicina Tradicional/métodos , Compostos Fitoquímicos/farmacologia , Fitoterapia/métodosRESUMO
Inflammation drives coronary artery disease and atherosclerosis implications. Lipoprotein entry, retention, and oxidative modification cause endothelial damage, triggering innate and adaptive immune responses. Recruited immune cells orchestrate the early atherosclerotic lesions by releasing proinflammatory cytokines, expediting the foam cell formation, intraplaque haemorrhage, secretion of matrix-degrading enzymes, and lesion progression, eventually promoting coronary artery syndrome via various inflammatory cascades. In addition, soluble mediators disrupt the dynamic anti- and prothrombotic balance maintained by endothelial cells and pave the way for coronary artery disease such as angina pectoris. Recent studies have established a relationship between elevated levels of inflammatory markers, including C-reactive protein (CRP), interleukins (IL-6, IL-1ß), and tumour necrosis factor-alpha (TNF-α) with the severity of CAD and the possibility of future cardiovascular events. High-sensitivity C-reactive protein (hs-CRP) is a marker for assessing systemic inflammation and predicting the risk of developing CAD based on its peak plasma levels. Hence, understanding cross-talk interactions of inflammation, atherogenesis, and CAD is highly warranted to recalculate the risk factors that activate and propagate arterial lesions and devise therapeutic strategies accordingly. Cholesterol-inflammation lowering agents (statins), monoclonal antibodies targeting IL-1 and IL-6 (canakinumab and tocilizumab), disease-modifying antirheumatic drugs (methotrexate), sodium-glucose transport protein-2 (SGLT2) inhibitors, colchicine and xanthene oxidase inhibitor (allopurinol) have shown promising results in reducing inflammation, regressing atherogenic plaque and modifying the course of CAD. Here, we review the complex interplay between inflammatory, endothelial, smooth muscle and foam cells. Moreover, the putative role of inflammation in atherosclerotic CAD, underlying mechanisms and potential therapeutic implications are also discussed herein.
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Aterosclerose , Doença da Artéria Coronariana , Humanos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/tratamento farmacológico , Proteína C-Reativa , Interleucina-6 , Células Endoteliais/metabolismo , Aterosclerose/metabolismo , Inflamação/complicações , Inflamação/tratamento farmacológicoRESUMO
Lung cancer is the one of the most prevalent cancer in the world. It kills more people from cancer than any other cause and is especially common in underdeveloped nations. With 1.2 million instances, it is also the most prevalent cancer in men worldwide, making about 16.7% of the total cancer burden. Surgery is the main form of curative treatment for early-stage lung cancer. However, the majority of patients had incurable advanced non-small cell lung cancer (NSCLC) recurrence after curative purpose surgery, which is indicative of the aggressiveness of the illness and the dismal outlook. The gold standard of treatment for NSCLC patients includes drug targeting of specific mutated genes drive in development of lung cancer. Furthermore, patients with advanced NSCLC and those with early-stage illness needing adjuvant therapy should use cisplatin as it is the more active platinum drug. So, this review encompasses the non-small cell lung cancer microenvironment, treatment approaches, and use of cisplatin as a first-line regimen for NSCLC, its mechanism of action, cisplatin resistance in NSCLC and also the prevention strategies to revert the drug resistance.
