Antioxidant and anti-inflammatory activity through inhibition of NF-κB and sEH of some citrus peel and phytoconstituent characteristics.

In Indonesia, there are many types of citrus where parts of the fruit, leaves, and peel can be utilized as food, drinks, spices, and medicine. This research aims to determine the phytochemical characteristics, antioxidant activities, and anti-inflammatory activity through inhibition of NF-κB and sEH, and the main phytoconstituents of three types of citrus fruits that are commonly used as herbs in Indonesia. The flesh and peel of Citrus amblycarpa/CAm, C. aurantiifolia/CAu, and C. hystrix/CH were extracted by Ultrasound-Assisted Extraction (UAE) with 70 % ethanol and then concentrated. All extracts were tested for total flavonoid content (TFC), total polyphenolic content (TPC), chemical constituents using LCMS, and DPPH radical scavenging activity. Molecular docking tests of 33 compounds containing CAm, CAu, and CH fruit peels from the literature study against NF-κB (Nuclear Factor Kappa Beta) and sEH (Soluble Epoxide Hydrolase) were also conducted. The TFC in fruit peels was 13.47-17.34 mg QE/g extract, and in flesh was 1.35-2.51 mg QE/g extract. The TPC in fruit peels was 4.28-6.3 mg GAE/g extract, and in flesh was 0.85-2.09 mg GAE/g extract. The IC50 values of antioxidant activity on fruit peel were 74.01-168.54 µg/mL; and flesh 185.62-2669 µg/mL. CAu peels provided the highest antioxidant activity and polyphenol content. The LC-MS/MS test on citrus peels shows the main chemical compounds: naringin (C27H32O14), naringenin (C15H12O5), hesperidin (C28H34O15), and hesperitin (C16H14O6). Molecular docking shows that naringin and neohesperidin predicted inhibit NF-κB, and hesperidin, neohesperidin, narirutin, naringin, apigenin, kaempferol, quercetin, rutin, eriocitrin, sinensetin, and vitamin A predicted can inhibit sEH enzyme. All citrus peel has stronger antioxidant activity and more flavonoids and phenolics than the flesh. Naringin and neohesperidin can inhibit NF-κB and sEH enzymes. The main flavonoid contents of the citrus peels and presumed to have activity are hesperidin and naringin. These flavonoids and their glycosides can be used as marker phytoconstituents in the quality assurance of pharmaceutical products.

Nanocurcumin preserves kidney function and haematology parameters in DMBA-induced ovarian cancer treated with cisplatin via its antioxidative and anti-inflammatory effect in rats.

CONTEXT: Cisplatin, as a first-line treatment for ovarian cancer, is associated with debilitating adverse effects, including nephrotoxic and haematotoxic effects. OBJECTIVE: This study determines whether nanocurcumin, combined with cisplatin, would give additional benefit to kidney function and haematological parameters in rats with ovarian cancer. MATERIALS AND METHODS: Twenty-five Wistar rats were divided into five untreated rats and 20-dimethylbenz(a)anthracene (DMBA)-induced ovarian cancer rats. The 20 ovarian cancer rats were divided into four treatment groups: vehicle, cisplatin, cisplatin-curcumin, and cisplatin-nanocurcumin. Cisplatin was given at the dose of 4 mg/kg BW once weekly, while curcumin or nanocurcumin was administered at 100 mg/kg BW daily for four weeks. At the end of treatment, we analysed kidney function, haematological parameters, and inflammatory and oxidative stress markers from plasma. RESULTS: Nanocurcumin alleviates the increase in kidney function markers and abnormalities in haematological indices in rats treated with cisplatin. Compared to cisplatin-treated rats, plasma urea levels decreased from 66.4 to 47.7 mg/dL, creatinine levels lowered from 0.87 to 0.82 mg/dL, and neutrophil gelatinase-associated lipocalin (NGAL) levels declined from 8.51 to 3.59 mIU/mg protein. Furthermore, the therapy increased glutathione activities (from 2.02 to 3.23 U/µL), reduced lipid peroxidation (from 0.54 to 0.45 nmol/mL), and decreased plasma TNF-α (from 270.6 to 217.8 pg/mL). CONCLUSIONS: Cisplatin with nanocurcumin in an ovarian cancer rat model may provide additional benefits as a preventive agent against renal impairment and cisplatin-induced haematological toxicity. However, further research is required to prove that using nanocurcumin for a more extended time would not affect its anticancer properties.

