Targeting SIRT1, NLRP3 inflammasome, and Nrf2 signaling with chrysin alleviates the iron-triggered hepatotoxicity in rats.

Blood transfusion-requiring diseases such as sickle cell anemia and thalassemia are characterized by an imbalance between iron intake and excretion, resulting in an iron overload (IOL) disorder. Hepatotoxicity is prevalent under the IOL disorder because of the associated hepatocellular redox and inflammatory perturbation. The current work was devoted to investigate the potential protection against the IOL-associated hepatotoxicity using chrysin, a naturally-occurring flavone. IOL model was created in male Wistar rats by intraperitoneal injection of 100 mg/kg elemental iron subdivided on five equal injections; one injection was applied every other day over ten days. Chrysin was administered in a daily dose of 50 mg/kg over the ten-day iron treatment period. On day eleven, blood and liver samples were collected and subjected to histopathological, biochemical, and molecular investigations. Chrysin suppressed the IOL-induced hepatocellular damage as revealed by decreased serum activity of the intracellular liver enzymes and improved liver histological picture. Oxidative damage biomarkers, and pro-inflammatory cytokines were significantly suppressed. Mechanistically, the levels of the redox and inflammation-controlling proteins SIRT1 and PPARγ were efficiently up-regulated. The liver iron load, NLRP3 inflammasome activation, and NF-κB acetylation and nuclear shift were significantly suppressed in the iron-intoxicated rats. Equally important, the level of the antioxidant protein Nrf2 and its target HO-1 were up-regulated. In addition, chrysin significantly ameliorated the IOL-induced apoptosis as indicated by reduction in caspase-3 activity and modulation of BAX and Bcl2 protein abundance. Together, these findings highlight the alleviating activity of chrysin against the IOL-associated hepatotoxicity and shed light on the role of SIRT1, NLRP3 inflammasome, and Nrf2 signaling as potential contributing molecular mechanisms.

Modulating SIRT1, Nrf2, and NF-κB signaling pathways by bergenin ameliorates the cadmium-induced nephrotoxicity in rats.

In light of the current industrial evolution, exposure to cadmium has become a significant public health concern. Cadmium accumulates in the renal tubular cells and causes nephrotoxicity largely through disruption of the redox homeostasis, induction of inflammation, and suppression of the histone deacetylase SIRT1 expression. The current work aimed at exploring the protective capability of bergenin, a naturally-occurring methyl gallic acid derivative, against the cadmium-evoked nephrotoxicity. Male Wistar rats were treated either with cadmium alone or with cadmium and bergenin for a 7-day experimental period followed by collection of kidney and blood specimens that were subjected to biochemical, molecular, and histological investigations. The results revealed the ability of bergenin to improve the renal functions in the cadmium-intoxicated rats as evidenced by increased glomerular filtration rate, and decreased serum creatinine and blood urea nitrogen. Equally important, bergenin reduced the renal tissue injury and enhanced its redox homeostasis as indicated by decreased protein expression of the kidney injury marker KIM-1, reduced lipid peroxidation, and improved antioxidant potential and histopathological picture of the renal tissues. Mechanistically, bergenin reduced the renal tissue cadmium content, markedly up-regulated protein expression of SIRT1 that regulates inflammation and the redox status of the renal tissues. Additionally, it improved the expression of the major antioxidant transcription factor Nrf2 and its responsive gene products heoxygenase-1 and NAD(P)H quinone dehydrogenase 1 in the cadmium-intoxicated rats. In the same context, bergenin down-regulated the acetylation and the nuclear translocation of the inflammatory transcription factor NF-κB and reduced levels of its responsive gene products TNF-α and IL-1ß, as well as the activity of the inflammatory cell infiltration biomarker myeloperoxidase. Collectively, the current study underscores the ameliorating activity of bergenin against the cadmium-evoked nephrotoxicity and highlights modulation of SIRT1, Nrf2, and NF-κB signaling as potential underlining molecular mechanisms.

Design, synthesis, docking, ADMET and anticancer evaluations of N-alkyl substituted iodoquinazoline derivatives as dual VEGFR-2 and EGFR inhibitors.

