Suppression of VEGF and inflammatory cytokines, modulation of Annexin A1 and organ functions by galloylquinic acids in breast cancer model.

The ongoing development of novel drugs for breast cancer aims to improve therapeutic outcomes, reduce toxicities, and mitigate resistance to chemotherapeutic agents. Doxorubicin (Dox) is known for its significant side effects caused by non-specific cytotoxicity. In this study, we investigated the antitumor activity of galloylquinic acids (BF) and the beneficial role of their combination with Dox in an Ehrlich ascites carcinoma (EAC)-bearing mouse model, as well as their cytotoxic effect on MCF-7 cells. The EAC-mice were randomized into five experimental groups: normal saline, Dox (2 mg/kg, i.p), BF (150 mg/kg, orally), Dox and BF combined mixture, and a control group. Mice were subjected to a 14-day treatment regimen. Results showed that BF compounds exerted chemopreventive effects in EAC mice group by increasing mean survival time, decreasing tumor volume, inhibiting ascites tumor cell count, modulating body weight changes, and preventing multi-organ histopathological alterations. BF suppressed the increased levels of inflammatory mediators (IL-6 and TNF-α) and the angiogenic marker VEGF in the ascitic fluid. In addition, BF and their combination with Dox exhibited significant cytotoxic activity on MCF-7 cells by inhibiting cell viability and modulating Annexin A1 level. Moreover, BF treatments could revert oxidative stress, restore liver and kidney functions, and normalize blood cell counts.

The emerging coloprotective effect of sildenafil against ulcerative colitis in rats via exerting counterbalance between NF-κB signaling and Nrf-2/HO-1 pathway.

The current work explored the influences of time dependent Sildenafil (SILD) administration, and the possible outcomes from its concomitant administration with dexamethasone against acetic acid-induced ulcerative colitis in rats. Rats were assigned into six random groups: diseased group (AA), injected once with 2 ml acetic acid (3%) intrarectally, 2 days before sacrification. SILD + AA, received sildenafil (25 mg/kg, orally) for 6 days starting 3 days pre-injection of AA; SILD-t + AA, received sildenafil (25 mg/kg, orally), starting at time of AA injection and continued for 3 days; DEXA + AA, received dexamethasone (2 mg/kg, i.p.) for 3 days, starting at time of AA injection; SILD-t + DEXA + AA, received sildenafil (25 mg/kg, orally) and dexamethasone (2 mg/kg, i.p.), as mentioned. Sildenafil markedly ameliorated disease activity index (DAI), ulcer scores, colon length shortening and colonic histopathological changes. Mechanistically, Sildenafil markedly attenuated immunoexpression of NF-κB p65/ TNF-α and COX-2, diminished oxidative stress (↓ MDA/NO levels and ↑ GSH level and SOD activity), increased levels of Nrf-2/HO-1, compared to untreated group. Taken together, Sildenafil treatment suppressed acetic acid-induced ulcerative colitis, probably via inhibiting NF-κB/TNF-α signaling dependent of Nrf-2/HO-1 pathway, reducing oxidative stress and attenuating inflammation. Surprisingly, effects of sildenafil were unpromoted in a time dependant manner. Short term treatment with sildenafil was sufficient to exert its coloprotective effect, while longer term pretreatment was only superior among other treatments in the macroscopical changes. Moreover, concurrent administration of sildenafil and dexamethasone had the preference in boosting the antioxidant defense and anti-inflammatory mechanisms, visualized by histopathological/immunohistochemical changes.

Novel anti-arthritic mechanisms of trans-cinnamaldehyde against complete Freund's adjuvant-induced arthritis in mice: involvement of NF-кB/TNF-α and IL-6/IL-23/ IL-17 pathways in the immuno-inflammatory responses.

Trans-cinnamaldehyde (TCA), a natural cinnamaldehyde derivative of cinnamon oil, is known for anti-inflammatory, anti-bacterial, anti-fungal, anti-diabetic, and anti-cancer activities. However, no study has examined the protective mechanisms of TCA on complete Freund's adjuvant (CFA)-induced arthritis. Chronic arthritis was induced in mice by triple dose injection of 0.1 ml CFA in the first two days, then a treatment with TCA (100 mg/kg, i.p.) and the anti-arthritic drug; methotrexate (MTX, 0.75 mg/kg, i.p., 3 times/week) started from day 10 after CFA and continued till day 35.TCA ameliorated the CFA-induced arthritis features, indicated by the decrease in serum rheumatoid factor, paw swelling, arthritis index and the arthritis changes in limb histology. Additionally, TCA treatment showed anti-inflammatory actions through downregulation of TNF-α, NF-κB and COX-2 expressions and marked reduction in IL-1ß, IL-6, IL-23 and IL-17 levels in inflamed paw tissues.Consequently, TCA can decrease arthritis progression and inhibit the immune/inflammatory responses initiated by TNF-α/IL-1ß/IL-6/IL-23/IL-17 signals, via NF-κB modulation, almost to the same extent accomplished by MTX. Therefore, TCA could be a promising anti-arthritic drug.

