Endang Kumolosasi

Self-assembled polymeric nanoparticles for percutaneous co-delivery of hydrocortisone/hydroxytyrosol: an ex vivo and in vivo study using an NC/Nga mouse model.

In this study, hydroxytyrosol (HT; a potent antioxidant) was co-administered with hydrocortisone (HC) to mitigate the systemic adverse effects of the latter and to provide additional anti-inflammatory and antioxidant benefits in the treatment of atopic dermatitis (AD). The co-loaded nanoparticles (NPs) prepared had shown different particle sizes, zeta potentials, loading efficiencies, and morphology, when the pH of the chitosan solution was increased from 3.0 to 7.0. Ex vivo permeation data showed that the co-loaded NPs formulation significantly reduced the corresponding flux (17.04μg/cm(2)/h) and permeation coefficient (3.4×10(-3)cm/h) of HC across full-thickness NC/Nga mouse skin. In addition, the NPs formulation showed higher epidermal (1560±31μg/g of skin) and dermal (880±28μg/g of skin) accumulation of HC than did a commercial HC formulation. Moreover, an in vivo study using an NC/Nga mouse model revealed that compared to the other treatment groups, the group treated with the NPs formulation efficiently controlled transepidermal water loss (13±2g/m(2)/h), intensity of erythema (207±12), and dermatitis index (mild). In conclusion, NPs co-loaded with HC/HT is proposed as a promising system for the percutaneous co-delivery of anti-inflammatory and antioxidative agents in the treatment of AD.

Effects of Novel Diarylpentanoid Analogues of Curcumin on Secretory Phospholipase A2, Cyclooxygenases, Lipo-oxygenase, and Microsomal Prostaglandin E Synthase-1

Arachidonic acid and its metabolites have generated a heightened interest due to their significant role in inflammation. Inhibiting the enzymes involved in arachidonic acid metabolism has been considered as the synergistic anti‐inflammatory effect. A series of novel curcumin diarylpentanoid analogues were synthesized and evaluated for their inhibitory effects on activity of secretory phospholipase A2, cyclooxygenases, soybean lipo‐oxygenase as well as microsomal prostaglandin E synthase‐1. Among the curcumin analogues, compounds 3, 6, 9, 12, and 17 exhibited strong inhibition of secretory phospholipase A2 activity, with IC50 values ranging from 5.89 to 11.02 μm. Seven curcumin analogues 1, 3, 6, 7, 9, 11, and 12 showed inhibition of cyclooxygenases‐2 with IC50 values in the range of 46.11 to 94.86 μm, which were lower than that of curcumin. Compounds 3, 6, 7, 12, and 17 showed strong inhibition of lipo‐oxygenase enzyme activity. Preliminary screening of diarylpentanoid curcumin analogues for microsomal prostaglandin E synthase‐1 activity revealed that four diarylpentanoid curcumin analogues 5, 6, 7, and 13 demonstrated higher inhibition of microsomal prostaglandin E synthase‐1 activity with IC50 ranging from 2.41 to 4.48 μm, which was less than that of curcumin. The present results suggest that some of these diarylpentanoid analogues were able to inhibit the activity of these enzymes. This raises the possibility that diarylpentanoid analogues of curcumin might serve as useful starting point for the design of improved anti‐inflammatory agents.

Immunostimulatory effects of the standardized extract of Tinospora crispa on innate immune responses in Wistar Kyoto rats