Fifteen new 1-alkyl-6-iodoquinazoline derivatives 5a-d to 9a-e were designed and synthesized and their anticancer activities were evaluated against HepG2, MCF-7, HCT116 and A549 cancer cell lines via dual targeting of EGFR and VEGFR-2. The newly synthesized compounds were designed based on the structure requirements of the target receptors and were confirmed using spectral data. Compound 9c showed the highest anticancer activities with EC50 = 5.00, 6.00, 5.17 and 5.25 µM against HepG2, MCF-7, HCT116 and A549 cell lines correspondingly. Moreover, compounds 5d, 8b, 9a, 9b, 9d, and 9e exhibited very good anticancer effects against the tested cancer cell lines. The highly effective seven derivatives 5d, 8b, 9a-e were examined against VERO normal cell lines to estimate their cytotoxic capabilities. Compounds 9c, 9b, 9d, 9a, 9e and 5d excellently inhibited VEGFR-2 activity with IC50 = 0.85, 0.90, 0.90, 1.00, 1.20 and 1.25 µM respectively. Moreover, compounds 9c, 9d, 9e, 5d, 8b and 9b excellently inhibited EGFRT790M activity with IC50 = 0.22, 0.26, 0.30, 0.40, 0.45 and 0.50 µM respectively. Also, compounds 9c, 9d and 9e excellently inhibited EGFRWT activity with IC50 = 0.15, 0.20 and 0.25 µM respectively. As planned, compound 9c showed excellent dual EGFR/VEGFR-2 inhibitory activities. Consonantly, ADMET study was calculated in silico for the supreme three worthwhile compounds 9b, 9c and 9e in contrast to sorafenib and erlotinib as reference drugs. The obtained results concluded that, our compounds might be useful as prototype for design, optimization, adaptation and investigation to have more powerful and selective dual VEGFR-2/EGFRT790M inhibitors with higher antitumor activity.

Five and six membered heterocyclic rings endowed with azobenzene as dual EGFRT790M and VEGFR-2 inhibitors: design, synthesis, in silico ADMET profile, molecular docking, dynamic simulation and anticancer evaluations.

Novel azobenzene scaffold-joined heterocyclic isoxazole, pyrazole, triazole, and/or triazine moieties have been developed and synthesized utilizing microwave and traditional methods. Our compounds were tested for growth inhibition of A549, MCF-7, HCT-116, and HepG2 tumors by dual targeting the VEGFR-2 and EGFRT790M enzymes. The suggested compound's manner of binding with EGFRT790M and VEGFR-2 active sites was explored through molecular design and MD modeling. The information from the results of the biological screening and the docking studies was highly correlated. The A549 cell line was the one that responded to the novel compound's effects most effectively. Having IC50 values of 5.15, 6.37, 8.44 and 6.23 µM, respectively, 14 was the most effective derivative on the four A549, MCF-7, HCT116 and HepG2 cancer cells. It had greater activity than erlotinib and slightly inferior activities on the tested cell lines than sorafenib, respectively. The cytotoxicity of the most effective derivatives, 5, 6, 10 and 14, was evaluated against typical VERO cell lines. Having IC50 values ranging from 42.32 to 55.20 µM, the results showed that the investigated drugs have modest toxicity against VERO normal cells. Additionally all derivatives were assessed for their dual VEGFR-2 and EGFRT790M inhibitory effects. Among them, derivatives 14, 5 and 10 were established as the greatest inhibitors of VEGFR-2 at IC50 values of 0.95, 1.25 and 1.50 µM correspondingly. As well, derivatives 14, 6, 5 and 10 could inhibit EGFRT790M activity demonstrating strongest effects with IC50 = 0.25, 0.35, 0.40 and 0.50 µM respectively. Furthermore, the ADMET profile was evaluated for compounds 5, 6, 10 and 14 in contrast to reference drugs sorafenib and erlotinib.

In vitro and computational investigations of novel synthetic carboxamide-linked pyridopyrrolopyrimidines with potent activity as SARS-CoV-2-MPro inhibitors.

An essential target for COVID-19 is the main protease of SARS-CoV-2 (Mpro). With the objective of targeting this receptor, a novel set of pyrido[1,2-a]pyrrolo[2,3-d]pyrimidines with terminal carboxamide fragments was designed, synthesized, and considered as an initial motif for the creation of effective pan-coronavirus inhibitors. Accordingly, nine derivatives (21-29) have been introduced for in vitro assay to evaluate their antiviral activity and cytotoxicity effect against COVID-19 virus using Vero cells. The obtained data revealed that the majority of these derivatives showed potent cellular anti-COVID-19 activity and prevent viral growth by more than 90% at two different concentrations with weak or even no detectable cytotoxic effect on Vero cells. Extensive molecular docking simulations highlighted proper non-covalent interaction of new compounds within the binding pocket of Mpro as a potential target for their antiviral activity. In vitro assay for all the synthesized derivatives against the viral Mpro target indicated that compounds 25 and 29 have promising inhibitory activity with IC50 values at low micromolar concentrations. The molecular dynamic simulation results predicted the stability of compound 29 in the binding cavity of SARS-CoV-2 Mpro and hence supported the high inhibitory activity shown by the In vitro assay. These results suggested that compounds 25 and 29 merit further investigations as promising drug candidates for the management of SARS-CoV-2.