Novel antitumor activity of the combined treatment of galloylquinic acid compounds with doxorubicin in solid Ehrlich carcinoma model via the Notch signaling pathway modulation.

AIMS: This study aims to investigate the potential synergistic effect of the combined treatment of galloylquinic acid compounds from Copaifera lucens with doxorubicin via the modulation of the Notch pathway in solid Ehrlich carcinoma-bearing mice model. MAIN METHODS: The solid tumor model was induced by subcutaneous inoculation of Ehrlich carcinoma cells in the right hind limb of mice, after serial syngeneic cell passages in the peritoneal cavity. Sixty mice were allocated into five groups including treated groups with galloylquinic acid compounds, doxorubicin, and their combination. Normal and tumor control groups were also assigned. Tissue homogenates were collected to measure the levels of the Notch-1, Hes-1, Jagged-1, TNF-α, IL-6 and VEGF, as well as SOD, MDA, and GSH. Histopathological and immunohistochemical examinations of tumor or control tissues were also performed for the levels of NF-κB p65, cyclin D1 and caspase 3 activity. KEY FINDINGS: Our results showed that the combined treatment of galloylquinic acid compounds with doxorubicin significantly decreased the levels of the Notch-1, Hes-1, Jagged-1, TNF-α, IL-6, VEGF, NF-κB p65, and cyclin D1 in tumor tissues. Moreover, the compounds induced cancer cell death as evidence by increasing the caspase 3 activity, and they possessed potent inhibitory effects on oxidative stress. SIGNIFICANCE: Galloylquinic acid compounds exhibited promising antineoplastic effects and promoted the chemosensitivity of doxorubicin, mainly by modulating the Notch signaling pathway and its downstream effectors. These compounds may be considered in solid tumors treatment for improving the efficacy and reducing the side effects of chemotherapeutic agents.

Protocatechuic acid protects against thioacetamide-induced chronic liver injury and encephalopathy in mice via modulating mTOR, p53 and the IL-6/ IL-17/ IL-23 immunoinflammatory pathway.

Protocatechuic acid (PCA), a natural phenolic acid, is known for antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic activities. However, the protective mechanisms of PCA on thioacetamide (TAA)-induced liver/brain injury are not well addressed. Chronic liver injury was induced in mice by intraperitoneal injection of TAA (200 mg/kg, 3 times/week) for 8 weeks. Simultaneously, PCA (100, 150 mg/kg/day, p.o.) was given daily from the 4th week. Protocatechuic acid ameliorated liver and brain damage indicated by the decrease in serum activities of aminotransferases, gamma-glutamyl transferase, alkaline phosphatase, lactate dehydrogenase, levels of bilirubin, and ammonia concomitant with restoration of normal albumin levels. Additionally, PCA treatment ameliorated oxidative stress in liver and brain, confirmed by the decrease in malondialdehyde and nitric oxide levels and the increase in antioxidant activities. Moreover, PCA showed anti-inflammatory actions through downregulation of TNF-α expression in the liver and IL-6/IL-17/IL-23 levels in the brain, which is confirmed by the decrease in CD4+ T brain cell numbers. Most importantly, PCA treatment showed a significant decrease in mTOR level and number of LC3 positive cells in both liver and brain tissues. Consequently, PCA could inhibit mTOR-induced apoptosis, as it showed anti-apoptotic actions through downregulation of caspase-3 expression in liver and p53 expression in liver and brain. Furthermore, liver and brain tissues of treated mice showed restoration of normal histology. It can be concluded that, several mechanisms, including: antioxidant, anti-inflammatory, anti-autophagic and anti-apoptotic activities can be implicated in the hepato- and neuroprotective potentials of PCA.

Lisinopril inhibits nuclear transcription factor kappa B and augments sensitivity to silymarin in experimental liver fibrosis.

