Protective Effect of Plumeria Pudica Latex Proteins on Intestinal Mucositis Induced by 5-Fluorouracil.

Intestinal mucositis is characterized by inflammation and ulceration of the mucosa that affects the gastrointestinal tract and is associated with administering some drugs, such as 5- Fluorouracil (5-FU), conventional chemotherapy used in clinics for cancer therapy. Inside intestinal mucosa, the 5-FU acts, leading to oxidative stress, stimulating the production/release of proinflammatory cytokines, local accumulation of neutrophils and consequent tissue damage. These alterations favor bacterial proliferation, triggering secondary infections, and are responsible for undesired effects such as myelosuppression and diarrhea. These factors negatively impact oncological patients' quality of life and explain why they commonly interrupt their treatment prematurely. Currently, there is no specific drug with the ability to completely avoid this condition, so the search for new molecules with pharmacological properties that can be used for preventing or ameliorating intestinal mucositis is important. Plumeria pudica is a plant that produces latexcontaining molecules with therapeutic potential. A protein fraction obtained from this latex (LPPp), which comprises a well-defined mixture of chitinases, proteinases proteinase inhibitors, was demonstrated to have antioxidant and anti-inflammatory activities, preserving tissue glutathione and malondialdehyde concentration, reducing superoxide dismutase and myeloperoxidase activity, and reducing the level of proinflammatory cytokines in different experimental models. Given this scenario, inflammation and oxidative stress are directly involved in the pathogenesis of intestinal mucositis promoted by 5-FU. So, the hypothesis is that LPPp could inhibit these factors to attenuate the cytotoxicity of this pathology associated with 5-FU-treatment. This article brings new insights into the potential of the laticifer proteins extracted from the latex of P. pudica and opens new perspectives for the treatment of this type of intestinal mucositis with LPPp.

Prevalence and Influence of the -174 G/C Polymorphism in the Interleukin-6 Gene in Arboviruses Infections.

Dengue virus and Chikungunya virus are arboviruses that affect thousands of people worldwide annually. The mechanisms involved in viral pathogenesis still need to be better understood. Single nucleotide polymorphisms (SNPs) in immune genes may be involved in the protection, susceptibility, and/or progression of these diseases. This study was performed to investigate the SNP -174 G/C in the interleukin-6 (IL-6) gene in patients with dengue or chikungunya from Northeastern Brazil. A total of 581 blood samples were analyzed, of which 244 were part of the negative control group, genomic DNA was extracted, and the SNP was genotyped using real-time polymerase chain reaction (PCR). The data obtained were used to conduct statistical analyses of the genotype and allele frequencies. We suggest that the G/C genotype and C allele of the SNP -174 G/C in the IL-6 gene are related to protection against dengue in the studied population. No significant differences were observed in chikungunya patients. This is the first study that assessed the association of the SNP -174 G/C in patients with chikungunya. We identified the presence of the C allele as a protective factor against dengue in the studied population.

Phosphatidylinositol 3-kinase gamma participates in nimesulide-induced hepatic damage.

OBJECTIVE: To evaluate the participation of the phosphatidylinositol 3-kinase pathway in the liver damage caused by nimesulide. METHODS: Liver damage been induced by nimesulide. Mice were treated with either 2% dimethyl sulfoxide or AS605240, a phosphatidylinositol 3-kinase gamma pathway antagonist. Blood samples were collected for function assays of liver. The liver was removed for analysis of liver weight/animal weight ratio, histopathological parameters, oxidative and nitrous stress, cytokine levels, and the immunostaining for cyclooxygenase 2 and nuclear factor kappa B. KEY FINDINGS: Liver injured by nimesulide and treated with phosphatidylinositol 3-kinase gamma inhibitor significantly reversed (P < 0.05) the damage; it decreased the liver weight/animal weight ratio, histopathological scores, and neutrophil infiltration, consequently reducing oxidative stress. In addition, we show that phosphatidylinositol 3-kinase gamma is associated with hepatic damage induced by nimesulide, because it altered liver function and increased the protein immunostaining of cyclooxygenase 2 and nuclear factor kappa B in the liver tissue of nimesulide-treated animals. CONCLUSIONS: The findings from the present study allows us to infer that nimesulide causes liver damage through the phosphatidylinositol 3-kinase gamma pathway.

McN-A-343, a muscarinic agonist, reduces inflammation and oxidative stress in an experimental model of ulcerative colitis.