Cross-talk between PPARγ, NF-κB, and p38 MAPK signaling mediates the ameliorating effects of bergenin against the iron overload-induced hepatotoxicity.

Hepatotoxicity is a serious health problem that associates the iron overload diseases such as thalassemia and sickle cell anemia. Induction of oxidative tissue injury and inflammation largely contributes to the iron-induced hepatotoxicity. The current study investigated the hepatoprotective potential of bergenin against the iron overload-associated hepatotoxicity. Male Wistar rats were treated with 30 mg/kg iron-dextran every other day over a ten-day period to establish an iron overload model. Bergenin was given in 80 mg/kg/day over the ten-day experimental period. Liver and blood specimens were then collected and subjected to various biochemical, histopathological, and molecular analyses. The results indicated that bergenin significantly decreased hepatic iron content and improved the hepatocellular integrity as demonstrated by reduced activity of the intracellular liver enzymes in the sera of the iron-intoxicated rats and alleviation of the iron-induced histopathological anomalies. Additionally, it alleviated the iron-induced oxidative tissue injury and improved the antioxidant potential of the liver tissue as reflected by decreased DNA oxidative damage and lipid peroxidation along with improved activity of the antioxidant enzymes. Equally important, bergenin attenuated the iron-evoked inflammation as indicated by down-regulation of the tumor necrosis factor alpha, interleukin-1 beta, myeloperoxidase, and cyclooxygenase-2. Mechanistically, bergenin suppressed the iron-induced nuclear translocation of the inflammatory transcription factor nuclear factor kappa B and phosphorylation of the inflammatory protein p38 mitogen-activated protein kinase. Interestingly, bergenin enhanced expression of the antioxidant and anti-inflammatory protein peroxisome proliferator-activated receptor gamma in the iron-intoxicated rats. Collectively, the presented study highlights the attenuating activity of bergenin on the iron-evoked hepatocellular injury and inflammation that is potentially mediated through targeting p38 mitogen-activated protein kinase and nuclear factor kappa B signaling as well as peroxisome proliferator-activated receptor gamma protein expression.

The Significance of FDG PET/CT-Derived Parameters in Determining Prognosis of Cases with Pancreatic Adenocarcinoma: A Prospective Study.

Background and objectives: Pancreatic adenocarcinoma represents one of the common malignancies with a relatively poor prognosis. However, early detection of this type of cancer may prove to be curable. Recent advancements in the radiological techniques might represent a hope for the early diagnosis and prediction of prognosis of pancreatic adenocarcinoma. This study aimed to assess the prognostic value of the primary tumor volumetric parameters obtained from FDG PET/CT first stage for the overall survival (OS) and progression-free survival (PFS) of patients with pancreatic adenocarcinoma and to explore the possible correlation between serum matrix metalloproteinase-2 (MMP-2) and the patients' characteristics. Methods: Fifty patients with pancreatic adenocarcinoma were subjected to FDG PET/CT scan. The SUVpeak, SUVmax, and the metabolic tumor volume (MTV) were determined, as well as the SUVmean of the liver. Moreover, serum levels of MMP-2 were assessed. Follow-up of the patients was carried out for sixty months with determination of PFS and OS. Results: Peak SUV ≥ 3.9 was significantly correlated with the primary pancreatic lesions' mean total glycolytic activity of >92 g, and MTV and was directly correlated with mortality. There was a positive correlation between peak SUV ≥ 3.9 and 50% SUVmax threshold > 82. Moreover, there was significant correlation between the total glycolytic activity and the studied clinicopathologic factors, except the age and sex of the patients and ECOG performance status. In addition, FDG uptake and the tumor glycolytic activity were substantially linked with a shorter PFS. Similarly, a strong correlation was found between MTV and PFS. Serum MMP-2 levels showed a significant relationship with the performance status, tumor stage, SUVmax threshold, and the glycolytic activity. Conclusions: Peak SUV, main lesion SUVmax, serum MMP-2, and the tumor glycolytic activity are good predictors of PFS of patients with pancreatic adenocarcinoma.

Targeting p-AKT/mTOR/MAP kinase signaling, NLRP3 inflammasome and apoptosis by fluvastatin with or without taxifolin mitigates gonadal dysfunction induced by bisphenol-A in male rats.