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Carcinoma Pulmonar de Células não Pequenas , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Terapia de Alvo MolecularRESUMO
Partial and full PPAR-γ agonists have shown promising effects and antihypertensive and antidiabetic agents through increased plasma adiponectin concentration. This study is aimed at examining the role of PPAR-γ, alpha-adrenoceptors, and adiponectin receptors in the modulation of vasopressor responses to angiotensin II (Ang II) and adrenergic agonists, after a subset treatment of partial and full PPAR-γ agonists, each individually, and also when coupled with adiponectin in SHRs. The antioxidant potential and metabolic indices for these animals were also determined. Group I (WKY) and group II (SHR) were designated as normotensive control and hypertensive control, respectively. Groups III (SHR) and IV (SHR) received irbesartan (30 mg/kg) and pioglitazone (10 mg/kg) orally for 28 days, and groups V (SHR), VI (SHR), and VII (SHR) were treated with adiponectin (2.5 µg/kg) intraperitoneally alone, in combination with irbesartan, and in combination with pioglitazone, respectively, from days 21 to 28 only. On day 29, sodium pentobarbitone (60 mg/kg) was used to anesthetize all test animals, and systemic hemodynamic and plasma adiponectin concentrations and in vitro and in vivo antioxidant potential were measured. As compared to the WKY control, the SHR control group's noninvasive blood pressure and basal mean arterial pressure were significantly greater, along with increased arterial stiffness, lower plasma nitric oxide, adiponectin concentration, and antioxidant enzyme levels (all P < 0.05). However, they were gradually normalized by single drug treatments in all groups, and to a greater extent in the SHR + Irb + Adp group (P < 0.05). In the acute study, the dose dependant mean arterial pressure responses to intravenously administered adrenergic agonists and angiotensin-II were significantly larger in SHRs as compared to WKY by 20-25%. Adiponectin alone and in combination significantly blunted vasopressor responses to these alpha-adrenergic agonists in the SHR + Pio + Adp group by 63%, whereas attenuated responses to ANG-II administration to 70% in SHR + Irb + Adp. In conclusion, the combined treatment of adiponectin with PPAR-agonists reduced the systemic vascular responses to adrenergic agonists and improved arterial stiffness. This an evidence of the interaction of adiponectin receptors, PPAR-γ, alpha-adrenoceptors, and ANG-II in the systemic vasculature of SHRs. A significant level of synergism has also been proved among full PPAR-γ agonists and adiponectin receptors.
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Unresolved inflammation is a pathological consequence of persistent inflammatory stimulus and perturbation in regulatory mechanisms. It increases the risk of tumour development and orchestrates all stages of tumorigenesis in selected organs. In certain cancers, inflammatory processes create the appropriate conditions for neoplastic transformation. While in other types, oncogenic changes pave the way for an inflammatory microenvironment that leads to tumour development. Of interest, hallmarks of tumour-promoting and cancer-associated inflammation are striking similar, sharing a complex network of stromal (fibroblasts and vascular cells) and inflammatory immune cells that collectively form the tumour microenvironment (TME). The cross-talks of signalling pathways initially developed to support homeostasis, change their role, and promote atypical proliferation, survival, angiogenesis, and subversion of adaptive immunity in TME. These transcriptional and regulatory pathways invariably contribute to cancer-promoting inflammation in chronic inflammatory disorders and foster "smouldering" inflammation in the microenvironment of various tumour types. Besides identifying common target sites of numerous cancer types, signalling programs and their cross-talks governing immune cells' plasticity and functional diversity can be used to develop new fate-mapping and lineage-tracing mechanisms. Here, we review the vital molecular mechanisms and pathways that establish the connection between inflammation and tumour development, progression, and metastasis. We also discussed the cross-talks between signalling pathways and devised strategies focusing on these interaction mechanisms to harness synthetic lethal drug combinations for targeted cancer therapy.
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Increased production and buildup of reactive oxygen species (ROS) can lead to various health issues, including metabolic problems, cancers, and neurological conditions. Our bodies counteract ROS with biological antioxidants such as SOD, CAT, and GPx, which help prevent cellular damage. However, if there is an imbalance between ROS and these antioxidants, it can result in oxidative stress. This can cause genetic and epigenetic changes at the molecular level. This review delves into how ROS plays a role in disorders caused by oxidative stress. We also look at animal models used for researching ROS pathways. This study offers insights into the mechanism, pathology, epigenetic changes, and animal models to assist in drug development and disease understanding.