Therapeutic interventions are still limited in the treatment of liver fibrosis even though an incredible number of publications related to silymarin are produced. This is due to the complex molecular pathogenesis. Several studies pointed to the role of renin-angiotensin system (RAS) in hepatic fibrogenesis. Therefore, the present study was designed to examine the effect of the combination of lisinopril (LIS) with silymarin (SIL) on CCl4-induced hepatic fibrosis along with an in-vitro confirmatory experiment. Rats were treated with LIS (1 mg kg-1) and SIL (30 mg kg-1) as a single agent and as combined to LIS (1 mg kg-1). Our results revealed that down-regulation of NFĸBp65 mRNA expression and inhibition of phosphorylation of NFĸBp65 (at Ser536) and NFĸBia were implicated in the anti-fibrotic effect of both LIS and SIL. Consequently lower levels of NFкB-induced TNF-α, TGF-ß1, MMP-2, TIMP-1 and VEGF compared to control group. In addition, levels of α-SMA protein expression and hydroxyproline are decreased in association with marked improvement in liver function, oxidative stress markers and histological picture. In addition, LIS augmented the inhibitory effect of SIL on NFĸB pathway at lower dose level. We concluded that LIS, via targeting NFĸB pathway, increases anti-oxidant capacity of liver tissue and exhibits anti-inflammatory, anti-fibrotic and anti-angiogenic activity and augments sensitivity to SIL. Therefore, LIS is a promising candidate for further clinical investigation in the treatment of liver fibrosis.

The NF-κB inhibitor celastrol attenuates acute hepatic dysfunction induced by cecal ligation and puncture in rats.

Acute hepatic dysfunction associating sepsis is mediated mainly by toll-like receptor-4 (TLR-4)/nuclear factor kappa-B (NF-κB) inflammatory pathway. This study explores potential hepatoprotective effect of the NF-κB inhibitor celastrol in cecal ligation and puncture (CLP) model in rats. Protective effect of celastrol (1mg/kg, i.p., 1h before CLP) was illustrated after 24h by preventing CLP-induced hepatic histopathological changes and elevation in serum hepatic biomarkers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB) and gamma aminotransferase (γ-GT)] without affecting mortality. Celastrol anti-inflammatory effect was illustrated by inhibiting increased serum and hepatic mRNA expression of interleukin-6 (IL-6) without affecting IL-10 elevation. Furthermore, celastrol inhibited CLP-induced elevations in hepatic mRNA expression of nuclear factor inhibitory protein kappa-B alpha (NFκBia), TLR-4, 5-lipoxygenase (5-LOX) and prevented NF-κB/p65 nuclear translocation and activation. In conclusion, celastrol prevented CLP-induced acute hepatic dysfunction through its anti-inflammatory effect by attenuating NF-κB activation, TLR-4 and 5-LOX expression with subsequent reduction in pro-inflammatory IL-6.

The lipoxin A4 agonist BML-111 attenuates acute hepatic dysfunction induced by cecal ligation and puncture in rats.

Sepsis is a systemic inflammatory response associating severe infection leading to multi-organ failure, such as hepatic dysfunction. This study investigates the possible hepatoprotective effect of the lipoxin A4 agonist (BML-111) in cecal ligation and puncture (CLP) model in rats. Pretreatment with BML-111 (1 mg/kg, i.p., 1 h before CLP) protected against CLP-induced mortality after 24 h. BML-111 prevented marked inflammatory cells in liver tissues and decreased elevation in serum hepatic biomarkers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), gamma-glutamyl transferase (γ-GT)] induced by CLP. Additionally, BML-111 attenuated elevated serum level of interleukin-6 (IL-6) and downregulated hepatic IL-6 mRNA expression. Meanwhile, BML-111 further increased serum IL-10 and upregulated hepatic IL-10 mRNA expression, while it downregulated hepatic mRNA expression of nuclear factor inhibitory protein kappa-B alpha (NFκBia), toll-like receptor-4 (TLR-4), and 5-lipooxygenase (5-LOX). Moreover, BML-111 prevented NF-κB/p65 nuclear translocation and activation. In conclusion, BML-111 attenuated CLP-induced acute hepatic dysfunction through its anti-inflammatory effect by decreasing NF-κB activity, TLR-4, and 5-LOX expression with subsequent decrease in pro-inflammatory IL-6 and elevation in anti-inflammatory IL-10.