Bisphenol-A (BPA) is a chemical substance that is widely used in industry for manufacturing of plastic bottles and resins. Recent reports found that BPA may mimic the effects of estrogen to a great manner that might disrupt the normal hormonal balance in the human body. Fluvastatin is an agent used for treatment of hypercholesterolemia that was proven to possess promising antioxidant ant anti-inflammatory properties. Taxifolin is a polyphenolic compound with potential antioxidant and antiestrogenic effects. The present study investigated the prospect of fluvastatin with or without taxifolin to mitigate testicular dysfunction elicited by BPA in rats. In a model of BPA-induced testicular toxicity, the hormonal profile was assessed and the testicular tissues were examined by biochemical analysis, histopathology, and immunohistochemistry. Fluvastatin with or without taxifolin improved the body weight gain, hormonal profile, testicular weight and functions, sperm characteristics, the antioxidant status, and the anti-inflammatory mechanisms together with enhancement of autophagy and suppression of the proapoptotic events induced by BPA in the testicular tissues. In addition, fluvastatin with or without taxifolin significantly mitigated the histopathological and the immunohistochemical changes induced by BPA in the testicular tissues. These desirable effects were more pronounced with fluvastatin/taxifolin combination relative to the use of each of these agents alone. In tandem, fluvastatin/taxifolin combination might counteract the pathogenic events induced by BPA in the testicular tissues which may be considered as a novel strategy for amelioration of these disorders.

Galangin attenuates cadmium-evoked nephrotoxicity: Targeting nucleotide-binding domain-like receptor pyrin domain containing 3 inflammasome, nuclear factor erythroid 2-related factor 2, and nuclear factor kappa B signaling.

The kidney is highly vulnerable to cadmium-evoked oxidative injury. Galangin is a natural flavone with reported antioxidant properties. This study investigated the potential modulating activity of galangin against cadmium-induced nephrotoxicity and explored the underlining mechanisms. Western blot analysis, spectrophotometric, ELISA, and histopathological techniques were employed. The results revealed that galangin suppressed tubular injury and improved glomerular function in the cadmium-intoxicated rats as evidenced by downregulation of kidney injury molecule-1, serum creatinine, and blood urea nitrogen. Galangin reduced cadmium-evoked inflammatory response and oxidative stress as indicated by reduced levels of interleukin-1 beta and TNF-α, decreased DNA damage, and improved antioxidant potential of the renal tissues. Mechanistically, galangin suppressed the nucleotide-binding domain-like receptor pyrin domain containing 3 inflammasome and efficiently decreased caspase-1 activity in the cadmium-intoxicated rats. Equally important, it inhibited the cadmium-induced nuclear translocation of nuclear factor kappa B and upregulated nuclear factor erythroid 2-related factor 2 signaling. The results highlight the ability of galangin to attenuate cadmium-evoked nephrotoxicity and support its therapeutic implementation although clinical investigations are warranted.

Upregulation of Nrf2 signaling and suppression of ferroptosis and NF-κB pathway by leonurine attenuate iron overload-induced hepatotoxicity.

Hepatotoxicity is a major health concern that associates the iron overload diseases including hemochromatosis, sickle cell anemia, and thalassemia. Induction of ferroptosis, oxidative stress, and inflammation substantially mediates the iron-evoked hepatotoxicity. The current work investigated the potential protective effect of the natural alkaloid leonurine against the iron-induced hepatotoxicity and elucidated the underlining molecular mechanisms. Male Wistar rats were treated with iron only (30 mg/kg every other day over a ten-day period via intraperitoneal injection) or with iron and leonurine (leonurine: 100 mg/kg/day per oral via gastric gavage for 10 days) to establish the iron-overload model. Liver and blood specimens were then collected and subjected to molecular, biochemical, and histopathological investigations. The results revealed the ability of leonurine to suppress the iron-induced ferroptosis as reflected by modulation of the ferroptotic biomarkers glutathione peroxidase 4, cyclooxygenase-2, liver iron content, lipid hydroperoxides, and the leakage of the liver intracellular enzymes. Leonurine alleviated the iron-induced oxidative damage and inflammatory response in the liver tissues as indicated by decreased levels of DNA oxidation, lipid peroxidation, and the pro-inflammatory cytokines. In the same context, it improved the antioxidant potential of the liver tissues and ameliorated the iorn-induced histopathological abnormalities. Mechanistically, leonurine enhanced nuclear translocation of the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and increased protein levels of its downstream targets NAD(P)H-quinone oxidoreductase 1 and heme oxygenase-1. Additionally, it suppressed the nuclear translocation of the inflammatory transcription factor nuclear factor kappa B (NF-κB) and downregulated its downstream pro-inflammatory cytokines tumor necrosis factor-alpha and interleukin-1 beta. The study highlights the hepatoprotective activity of leonurine against the iron-evoked hepatotoxicity that is potentially mediated through modulation of Nrf2 and NF-κB signaling.