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Hypoadiponectinemia is associated with renal dysfunctions. Irbesartan and pioglitazone activate Peroxisome proliferator-activated gamma receptor (PPAR-γ) as partial and full agonists. We investigated a crosstalk interaction and synergistic action between adiponectin receptors, PPAR-γ agonists in attenuating renal hemodynamics to adrenergic agonists in diabetic Wistar Kyoto rats (WKY). Streptozotocin (40 mg/kg) was used to induce diabetes, whereas, pioglitazone (10 mg/kg/day), irbesartan (30 mg/kg/day) administered orally for 28 days and adiponectin intraperitoneally (2.5 µg/kg/day) for last 7 days. Metabolic and plasma samples were analyzed on days 0, 8, 21, and 28. During the acute study (day 29), renal vasoconstrictor actions to adrenergic agonists and angiotensin-II were determined. Diabetic WKYs had lower plasma adiponectin, higher creatinine clearance, urinary and fractional sodium excretion but were normalized to a greater extent in pioglitazone and adiponectin combined treatment. Responses to intra-renal administration of adrenergic agonists including noradrenaline (NA), phenylephrine (PE), methoxamine (ME), and angiotensin-II (ANG-II) were larger in diabetic WKY, but significantly blunted with adiponectin treatment in diabetic WKYs to 35-40%, and further reduced by 65-70% in combination with pioglitazone. Attenuation to ANG-II responses in adiponectin and combination with irbesartan was 30-35% and 75-80%, respectively (P < 0.05). Pharmacodynamically, a crosstalk interaction exists between PPAR-γ, adiponectin receptors (adipo R1 & R2), alpha adrenoceptors, and angiotensin-I (ATI) receptors in the renal vasculature of diabetic WKYs. Exogenously administered adiponectin with full PPAR-γ agonist substantially attenuated renal hemodynamics and improved excretory functions, signifying their renoprotective action. Additionally, a degree of synergism exists between adiponectin and pioglitazone to a large extent compared to combination therapy with irbesartan (partial PPAR-γ agonist) in attenuating the renal vascular receptiveness to adrenergic agonists.
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Receptores de AdiponectinaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Numerous Alphonsea species including Alphonsea elliptica (mempisang) leaves and fruits are indigenously used in inflammatory conditions such as postpartum swelling and rheumatism in southeast Asian countries. In our previous in-vitro findings, A. elliptica methanol extract exhibited platelet-activating factor inhibition, suggesting the presence of phyto-constituents with anti-inflammatory potential. AIM OF THE STUDY: However, so far there is no literature available on the anti-inflammatory activity of this species. Henceforth, based on the above background and our previous laboratory findings, we hypothesize that phytoconstituents of A. elliptica could possess anti-inflammatory potential against inflammatory mediators including prostaglandin-E2 (PGE2), cyclooxegenase-2 (COX-2) and cytokines (IL-1ß and IL-6). MATERIALS AND METHODS: Vacuum and column chromatography techniques were employed for the isolation of phytoconstituents. The structure elucidation was carried out using HRESI-MS, 1H and 13C-NMR analysis and compared with the published literature. For cytotoxicity analysis, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed on peripheral blood mononuclear cells. In-vitro anti-inflammatory activities were evaluated against the levels of PGE2, COX-2, IL-1ß and IL-6 in lipopolysaccharide (LPS)-induced human plasma using enzyme-linked immunosorbent assay and radioimmunoassay. RESULTS: Unprecedentedly, chromatographic purification of methanolic leaves extract afforded five flavones namely vitexin, isovitexin, orientin, isoorientin, schaftoside with three flavanols; kaempferol, myricetin and rutin from A elliptica. In cell viability analysis, isolates did not present cytotoxicity up to 50 µM. In anti-inflammatory evaluation, orientin and isoorientin exhibited strong (≥70%), while isovitexin and vitexin produced strong to moderate (50-69%) PGE2, COX-2, IL-1ß and IL-6 inhibition at 25 and 50 µM. Isoorientin, orientin, isovitexin, and vitexin showed significant (p < 0.05) and concentration-dependent PGE2 inhibition with IC50 values (µM) of 11.40, 14.71, 17.70 and 20.58 against indomethacin (8.80). Furthermore, isoorientin, orientin, isovitexin, and vitexin produced significant concentration-dependent inhibition with IC50 values (µM) of COX-2: 7.13, 9.51, 12.81, 16.61; IL-1ß 4.80, 6.20, 10.85, 14.51; IL-6: 4.01, 5.90, 11.51 and 14.88 as compared to dexamethasone: 5.29, 2.93, 3.72, respectively (p < 0.05). CONCLUSION: Conclusively, isolated phytoconstituents are reported for the first time from the A. elliptica. Moreover, isovitexin, vitexin orientin and isoorientin abrogated LPS-induced inflammatory responses in human plasma at non-cytotoxic concentrations.