Enhancement of curcumin level and hepatoprotective effect in rats through antioxidant activity following modification into nanosized particles.

Background and Aim: Developing curcumin into nanosized particles is one of the approaches to overcome the limited use of curcumin. This study aimed to prepare curcumin into nanosized particles to increase the curcumin level in the rat's liver and hepatoprotective effect in rats. Materials and Methods: Curcumin into nanosized particles formulated using ionic gelation method. Rats were divided into four groups (n = 6): Normal, negative, curcumin, and curcumin modified into nanosized particles were treated with 100 mg/kg body weight orally for 14 days. Hepatic curcumin level was investigated using liquid chromatography with tandem mass spectrometry, antioxidant activity by malondialdehyde (MDA), and hepatoprotective effect by aspartate transaminase (AST), alanine transaminase (ALT), and histopathology. Results: The curcumin level in the rat's liver in the curcumin group was 12.19 ng/mL, and that in those receiving modified into nanosized curcumin was 209.36 ng/mL. The MDA levels in the normal, negative, curcumin, and curcumin modified into nanosized particles groups were 1.88, 4.87, 3.38, and 1.04 nmol/L, respectively. The AST levels in these groups were 57.12, 130.00, 102.13, and 74.28 IU/L, and the ALT levels were 21.63, 61.97, 39.38, and 28.55 IU/L. The liver histopathology scoring showed that curcumin in nanosized particles was better than curcumin in degeneration of fat, lymphocyte infiltration, and necrosis. Conclusion: There was a 17 times increase in curcumin level in the liver of rats treated with curcumin modified into nanosized particles. Curcumin modified into nanosized particles showed more significant improvement as antioxidant and hepatoprotector than curcumin.

Curcumin Prevents Epithelial-to Mesenchymal Transition-Mediated Ovarian Cancer Progression through NRF2/ETBR/ET-1 Axis and Preserves Mitochondria Biogenesis in Kidney after Cisplatin Administration.

Purpose: Ovarian carcinoma is one of the gynaecological malignancies that have the highest mortality rates due to its progressivity. Endothelin signalling plays a leading role in the progression of ovarian cancer through Epithelial-to-Mesenchymal Transition (EMT). Cisplatin commonly used as potent chemotherapy; however, its application hindered by its nephrotoxic effect. Curcumin, a turmeric-derived compound, has an anticancer property, as well as a renal protective effect. Moreover, curcumin augments the affinity of the antioxidant enzyme, while inhibits endothelin-1 (ET-1) signalling. The effects of curcumin on ovarian cancer progression and cisplatin-induced kidney injury remain unknown. Methods: Curcumin was used as a supplementary therapy together with cisplatin in Human Ovarian Cancer Cell line (SKOV3) and also in rodent-induced ovarian cancer. The kidney phenotype in the ovarian cancer rat model after cisplatin ± curcumin administration will also be analyzed Results: Co-treatment of cisplatin with curcumin enhanced the expression of a gene involved in apoptosis in association with NRF2 enhancement, thus activated ETBR-mediated ET-1 clearance in SKOV3 cell and ovarian cancer model in rat. Moreover, curcumin treatment improved mitochondria biogenesis markers such as PGC-1α and TFAM and prevented the elevated of ET-1-mediated renal fibrosis and apoptosis in kidney isolated from cisplatin-treated ovarian cancer rat. Conclusion: Curcumin could be potentially added as an anticancer adjuvant with protective effects in the kidney; thus, improves the efficacy and safety of cisplatin treatment in the clinical setting.

Development, Characterization and Pharmacokinetic Profile of Chitosan-Sodium Tripolyphosphate Nanoparticles Based Drug Delivery Systems for Curcumin.