Arctigenin alleviates cadmium-induced nephrotoxicity: Targeting endoplasmic reticulum stress, Nrf2 signaling, and the associated inflammatory response.

AIM: Nephrotoxicity is a critical consequence of cadmium toxicity. Cadmium induces nephrotoxicity through disruption of cellular redox balance and induction of endoplasmic reticulum stress (ERS) and inflammatory responses. The present study investigated the renoprotective effects of the naturally occurring arctigenin against the cadmium-induced nephrotoxicity. MAIN METHODS: Male Wistar rats were randomized into normal control, arctigenin control, cadmium, and cadmium/arctigenin groups. Cadmium and arctigenin were administered daily over a seven-day period. On the eighth day, blood and kidney tissue specimens were collected and subjected to spectrophotometric, ELISA, and immunoblotting analysis. KEY FINDINGS: Arctigenin significantly improved renal functions and reduced renal tubular injury in the cadmium-intoxicated rats as reflected by increased GFR and reduced levels of serum creatinine, BUN, urinary albumin-to-creatinine ratio, and protein expression of KIM-1. Arctigenin alleviated the cadmium-induced oxidative DNA damage and lipid peroxidation while boosted reduced glutathione level and antioxidant enzymes activity. Mechanistically, arctigenin enhanced nuclear translocation of the antioxidant transcription factor Nrf2 and up-regulated its downstream redox-regulating enzymes HO-1 and NQO1. Importantly, arctigenin ameliorated the cadmium-evoked ERS as demonstrated by reduced protein expression of the key molecules Bip, PERK, IRE1α, CHOP, phspho-eIF2α, and caspase-12 and diminished activity of caspase-12. Additionally, arctigenin down-regulated the cadmium-induced NF-κB nuclear translocation and decreased its downstream pro-inflammatory cytokines TNF-α and IL-1ß. SIGNIFICANCE: The current work underlines the alleviating activity of arctigenin against cadmium-evoked nephrotoxicity potentially through mitigating ERS and targeting Nrf2 and NF-κB signaling. The current findings support possible therapeutic application of arctigenin in controlling cadmium-induced nephrotoxicity although clinical investigations are necessary.

Targeting Oxidative Stress, NLRP3 Inflammasome, and Autophagy by Fraxetin to Combat Doxorubicin-Induced Cardiotoxicity.

Doxorubicin belongs to the class of anthracycline antibiotics that is widely used in the treatment protocols of a wide range of malignancies. The major deleterious effect of doxorubicin use is the possible occurrence of cardiotoxicity. This study aimed to delineate the possible effects of targeting oxidative stress, NLRP3 inflammasome, and autophagy by fraxetin on doxorubicin-induced cardiac dysfunction in rats. In a model of doxorubicin-induced cardiotoxicity, the effects of different doses of fraxetin were assessed by determination of biochemical, histopathological, immunohistochemical, and electron microscopic changes. Fraxetin, in a dose-dependent manner, was found to have the ability to mitigate the harmful effects of oxidative stress and inflammation on myocardial muscles with significant decrease in NLRP3 inflammasome, augmentation of autophagy, and amelioration of the apoptotic signaling pathways. In addition, fraxetin, in a dose-dependent manner, had the ability to combat the echocardiographic, histopathological, immunohistochemical, and electron microscopic changes induced by doxorubicin in cardiomyocytes. As a result, fraxetin may be put into consideration as a new adjuvant line of therapy on the way to mitigate doxorubicin-induced cardiotoxicity.

The Expression of Circulating miR-497 and Metadherin in Hepatocellular Carcinoma: Relation to the Tumor Characteristics and Patients' Survival.