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Apigenina/farmacologia , Glicosídeos/farmacologia , Inflamação/tratamento farmacológico , Luteolina/farmacologia , Magnoliopsida/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Anti-Inflamatórios/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/antagonistas & inibidores , Dinoprostona/metabolismo , Humanos , Inflamação/induzido quimicamente , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Extratos Vegetais/isolamento & purificaçãoRESUMO
The coronavirus disease (COVID-19) has once again reminded us of the significance of host immune response and consequential havocs of the immune dysregulation. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) inflicts severe complications to the infected host, including cough, dyspnoea, fever, septic shock, acute respiratory distress syndrome (ARDs), and multiple organ failure. These manifestations are the consequence of the dysregulated immune system, which gives rise to excessive and unattended production of pro-inflammatory mediators. Elevated circulatory cytokine and chemokine levels are accompanied by spontaneous haemorrhage, thrombocytopenia and systemic inflammation, which are the cardinal features of life-threatening cytokine storm syndrome in advanced COVID-19 diseases. Coronavirus hijacked NF-kappa B (NF-κB) is responsible for upregulating the expressions of inflammatory cytokine, chemokine, alarmins and inducible enzymes, which paves the pathway for cytokine storm. Given the scenario, the systemic approach of simultaneous inhibition of NF-κB offers an attractive therapeutic intervention. Targeted therapies with proteasome inhibitor (VL-01, bortezomib, carfilzomib and ixazomib), bruton tyrosine kinase inhibitor (acalabrutinib), nucleotide analogue (remdesivir), TNF-α monoclonal antibodies (infliximab and adalimumab), N-acetylcysteine and corticosteroids (dexamethasone), focusing the NF-κB inhibition have demonstrated effectiveness in terms of the significant decrease in morbidity and mortality in severe COVID-19 patients. Hence, this review highlights the activation, signal transduction and cross-talk of NF-κB with regard to cytokine storm in COVID-19. Moreover, the development of therapeutic strategies based on NF-κB inhibition are also discussed herein.
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COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , NF-kappa B/imunologia , SARS-CoV-2 , Animais , Cromossomos Humanos X/imunologia , Exoftalmia , Hormônios Esteroides Gonadais/imunologia , Humanos , Transdução de SinaisRESUMO
Oxidative stress, which is associated with metabolic and anthropometric perturbations, leads to reactive oxygen species production and decrease in plasma adiponectin concentration. We investigated pharmacodynamically the pathophysiological role and potential implication of exogenously administered adiponectin with full and partial peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists on modulation of oxidative stress, metabolic dysregulation, and antioxidant potential in streptozotocin-induced spontaneously hypertensive rats (SHR). Group I (WKY) serves as the normotensive control, whereas 42 male SHRs were randomized equally into 7 groups (n = 6); group II serves as the SHR control, group III serves as the SHR diabetic control, and groups IV, V, and VI are treated with irbesartan (30 mg/kg), pioglitazone (10 mg/kg), and adiponectin (2.5 µg/kg), whereas groups VII and VIII received cotreatments as irbesartan+adiponectin and pioglitazone+adiponectin, respectively. Diabetes was induced using an intraperitoneal injection of streptozotocin (40 mg/kg). Plasma adiponectin, lipid contents, and arterial stiffness with oxidative stress biomarkers were measured using an in vitro and in vivo analysis. Diabetic SHRs exhibited hyperglycemia, hypertriglyceridemia, hypercholesterolemia, and increased arterial stiffness with reduced plasma adiponectin and antioxidant enzymatic levels (P < 0.05). Diabetic SHRs pretreated with pioglitazone and adiponectin separately exerted improvements in antioxidant enzyme activities, abrogated arterial stiffness, and offset the increased production of reactive oxygen species and dyslipidemic effects of STZ, whereas the blood pressure values were significantly reduced in the irbesartan-treated groups (all P < 0.05). The combined treatment of exogenously administered adiponectin with full PPAR-γ agonist augmented the improvement in lipid contents and adiponectin concentration and restored arterial stiffness with antioxidant potential effects, indicating the degree of synergism between adiponectin and full PPAR-γ agonists (pioglitazone).