AIM: The aim of the present study was to investigate the anti-inflammatory response mediated of the M1 muscarinic acetylcholine receptor (mAChR) during experimental colitis. MATERIAL AND METHODS: After the induction of 6% acetic acid colitis, mice were treated with McN-A-343 0.5, 1.0, and 1.5 mg/kg or dexamethasone (DEXA, 2.0 mg/kg) or pirenzepine (PIR, 10 mg/kg; M1 mAChR antagonist). Colonic inflammation was assessed by macroscopic and microscopic lesion scores, colonic wet weight, myeloperoxidase (MPO) activity, interleukin-1 beta (IL1-ß) levels and tumor necrosis factor alpha (TNF-α), glutathione (GSH), malondialdehyde (MDA) and nitrate and nitrite (NO3/NO2), mRNA expression of IKKα, nuclear factor kappa beta (NF-kB) and cyclooxygenase-2 (COX-2), as well protein expression of NF-kB and COX-2. RESULTS: Treatment with McN-A-343 at a concentration of 1.5 mg/kg showed a significant reduction in intestinal damage as well as a decrease in wet weight, MPO activity, pro-inflammatory cytokine concentration, markers of oxidative stress and expression of inflammatory mediators. The action of the M1 agonist by the administration of pirenzepine, which promoted the blocking of the mAChR M1-mediated anti-inflammatory response, has also been proven. CONCLUSION: The results suggest that peripheral colonic M1 mAChR is involved in reversing the pro-inflammatory effect of experimentally induced colitis, which may represent a promising therapeutic alternative for patients with ulcerative colitis.

Latex Proteins from Plumeria pudica with Therapeutic Potential on Acetaminophen-Induced Liver Injury.

Liver disease is global health problem. Paracetamol (APAP) is used as an analgesic drug and is considered safe at therapeutic doses, but at higher doses, it causes acute liver injury. N-acetyl-p- Benzoquinone Imine (NAPQI) is a reactive toxic metabolite produced by biotransformation of APAP. NAPQI damages the liver by oxidative stress and the formation of protein adducts. The glutathione precursor N-acetylcysteine (NAC) is the only approved antidote against APAP hepatotoxicity, but it has limited hepatoprotective effects. The search for new drugs and novel therapeutic intervention strategies increasingly includes testing plant extracts and other natural products. Plumeria pudica (Jacq., 1760) is a plant that produces latex containing molecules with therapeutic potential. Proteins obtained from this latex (LPPp), a well-defined mixture of chitinases, proteinases proteinase inhibitors have shown anti-inflammatory, antinociceptive, antidiarrheal effects as well as a protective effect against ulcerative colitis. These studies have demonstrated that LPPp acts on parameters such as Glutathione (GSH) and Malondialdehyde (MDA) concentration, Superoxide Dismutase (SOD) activity, Myeloperoxidase (MPO) activity, and TNF- α IL1-ß levels. Since oxidative stress and inflammation have been reported to affect the initiation and progression of liver injury caused by APAP, it is suggested that LPPp can act on aspects related to paracetamol hepatoxicity. This article brings new insights into the potential of the laticifer proteins extracted from the latex of P. pudica and opens new perspectives for the treatment of this type of liver disease with LPPp.

Gabapentin attenuates intestinal inflammation: Role of PPAR-gamma receptor.

Gabapentin is an anticonvulsant drug that is also used for post-herpetic neuralgia and neuropathic pain. Recently, gabapentin showed anti-inflammatory effect. Nuclear factor kappa B (NFκB) is a regulator of the inflammatory process, and Peroxisome Proliferator-activated Receptor gamma (PPAR-gamma) is an important receptor involved in NFκB regulation. The aim of the present work was to study the potential role of PPAR-gamma receptor in gabapentin-mediated anti-inflammatory effects in a colitis experimental model. We induced colitis in rats using trinitrobenzenosulfonic acid and treated them with gabapentin and bisphenol A dicyldidyl ether (PPAR-gamma inhibitor). Macroscopic lesion scores, wet weight, histopathological analysis, mast cell count, myeloperoxidase, malondialdehyde acid, glutathione, nitrate/nitrite, and interleukin levels in the intestinal mucosa were determined. In addition, western blots were performed to determine the expression of Cyclooxygenase-2 (COX-2) and NFκB; Nitric Oxide Inducible Synthase (iNOS) and Interleukin 1 beta (IL-1ß) levels were also determined. Gabapentin was able to decrease all inflammatory parameters macroscopic and microscopic in addition to reducing markers of oxidative stress and cytokines such as IL-1ß and Tumor Necrosis Factor alpha (TNF-α) as well as enzymes inducible nitric oxide synthase and cyclooxygenase 2 and inflammatory genic regulator (NFκB). These effect attributed to gabapentin was observed to be lost in the presence of the specific inhibitor of PPAR-gamma. Gabapentin inhibits bowel inflammation by regulating mast cell signaling. Furthermore, it activates the PPAR-gamma receptor, which in turn inhibits the activation of NFκB, and consequently results in reduced activation of inflammatory genes involved in inflammatory bowel diseases.