Objectives: This study aimed to evaluate the prognostic significance and relationship of miR-497 and metadherin to hepatocellular carcinoma (HCC) tumor characteristics and patients' survival. Methods: This study enrolled 120 (60 HCC patients and 60 healthy) subjects. Serum miR-497 and metadherin mRNA relative expression were analyzed by real-time quantitative reverse transcription polymerase chain reaction. The overall survival (OS) of HCC patients was assessed using the Kaplan-Meier curve and log-rank test. Results: Serum miR-497 showed statistically significant downregulation in HCC patients compared to controls (p < 0.001). Serum metadherin mRNA relative expression was significantly upregulated in HCC patients compared to controls (p < 0.001). Both serum miR-497 and metadherin mRNA expression were significantly associated with the number of tumor foci (p = 0.028 and 0.001, respectively), tumor size (p = 0.022 and <0.001, respectively), nodal metastasis (p = 0.003 and 0.003, respectively), distant metastasis (p = 0.003 and 0.003, respectively), vascular invasion (p = 0.040 and <0.001, respectively), and BCLC staging (p = 0.043 and 0.004, respectively). The overall survival was lower in patients with low miR-497 expression (p = 0.046) and in patients with high metadherin expression (p < 0.001). Conclusions: The expression levels of miR-497 showed downregulation in HCC patients, but metadherin expression showed upregulation. Both markers were inversely related and closely correlated with tumor characteristics and patients' survival.

The Prognostic Significance of MACC1 Expression in Breast Cancer and Its Relationship to Immune Cells in the Tumor Microenvironment and Patient Survival.

Breast cancer (BC) is one of the most prevalent malignancies among females worldwide. Globally, distant metastases were reported to be responsible for a large proportion of breast cancer-related deaths. The metastasis-associated colon cancer-1 (MACC1) gene was reported as a reliable biomarker for early detection of metastasis and prediction of prognosis of breast cancer. This study investigated the prognostic significance of MACC1 in breast cancer in relation to the clinicopathologic characteristics and patients' survival. Furthermore, the possible correlation between MACC1 expression and the different immune cells in the tumor microenvironment was explored. MACC1 mRNA was identified using quantitative reverse transcription polymerase chain reaction in 120 breast cancer specimens and adjacent non-cancerous tissues. MACC1 mRNA expression was significantly higher in the cancerous relative to the non-cancerous tissues (p < 0.001). High MACC1 expression was significantly associated with poor prognostic parameters, such as larger tumor size, grade III tumors, positive nodal metastasis, lymphovascular invasion, stage III tumors, and elevated Ki-67 expression. Higher MACC1 mRNA levels were positively correlated with CD163+ tumor-associated macrophages (r = 0.614, p < 0.001), and were negatively correlated with CD56+ natural killer cells (r = -0.398, p < 0.001) and CD8+ cytotoxic T lymphocytes (r = -0.323, p < 0.001). MACC1 expression was associated with poor patient overall survival (OS) and progression-free survival (PFS) (p < 0.001). Multivariate analysis suggested that MACC1 expression and the presence of lymphovascular invasion could be independent prognostic indicators for breast cancer (p = 0.015 and 0.042, respectively). In conclusion, MACC1 is highly expressed in cancerous tissues and is significantly related to poor prognostic factors, overall survival, and progression-free survival. MACC1 may influence infiltration of the immune cells in the tumor microenvironment, enhance immune escape of tumor cells, and may serve as a reliable independent prognostic factor for breast cancer.

Galangin mitigates iron overload-triggered liver injury: Up-regulation of PPARγ and Nrf2 signaling, and abrogation of the inflammatory responses.

AIM: Hepatotoxicity is a critical consequence of the iron overload conditions such as hemochromatosis and blood transfusion-requiring anemia. Iron induces hepatotoxicity largely through disruption of cellular redox homeostasis and induction of inflammatory responses. The present work explored the hepatoprotective activity of the bio-active flavone galangin against iron-evoked hepatotoxicity. MAIN METHODS: Iron overload model was established in male Wistar rats via intraperitoneal injection of 150 mg/kg iron-dextran subdivided over a ten-day experimental period. Galangin was administered in a daily oral dose of 15 mg/kg throughout the experimental period. Blood and liver tissue samples were collected on day eleven and subjected to biochemical and molecular investigations. KEY FINDINGS: Galangin significantly reduced liver iron content and serum ferritin level, and alleviated the iron-evoked oxidative stress. It enhanced the liver cell integrity as reflected by decreased serum activity of the liver enzymes. Mechanistically, galangin up-regulated the redox-regulating transcription factor Nrf2 and its responsive proteins HO-1 and NQO1. Interestingly, galangin up-regulated the antioxidant and anti-inflammatory protein PPARγ and serum hepcidin levels under the iron overload conditions. Equally important, it diminished the nuclear shift of the inflammatory transcription factor NF-κB p65 and down-regulated the levels of the pro-inflammatory cytokines TNF-α and IL-1ß. SIGNIFICANCE: The results of the present study highlight the mitigating activity of galangin against iron-induced hepatotoxicity. The study accentuated targeting of Nrf2, PPARγ, and NF-κB signaling as potential contributing mechanisms. While clinical studies are still required, the current study supports the possible implementation of galangin in controlling iron overload-associated hepatotoxicity.