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ETHNOPHARMACOLOGICAL RELEVANCE: Polyalthia is one of the largest and notable genera in Annonaceae family. Polyalthia species have been widely used in folklore medicine for the treatment of rheumatic fever, gastrointestinal ulcer and generalized body pain. Numerous in vitro and in vivo studies on Polyalthia Species have also corroborated the significant anti-inflammatory potential of its extracts and secondary metabolites. AIM OF THE STUDY: This review is an attempt to assess the anti-inflammatory activity of Polyalthia species by giving critical appraisal and establishing evidences of their traditional uses. Moreover this review will highlight the lead compounds for future drug development that can serve as a potential anti-inflammatory drug with comparative efficacy and minimum side effects. MATERIALS AND METHODS: An extensive literature review, focusing the anti-inflammatory potential of Polyalthia species was conducted using the following databases:PubMed, ScienceDirect, SpringerLink, Ovid, Scopus and ProQuest, as well as the locally available books, journals and relevant documents. The reference lists of retrieved papers were also searched for additional studies. RESULTS: The Polyalthia species have shown significant anti-inflammatory activity through various mechanism of action. The most significant anti-inflammatory mechanism includes the inhibition of nuclear factor kappa B (NF-κB), prostaglandins (PGs), pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS). The data suggests that hydroxycleroda-3,13-dien-15,16-olide and 16-oxocleroda-3,13-dien-15-oic acid, quercetin, rutin, spinasterol, α-spinasterol, goniothalamin and (-)-5-hydroxygoniothalamin are the most potent anti-inflammatory compounds from Polyalthia species with comparable IC50 with positive controls. CONCLUSIONS: Numerous pharmacological studies have supported the use of Polyalthia species against pain, rheumatic fever, haemorrhages and inflammation in traditional medicine. Flavonoids, diterpenoids, sterols and styrylpyrones from genus Polyalthia are the most significant class of compounds with potent anti-inflammatory activity. Secondary metabolites from these classes should be brought into further research to fill the gaps of knowledge in pharmacokinetics, pharmacodynamics, bioavailability, and toxicity in order to convert the pre-clinical results into clinical data for further investigation.
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Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Polyalthia , Animais , Ásia , Humanos , Medicina Tradicional , FitoterapiaRESUMO
Over the last few decade Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are the drugs of choice for treating numerous inflammatory diseases including rheumatoid arthritis. The NSAIDs produces anti-inflammatory activity via inhibiting cyclooxygenase enzyme, responsible for the conversation of arachidonic acid to prostaglandins. Likewise, cyclooxegenase-2 inhibitors (COX-2) selectively inhibit the COX-2 enzyme and produces significant anti-inflammatory, analgesic, and anti-pyretic activity without producing COX-1 associated gastrointestinal and renal side effects. In last two decades numerous selective COX-2 inhibitors (COXIBs) have been developed and approved for various inflammatory conditions. However, data from clinical trials have suggested that the prolong use of COX-2 inhibitors are also associated with life threatening cardiovascular side effects including ischemic heart failure and myocardial infection. In these scenario secondary metabolites from natural product offers a great hope for the development of novel anti-inflammatory compounds. Although majority of the natural product based compounds exhibit more selectively toward COX-1. However, the data suggest that slight structural modification can be helpful in developing COX-2 selective secondary metabolites with comparative efficacy and limited side effects. This review is an effort to highlight the secondary metabolites from terrestrial and marine source with significant COX-2 and COX-2 mediated PGE2 inhibitory activity, since it is anticipated that isolates with ability to inhibit COX-2 mediated PGE2 production would be useful in suppressing the inflammation and its classical sign and symptoms. Moreover, this review has highlighted the potential lead compounds including berberine, kaurenoic acid, α-cyperone, curcumin, and zedoarondiol for further development with the help of structure-activity relationship (SAR) studies and their current status.