Tinospora crispa (TC) has been used in folkloric medicine for the treatment of various diseases and has been reported for several pharmacological activities. However, the effects of TC extract on the immune system are largely unknown. Therefore, the present study was aimed to investigate the immunomodulatory effects of a standardized 80% ethanol extract of the stem of TC on innate immune responses. Male Wistar Kyoto rats were treated daily at 100 mg/kg, 200 mg/kg, and 400 mg/kg doses of the extract for 21 days by oral gavage. The immunomodulatory potential of TC was evaluated by determining its effect on chemotaxis and phagocytic activity of neutrophils isolated from the blood of rats. To further elucidate the mechanism of action, its effects on the proliferation of T- and B-lymphocytes and T-lymphocytes subsets (CD4+ and CD8+) and on the secretion of Th1 and Th2 cytokines were also monitored. The main components of the extracts, syringin and magnoflorine, were identified and quantitatively analyzed in the extracts by using a validated reversed-phase high-performance liquid chromatography method. It was observed that the chemotactic activity of neutrophils obtained from extract-treated rats increased as compared to controls. A dose-dependent increase in the number of migrated cells and phagocytosis activity of neutrophils was observed. Dose-dependent increase was also observed in the T- and B-lymphocytes proliferation stimulated with concanavalin A (5 μg/mL) and lipopolysaccharide (10 μg/mL), and was statistically significant at 400 mg/kg (P>0.01). Apart from cell-mediated immune response, the concentrations of Th1 (TNF-α, IL-2, and IFN-γ) and Th2 (IL-4) cytokines were significantly increased in sera of rats treated with different doses as compared with the control group. From these findings, it can be concluded that TC possesses immunostimulatory activity and has therapeutic potential for the prevention of immune diseases.

Efficient Immuno-Modulation of TH1/TH2 Biomarkers in 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis: Nanocarrier-Mediated Transcutaneous Co-Delivery of Anti-Inflammatory and Antioxidant Drugs

The present study was conducted with the aim to investigate the immuno-modulatory and histological stabilization effects of nanocarrier–based transcutaneous co-delivery of hydrocortisone (HC) and hydroxytyrosol (HT). In this investigation, the clinical and pharmacological efficacies of nanoparticle (NP)-based formulation to alleviate 2,4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis (AD) was explored by using an NC/Nga mouse model. Ex vivo visual examination of AD induction in experimental mice indicated remarkable control of NP-based formulations in reducing pathological severity of AD-like skin lesions. Therapeutic effectiveness of NP-based formulations was also evaluated by comparing skin thickness of AD-induced NP-treated mice (456±27 µm) with that of atopic mice (916±37 µm). Analysis of the immuno-spectrum of AD also revealed the dominance of NP-based formulations in restraining immunoglobulin-E (IgE), histamine, prostaglandin-E2 (PGE2), vascular endothelial growth factor-α (VEGF-α), and T-helper cells (TH1/TH2) producing cytokines in serum and skin biopsies of tested mice. These anti-AD data were further supported by histological findings that revealed alleviated pathological features, including collagen fiber deposition, fibroblasts infiltration, and fragmentation of elastic fibers in experimental mice. Thus, NP-mediated transcutaneous co-delivery of HC and HT can be considered as a promising therapy for managing immunological and histological spectra associated with AD.

Downregulation of immunological mediators in 2,4-dinitrofluorobenzene-induced atopic dermatitis-like skin lesions by hydrocortisone-loaded chitosan nanoparticles

Background Atopic dermatitis is a chronic, noncontiguous, and exudative disorder accompanied by perivascular infiltration of immune mediators, including T-helper (Type 1 helper/Type 2 helper) cells, mast cells, and immunoglobulin E. The current study explores the immunomodulatory and histological effects of nanoparticle (NP)-based transcutaneous delivery of hydrocortisone (HC). Methods In this study, HC, the least potent topical glucocorticoid, was administered transcutaneously as chitosan NPs. The pharmacological and immunological effects of the NP-based HC delivery on the alleviation of 2,4-dinitrofluorobenzene-induced atopic dermatitis (AD)-like skin lesions were evaluated using the NC/Nga mouse model. Results In vivo Dino-Lite® microscopic assessment revealed that the NP-based formulation displayed a remarkable ability to reduce the severity of the pathological features of AD (dermatitis index, 3.0). The AD suppressive activity of the NP-based topical formulation was expected owing to the interruption of a series of immunopathological events, including the production of immunoglobulin E, release of histamine, and expression of prostaglandin-E2 and vascular endothelial growth factor-α in the sera and skin of the tested animals. Analysis of the cytokine expression in AD-like skin lesions further revealed that the NP-based formulation inhibited the pathological expression of interleukin (IL)-4, IL-5, IL-6, IL-13, IL-12p70, interferon-γ, and tumor necrosis factor-α in serum and skin homogenates of NC/Nga mice. Further, our histological findings indicated that the NP-based formulation inhibited fibroblast infiltration and fragmentation of elastic fibers, further supporting the clinical importance of these formulations in maintaining the integrity of elastic connective tissues. Conclusion The current investigation suggests that NP-mediated transcutaneous delivery of HC could be considered an effective therapeutic approach to manage dermatitis.