Design, synthesis, molecular docking and in silico ADMET profile of pyrano[2,3-d]pyrimidine derivatives as antimicrobial and anticancer agents.

Pyrano[2,3-d]pyrimidine derivatives were synthesized by treating cyclic compounds containing active methylene group with aldehyde and malononitrile in butanol. The behavior of pyrano[2,3-d]pyrimidine towards some electrophlies namely triethylorthoformate followed by nitrogen nucleophiles as isobutylamine, urea, phenylthiourea, p-toluidine, o-phenylenediamine, o-aminophenol, 2-amino-4-methyl-pyridine and acetic acid with the aim of obtaining some interesting non-mixed heterocyclic compounds. All synthesized compounds to some extent have shown good antimicrobial activity against different microbial strains that had been extracted by inhibiting cell wall synthesis. Compound 5b showed the highest antibacterial activities against B. subtilis, S. aureus and E. coli. On the other hand compound 5 g exhibited the highest antibacterial and antifungal activities against P. aeruginosa and A. niger respectively. In addition, they explore cytotoxic potentialities against different cell lines via DNA intercalation and Top-II inhibition. The cytotoxic activities clarify the strong inhibitory activity of derivative 5a against HepG2 cells with IC50 = 2.09 µM, while HCT-116 cells were highly susceptible to derivative 5c with IC50 = 2.61 µM, in the meantime, derivative 5f showed pronounced negative impact against MCF-7 (IC50 = 2.43 µM) when compared with other prepared compounds. All derivatives exhibited higher anticancer activities than doxorubicin against the three cell lines except compound 2 against both HepG2 and MCF-7 and compound 5e against HepG2 cell lines. Compounds 5a, 5c and 5f potently intercalate DNA at IC50 values of 26.96, 27.13 and 29.86 µM respectively, which were more potent than doxorubicin (IC50 value of 31.27 µM). Moreover, compounds 5a, 5c and 5f exhibited very good Topoisomerase II inhibitory activities with IC50 values of 0.752, 0.791 and 0.776 µM respectively, that were more potent than that of doxorubicin (IC50 = 0.94 µM). For a great extent, the molecular modeling studies were in agreement with that of in vitro cytotoxicity activity, DNA binding and Top-II inhibition results.

Ergothioneine mitigates cisplatin-evoked nephrotoxicity via targeting Nrf2, NF-κB, and apoptotic signaling and inhibiting γ-glutamyl transpeptidase.

AIM: Cisplatin is a potent chemotherapeutic agent whose therapeutic application is hindered by the associated nephrotoxicity. Cisplatin-evoked nephrotoxicity has been largely attributed to the induction of oxidative stress and inflammatory responses. The current study aimed at investigating the ability of ergothioneine to mitigate cisplatin-evoked nephrotoxicity and to elucidate the underlining molecular mechanisms. MAIN METHODS: Wistar rats were treated with a daily dose of ergothioneine (70 mg/kg, po) for fourteen days and a single dose of cisplatin (5 mg/kg, ip) on day ten. On day fifteen, kidneys and blood specimens were collected and subjected to Western blotting, ELISA, histopathological, and spectrophotometric analysis. KEY FINDINGS: Ergothioneine significantly enhanced renal function in cisplatin-treated rats as manifested by increased GFR and decreased serum creatinine and blood urea nitrogen. Ergothioneine effectively reduced the cisplatin-induced oxidative stress and mitigated apoptosis and the histopathological changes. Mechanistically, ergothioneine induced the expression of the antioxidant transcription factor Nrf2 and up-regulated its downstream targets NQO1 and HO-1. Equally important, ergothioneine inhibited γ-glutamyl transpeptidase that plays crucial roles in biotransformation of cisplatin into a toxic metabolite. Additionally, it reduced the pro-apoptotic protein p53 and the inflammatory transcription factor NF-κB along with its downstream pro-inflammatory cytokines TNF-α and IL-1ß. SIGNIFICANCE: The results of the current work shed the light on the ameliorating effect of ergothioneine on cisplatin-evoked nephrotoxicity that is potentially mediated through modulation of Nrf2, p53, and NF-κB signaling and inhibition of γ-glutamyl transpeptidase. This findings support the potential application of ergothioneine in controlling cisplatin-associated nephrotoxicity although clinical investigations are warranted.

Design of molecular hybrids of phthalimide-triazole agents with potent selective MCF-7/HepG2 cytotoxicity: Synthesis, EGFR inhibitory effect, and metabolic stability.