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Inventories of tropical forests have listed Annonaceae as one of the most diverse plant families. For centuries, it is employed in traditional medicines to cure various pathological conditions including snakebite, analgesic, astringent, diarrhea, dysentery, arthritis pain, rheumatism, neuralgia, and weight loss etc. Phytochemical analysis of Annonaceae family have reported the occurrence of alkaloids, flavonoids, triterpenes, diterpenes and diterpene flavone glycosides, sterols, lignans, and annonaceous acetogenin characteristically affiliated with Annonaceae sp. Numerous past studies have underlined the pleotropic pharmacological activities of the crude extracts and isolated compounds from Annonaceae species. This review is an effort to abridge the ethnobotany, morphology, phytochemistry, toxicity, and particularly focusing on the anti-inflammatory activity of the Annonaceae species.
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Pathophysiological changes in diabetes like hyperglycemia, oxidative stress, insulin resistance and compensatory hyperinsulinemia predispose cells to malignant transformation and damage DNA repair mechanism. This study was designed to explore the potential synergistic toxic effects of anti-diabetic drug (Metformin), and an analgesic drug (Celecoxib) at cellular level. MTT assay run on Vero cell line revealed that the combinations of Metformin and Celecoxib augment the anti-proliferative effects, whereas Single cell gel electrophoresis spotlighted that Metformin produce non-significant DNA damage with the threshold concentration of 400µg/ml in peripheral blood mononuclear cells (lymphocytes and monocytes), while Celecoxib produced significant (P<0.05) DNA damage (class III comets) above the concentration of 75µg/ml, however the DNA damage or DNA tail protrusions by combinations of both drugs were less than what was observed with Celecoxib alone. Metformin or Celecoxib did not appear mutagenic against any mutant strains (TA 100 and TA 98) but their combination exhibited slight mutagenicity at much higher concentration. The results obtained at concentrations higher than the therapeutic level of drugs and reflect that Metformin in combination with Celecoxib synergistically inhibits the cell proliferation in a concentration dependent pattern. Since, this increase in cytotoxicity did not confer an increase in DNA damage; this combination could be adopted to inhibit the growth of malignant cell without producing any genotoxic or mutagenic effects at cellular level.
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Celecoxib/toxicidade , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Metformina/toxicidade , Animais , Celecoxib/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Ensaio Cometa , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Metformina/administração & dosagem , Microscopia de Fluorescência , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Células VeroRESUMO
It is understood that drugs regardless of their order of administration can exhibit drug interactions. Established on the fact that treatment of hypertension may last for decades and prolong usage of multiple drug regimen may induce substantial pathophysiological changes. Hence, This study was designed to evaluate the possible synergistic toxic effects of anti-hypertensive (carvedilol), and anti-inflammatory drug (celecoxib) alone and in combinations. Well-established MTT assay, Single Cell Gel Electrophoresis (SCGE) and Ames assay were employed to evaluate the toxicity at cellular level. Results from MTT assay on Vero cell line revealed that drug combinations have more pronounced anti-proliferative activity with combine IC50 value of 13.7:47.8 µg/mL. Likewise, exposure of peripheral blood mononuclear cells with drug combinations revealed significant (P<0.05) DNA damage (Class 3) in a dose dependent manner at concentrations ≥ 0.78: 2.34 µg/mL. However, carvedilol and celecoxib were non mutagenic against either mutant strain (TA 100 and TA 98) and combinations have also shown mild to moderate mutagenic potential. Nevertheless, upon addition of metabolic activation enzyme, concentration <12.5:37.5 µg/plate exhibited significant (P<0.05) mutagenicity against both tester strains. In conclusion, this study provides additional genotoxicity and mutagenicity data that could be used in considering options for formulating regimens with reduced mutagenic potential