Purpose: This study aimed to provide the method of preparation, characterization of curcumin-loaded chitosan-sodium tripolyphosphate (NaTPP) nanoparticle, and evaluate its pharmacokinetic profiles. Methods: Curcumin-loaded chitosan-NaTPP nanoparticles were synthesized using ionic gelation methods. Curcumin was dissolved using surfactants and cosurfactants. Chitosan polymer was then mixed in the curcumin solution and dripped with NaTPP solution until nanoparticle formation. The mucoadhesive study was evaluated by measuring the fluorescence of curcumin within the prepared nanoparticles. The pharmacokinetic profiles of curcumin particles and nanoparticles were then assessed in rats by administering a single oral dose of 100 mg/kg BW. Blood samples were taken from nine predetermined time points, and curcumin plasma concentrations were then analyzed using UPLC-MS/MS. Results: The particle size of the curcumin nanoparticles obtained were 11.5 nm. Entrapment efficiency (EE) of curcumin nanoparticles were exceeding 99.97%, and drug loading capacity (DLC) was 11.34%. The mucoadhesive properties of the nanoparticles were superior to that of curcumin particles. Pharmacokinetic evaluation in rats revealed that curcumin nanoparticles resulted in an increase of area under the curve (AUC), maximum concentration (Cmax), earlier time to reach maximum concentration (Tmax), and lower clearance (CL). Conclusion: Curcumin-loaded chitosan-NaTPP nanoparticles is an effective formulation to improve curcumin plasma concentrations. Thus, enable its applications for the treatment of various diseases.

Curcumin Nanoparticle Enhances the Anticancer Effect of Cisplatin by Inhibiting PI3K/AKT and JAK/STAT3 Pathway in Rat Ovarian Carcinoma Induced by DMBA.

Cisplatin has been used for decades for the treatment of ovarian cancer. However, despite its potent anticancer effect, cisplatin's efficacy as a single agent was inadequate in patients with advanced stage. Curcumin has been shown to sensitize cisplatin activity in several cancer models. However, the low bioavailability of curcumin has limited its anticancer potential. Hence, nano-formulation of curcumin was developed to increase its therapeutic efficacy in ovarian cancer. The objective of this study was to investigate the mechanism of curcumin nanoparticles given in combination with cisplatin in rat ovarian carcinoma induced by dimethylbenz(a)anthracene (DMBA). The administration of cisplatin and nanocurcumin resulted in a significant reduction in ovarian tumor volume and weight. Furthermore, there were reduction in expressions of Ki67, TGF-ß, PI3K, and Akt phosphorylation. Co-treatment of cisplatin and nanocurcumin also reduced JAK expression, STAT3 phosphorylation, and reduced IL-6 concentrations. Altogether, nanocurcumin, given as a co-treatment with cisplatin has therapeutic potential in ovarian cancer models by inhibiting proliferation through downregulation of PI3K/Akt and JAK/STAT3 signaling pathways.

In vitro assesment of anti-inflammatory activities of coumarin and Indonesian cassia extract in RAW264.7 murine macrophage cell line.

OBJECTIVES: Inflammation is an immune response toward injuries. Although inflammation is healing response, but in some condition it will lead to chronic disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, Alzheimer's and various cancer. Indonesian cassia (Cinnamomum burmannil C. Nees & T. Ness) known to contain coumarin, is widely used for alternative medicine especially as an anti-inflammatory. This study was conducted to determine the anti-inflammatory properties of coumarin and Indonesian cassia extract (ICE) in LPS-induced RAW264.7 cell line. MATERIALS AND METHODS: The cytotoxic assay of coumarin and ICE against RAW264.7 cells was conducted using MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium). The anti-inflammatory potential was determined using LPS-induced RAW 267.4 macrophages cells to measure inhibitory activity of compound and ISEon production of nitric oxide (NO), prostaglandin E2 (PGE2), and also cytokines such as interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and TNF-α. RESULTS: Coumarin 10 µM and ICE 10 µg/ml were nontoxic to the RAW264.7 cells. Both of coumarin and ICE were capable to reduce the PGE2, TNF-α, NO, IL-6, and IL-ß level in LPS-induced RAW264.7 cells. Coumarin had higher activity to decrease PGE2 and TNF-α, whilst ICE had higher activity to inhibit NO, IL-6, and IL-ß levels. CONCLUSION: Coumarin and ICE possess anti-inflammatory properties through inhibition of PGE2 and NO along with pro-inflammatory cytokines TNF-α, IL-6, IL-1ß production.