Polysaccharides derived from Morinda citrifolia Linn reduce inflammatory markers during experimental colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: There are many reports of pharmacological activities of extracts and fractions of different vegetable-derived products in the scientific literature and in folk medicine. Ethnopharmacological use of these products by various communities continues to be extensively explored, and they account for more than half of all medications used worldwide. Polysaccharides (PLS) extracted from plants such as Morinda Citrifolia Linn present therapeutic potential in treatment of inflammatory bowel diseases (IBD) such as ulcerative colitis (UC). AIM OF THE STUDY: To evaluate the anti-inflammatory action of Noni-PLS against the intestinal damage in UC induced by acetic acid in mice. MATERIALS AND METHODS: In acetic acid-induced colitis, the mice were treated intraperitoneally (ip) with Noni-PLS (0.1, 0.3, and 3.0 mg/kg) or subcutaneously (sc) with dexamethasone (2.0 mg/kg) 30 min before euthanasia to determine the best dose of Noni-PLS with an anti-inflammatory effect in the course of UC. The colonic tissue samples were collected for macroscopic, wet weight, microscopic and biochemical (myeloperoxidase (MPO), glutathione (GSH), malondialdehyde (MDA), nitrate/nitrite (NO3/NO2), cytokines, cyclooxygenase (COX-2) and inducible nitric oxide (iNOS)) analyses. RESULTS: Treatment with Noni-PLS reduced the intestinal damage induced by acetic acid as it reduced macroscopic and microscopic scores and the wet weight of the colon. In addition, MPO activity and levels of GSH, MDA, NO3/NO2, pro-inflammatory cytokines, and COX-2 expression reduced. CONCLUSIONS: This study suggests that Noni-PLS exhibits anti-inflammatory action against intestinal damage by reducing inflammatory cell infiltration, oxidative stress, pro-inflammatory action of cytokines, COX-2 and iNOS expression in the inflamed colon. Noni-PLS shows therapeutic potential against inflammatory disorders like UC.

Antifungal Proteins from Plant Latex.

Latex, a milky fluid found in several plants, is widely used for many purposes, and its proteins have been investigated by researchers. Many studies have shown that latex produced by some plant species is a natural source of biologically active compounds, and many of the hydrolytic enzymes are related to health benefits. Research on the characterization and industrial and pharmaceutical utility of latex has progressed in recent years. Latex proteins are associated with plants' defense mechanisms, against attacks by fungi. In this respect, there are several biotechnological applications of antifungal proteins. Some findings reveal that antifungal proteins inhibit fungi by interrupting the synthesis of fungal cell walls or rupturing the membrane. Moreover, both phytopathogenic and clinical fungal strains are susceptible to latex proteins. The present review describes some important features of proteins isolated from plant latex which presented in vitro antifungal activities: protein classification, function, molecular weight, isoelectric point, as well as the fungal species that are inhibited by them. We also discuss their mechanisms of action.

Sulfated polysaccharides from the marine algae Gracilaria caudata prevent tissue damage caused by ligature-induced periodontitis.

Sulfated polysaccharides (PLS) extracted from the marine algae of the genus Gracilaria showed biological activity in different inflammatory models, except for periodontitis. Thus, this study aimed to evaluate the effectiveness of the treatment with PLS from Gracilaria caudata in ligature-induced periodontitis. 40 animals distributed into 5 groups were used (the control group (unligated), the ligated untreated group, and the ligated groups treated with 2.5, 5.0 and 10.0 mg/kg of PLS with intraperitoneal injection, respectively). After 20 days of treatment, the animals were killed and the following parameters were evaluated: Gingival Bleeding Index (GBI), Probing Pocket Depth (PPD), Myeloperoxidase (MPO) activity, Alveolar Bone Loss (ABL) for periodontal tissues; histopathological examination of gingival and liver tissues (Steatosis score); glutathione and malondialdehyde concentrations in the liver, serum levels of alanine aminotransferase and aspartate aminotransferase. The data revealed that treatment with 2.5 mg/kg of PLS showed the best anti-inflammatory effects with reduction of GBI, PPD and MPO activity, as well as oxidative stress and steatosis in liver. Our results indicated that the adjunct treatment with PLS from Gracilaria caudata could prevent the periodontal and hepatic tissue alteration caused by periodontitis.