Anti-Inflammatory Effects of Hypophyllanthin and Niranthin Through Downregulation of NF-κB/MAPKs/PI3K-Akt Signaling Pathways

Hypophyllanthin (HYP) and niranthin (NIR) are major lignans in Phyllanthus spp. and have been shown to possess strong anti-inflammatory activity. In this study, we investigated the anti-inflammatory effects and the underlying molecular mechanisms of HYP and NIR in in vitro cellular model of LPS-induced U937 macrophages. The effects of HYP and NIR on the production of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were measured by using ELISA, Western blot, and qRT-PCR. The expressions of signaling molecules related to nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs), and phosphatidylinositol 3′-kinase-Akt (PI3K-Akt) signaling pathways were examined. The role of NF-κB, MAPKs, and Akt signaling pathways was confirmed by using specific inhibitors (BAY 11-7082, U0126, SB202190, SP600125, and LY294002) mediated suppression of TNF-α and COX-2 production. HYP and NIR significantly inhibited the protein and gene levels of COX-2 as well as the downstream signaling products of PGE2, TNF-α, and IL-1β. HYP and NIR also suppressed the inhibitors of kappa B (IκB), IkB kinases (Ikkα/β), NF-κB phosphorylation, and IκB degradation. HYP suppressed the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 while NIR only suppressed JNK and ERK but did not have effect on p38. These results demonstrate that HYP and NIR downregulated COX-2, TNF-α, and IL-1β gene expressions in U937 macrophages by interfering with the activation of NF-κB, MAPKs, and Akt. In conclusion, these lignans have potential to be developed as anti-inflammatory agents targeting the NF-κB, MAPK, and PI3K-Akt pathways.

Moringa Genus: A Review of Phytochemistry and Pharmacology

Moringa is a genus of medicinal plants that has been used traditionally to cure wounds and various diseases such as colds and diabetes. In addition, the genus is also consumed as a source of nutrients and widely used for purifying water. The genus consists of 13 species that have been widely cultivated throughout Asia and Africa for their multiple uses. The purpose of this review is to provide updated and categorized information on the traditional uses, phytochemistry, biological activities, and toxicological research of Moringa species in order to explore their therapeutic potential and evaluate future research opportunities. The literature reviewed for this paper was obtained from PubMed, ScienceDirect, and Google Scholar journal papers published from 1983 to March 2017. Moringa species are well-known for their antioxidant, anti-inflammatory, anticancer, and antihyperglycemic activities. Most of their biological activity is caused by their high content of flavonoids, glucosides, and glucosinolates. By documenting the traditional uses and biological activities of Moringa species, we hope to support new research on these plants, especially on those species whose biological properties have not been studied to date.

Immunomodulatory effects of diarylpentanoid analogues of curcumin

Diarylpentanoid analogues of curcumin are known for their various pharmacological activities which include the inhibition of inflammatory mediators and are good candidates as immunomodulators that could be useful in the treatment of inflammation. In the work described here, seventeen diarylpentanoid curcumin analogues were assessed for their inhibitory effects on the reactive oxygen species (ROS) production, chemotaxis and phagocytosis of human neutrophils. ROS production was evaluated using luminol and lucigenin-based chemiluminesence assay, while inhibition of isolated polymorphonuclear neutrophils chemotaxis and phagocytosis abilities were investigated using the Boyden chamber technique and the Phagotest kit, respectively. Two of the analogues, compounds 1e and 2e, which contain the 2-methyl-4(N-ethyl-N-ethylacetonitrile)aniline functional group, were active in all the assays performed. Moreover, analogues containing heteroatoms (1a, 1e, 2c, 2d, 2e, 3a and 3c) were active in suppressing the neutrophil phagocytic activity. The information obtained gave new insight into curcumin analogues with the potential to be developed as new immunomodulators.