This study reports an efficient and convenient click chemistry synthesis of a novel series of phthalimide scaffold linked to 1,2,3 triazole ring and terminal lipophilic fragments. Structures of newly synthesized compounds were well characterized by different spectroscopic tools. In vitro MTT cytotoxicity assay was performed comparing the cytotoxic effects of newly synthesized compounds to staurosporine using three different types: human liver cancer cell line (HepG2), Michigan cancer foundation-7 (MCF-7) and human colorectal carcinoma cell line (HCT116). The initial screening showed excellent to moderate anticancer activity for these newly synthesized compounds with high degree of cell line selectivity with micromolar (µM) half maximal inhibitory concentration (IC50) values against tumor cells. The SAR analysis of these derivatives confirmed the role of molecular fragments including phthalimide, linker, triazole, and terminal tails in correlation to activity. In addition, enzymatic inhibitory assay against wild type EGFR was performed for the most active compounds to get more details about their mechanism of action. In order to further explore their binding affinities, molecular docking simulation was studied against EGFR site. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated. One of the most prominent analogs is (6f) with terminal disubstituted ring and amide linker showed selective MCF-7 cytotoxicity profile with IC50 0.22 µM and 79 nM to EGFR target. Extensive structure activity relationship (SAR) analyses were also carried out. The pharmacokinetic profile of (6f) was studied showing good metabolic stability and long duration behavior. This design offered a potent selective anticancer phthalimide-triazole leads for further optimization in cancer drug discovery.

Modulating NF-κB, MAPK, and PI3K/AKT signaling by ergothioneine attenuates iron overload-induced hepatocellular injury in rats.

The liver is highly susceptible to iron overload-evoked oxidative injury. Ergothioneine is a thio-histidine amino acid that has exhibited strong antioxidant and metal chelating activities. This study aimed at exploring the potential modulating effects of ergothioneine on iron-triggered liver injury. The results showed that ergothioneine inhibited iron-evoked inflammation and apoptosis as demonstrated by a significant reduction in tumor necrosis factor-α and interleukin-6 levels and in caspase-3 activity. Ergothioneine significantly improved liver cell survival as indicated by modulating phosphatidylinositol 3-kinase/protein kinase B signaling. Consistent with reduced necrotic cell death, ergothioneine diminished the iron-evoked histopathological changes and decreased serum activity of the liver enzymes. Mechanistically, ergothioneine reduced nuclear translocation of nuclear factor kappa B p65 and modulated p38 mitogen-activated protein kinase/c-Fos signaling. In addition, it enhanced the liver tissue antioxidant potential and curbed hepatic iron load. Together, these results point out the modulatory effects of ergothioneine on iron-evoked liver cell injury that are possibly mediated via anti-inflammatory, antioxidant, and possible iron chelation capabilities.

Taxifolin ameliorates iron overload-induced hepatocellular injury: Modulating PI3K/AKT and p38 MAPK signaling, inflammatory response, and hepatocellular regeneration.

Although physiological levels of iron are essential for numerous biological processes, excess iron causes critical tissue injury. Under iron overload conditions, non-chelated iron generates reactive oxygen species that mediate iron-induced tissue injury with subsequent induction of apoptosis, necrosis, and inflammatory responses. Because liver is a central player in iron metabolism and storage, it is vulnerable to iron-induced tissue injury. Taxifolin is naturally occurring compound that has shown potent antioxidant and potential iron chelation competency. The aim of the current study was to investigate the potential protective effects of taxifolin against iron-induced hepatocellular injury and to elucidate the underlining mechanisms using rats as a mammalian model. The results of the current work indicated that taxifolin inhibited iron-induced apoptosis and enhanced hepatocellular survival as demonstrated by decreased activity of caspase-3 and activation of the pro-survival signaling PI3K/AKT, respectively. Western blotting analysis revealed that taxifolin enhanced liver regeneration as indicated by increased PCNA protein abundance. Taxifolin mitigated the iron-induced histopathological aberration and reduced serum activity of liver enzymes (ALT and AST), highlighting enhanced liver cell integrity. Mechanistically, taxifolin modulated the redox-sensitive MAPK signaling (p38/c-Fos) and improved redox status of the liver tissues as indicated by decreased lipid peroxidation and protein oxidation along with enhanced total antioxidant capacity. Interestingly, it decreased liver iron content and down-regulated the pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß. Collectively, these data highlight, for the first time, the ameliorating effects of taxifolin against iron overload-induced hepatocellular injury that is potentially mediated through anti-inflammatory, antioxidant, and potential iron chelation activities.