Cytotoxicity against tumor cell lines and anti-inflammatory properties of chitinases from Calotropis procera latex.

The role of chitinases from the latex of medicinal shrub Calotropis procera on viability of tumor cell lines and inflammation was investigated. Soluble latex proteins were fractionated in a CM Sepharose Fast-Flow Column and the major peak (LPp1) subjected to ion exchange chromatography using a Mono-Q column coupled to an FPLC system. In a first series of experiments, immortalized macrophages were cultured with LPp1 for 24 h. Then, cytotoxicity of chitinase isoforms (LPp1-P1 to P6) was evaluated against HCT-116 (colon carcinoma), OVCAR-8 (ovarian carcinoma), and SF-295 (glioblastoma) tumor cell lines in 96-well plates. Cytotoxic chitinases had its anti-inflammatory potential assessed through the mouse peritonitis model. We have shown that LPp1 was not toxic to macrophages at dosages lower than 125 µg/mL but induced high messenger RNA expression of IL-6, IL1-ß, TNF-α, and iNOs. On the other hand, chitinase isoform LPp1-P4 retained all LPp1 cytotoxic activities against the tumor cell lines with IC50 ranging from 1.2 to 2.9 µg/mL. The intravenous administration of LPp1-P4 to mouse impaired neutrophil infiltration into the peritoneal cavity induced by carrageenan. Although the contents of pro-inflammatory cytokines IL-6, TNF-α, and IL1-ß were high in the bloodstreams, such effect was reverted by administration of iNOs inhibitors NG-nitro-L-arginine methyl ester and aminoguanidine. We conclude that chitinase isoform LPp1-P4 was highly cytotoxic to tumor cell lines and capable to reduce inflammation by an iNOs-derived NO mechanism.

The anti-inflammatory and antinociceptive activity of albumins from Crotalaria retusa seeds.

Seeds of Crotalaria retusa L. are used in popular medicine because of their pharmacological properties. The albumin fraction obtained from its seeds contains lectin, a protein known to have analgesic and anti-inflammatory properties. Thus, albumins extracted from C. retusa were investigated for their anti-inflammatory and antinociceptive effects. The intraperitoneal administration of different doses of albumins (5, 10 or 20mg/kg) significantly inhibited the mice paw edema induced by carrageenan (maximum inhibition rate of 80.9% at four hours, 20mg/kg), and this event was followed by diminishing paw myeloperoxidase measurements. Albumins (20mg/kg) also inhibited neutrophil migration into the peritoneal cavity induced by carrageenan. However, no effect was observed in the dextran-induced paw edema and abdominal contortions induced by acetic acid. Moreover, albumins (20mg/kg) significantly reduced the second (inflammatory) phase of the licking time induced by formalin. The detection of heammaglutinating activity against human erythrocytes in albumins evidences the presence of lectin in seeds of C. retusa. Our data showed that seeds of C. retusa had anti-inflammatory and antinociceptive properties and such activities are probably due to the inhibitory effect on neutrophil migration of lectin present in albumins.

Biological Effects of Medicinal Plants on Induced Periodontitis: A Systematic Review.

Objective. The aim of this systematic review was to investigate the advances in the study of medicinal plants and their biologic effects on periodontitis in animal models. Study Design. A systematic search was conducted by three independent researchers, who screened articles published up to March/2016, to identify the studies that contained sufficient and clear information on the association of the medicinal plants and periodontitis in murine models. The searches were performed using PubMed, Cochrane, and Science Direct databases. Results. After a critical analysis of titles and abstracts, 30 studies were finally eligible for analysis. The studies presented a great diversity of the experiment designed regarding the methods of induced periodontitis and the evaluation of the medicinal plants efficacy. None of the studies described the possible toxic effects associated with the administration of the plant material to animals and whether they could prevent damage to organs caused by systemic effect of induced periodontitis. Gel-based formulations containing plant substances are seen as an interesting strategy to treat periodontitis. Conclusions. In this systematic review, the state-of-the-art knowledge on the medicinal plants and the induced periodontitis was critically evaluated and discussed from the experiment designed to the possible clinical application.