Immunomodulatory effects of Tinospora crispa extract and its major compounds on the immune functions of RAW 264.7 macrophages

ABSTRACT The in vivo immunomodulatory activities of Tinospora crispa have been reported but its molecular mechanisms underlying its immunomodulatory properties remains obscure and the active constituents contributing to the activities have not been identified. The present study was aimed to investigate the immunomodulatory effects of T. crispa extract (TCE) and its chemical constituents on RAW 264.7 macrophages. Six known compounds including magnoflorine and syringin were isolated by various chromatographic techniques from TCE and their structures were determined spectroscopically. A validated HPLC method was used to quantify magnoflorine and syringin in the extract. The immunomodulatory effects of TCE and its isolated compounds on chemotaxis, phagocytosis, production of inflammatory mediators including reactive oxygen species (ROS), nitric oxide (NO), prostaglandin E2 (PGE2) and pro‐inflammatory cytokines which include tumor necrosis factor‐&agr; (TNF‐&agr;), interleukin (IL)‐1&bgr;, IL‐6 and monocyte chemoattractant protein‐1 (MCP‐1) on macrophages were assessed. TCE increased the chemotaxis and phagocytic activity of macrophages and significantly enhanced the production of ROS, NO and pro‐inflammatory cytokines. All alkaloids isolated, specifically magnoflorine showed remarkable inducing effects on the chemotaxis, phagocytic activity, ROS and NO productions and the secretions of IL‐1&bgr;, TNF‐&agr;, IL6, PGE2 and MCP‐1. In contrast, syringin potently reduced the chemotaxis, phagocytic activity, ROS and NO productions and secretions of IL‐1&bgr;, TNF‐&agr;, IL6, PGE2 and MCP‐1. TCE showed strong immunostimulant effects on various components of the immune system and these activities were possibly contributed mainly by the alkaloids specifically magnoflorine. TCE has potential to be developed as an effective natural immunostimulant for improvement of immune‐related disorders. HIGHLIGHTSTinospora crispa stimulated various immune functions of RAW264.7 macrophages.Magnoflorine significantly induced phagocytosis and secretions of NO and cytokines.Syringin remarkably reduced phagocytosis and productions of NO and cytokines.Immunostimulant effect was contributed by the alkaloids specifically magnoflorine.

Effects of synthetic chalcone derivatives on oxidised palmitoyl arachidonoyl phosphorylcholine-induced proinflammatory chemokines production

Oxidised 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) induces the production of proinflammatory chemokines has been widely studied for its role in vascular inflammation. There is increasing evidence on the role of chalcones as potential anti-inflammatory agents but less is known about its effects on OxPAPC-induced chemokines production and the involvement of unfolded protein response (UPR) signalling, particularly through XBP1 pathway. The present study sought to investigate the inhibitory potential of synthetic chalcone derivatives on the release of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), induced by OxPAPC through XBP1 signalling pathway on differentiated U-937 macrophages. The effects of synthetic chalcone derivatives on the chemokines productions were investigated using enzyme-linked immunosorbent assays, while the inhibitions of XBP1 signalling were detected using western immunoblot. Results show that all the three tested synthetic chalcone derivatives inhibited OxPAPC-induced chemokines production in a concentration-dependent manner. Compound 1.5 exhibited the strongest inhibition of IL-8 and MCP-1 at 61.4 ± 4.23% and 63.8 ± 2.16%, respectively. Compound 1.5 also achieved the lowest IC50 values for both IL-8 (18.33 ± 1.59 μM) and MCP-1 (13.05 ± 1.37 μM) inhibitions. For XBP1 protein expression, both compound 1.4 and 1.5 exhibited significant concentration-dependent suppression of the protein expressions. The results suggest that synthetic chalcone derivatives may serve as potential alternatives for future development of anti-inflammatory agents, particularly in vascular inflammation.