Geraniol prevents CCl4-induced hepatotoxicity via suppression of hepatic oxidative stress, pro-inflammation and apoptosis in rats.

Carbon tetrachloride (CCl4) is a classic chemical hepatotoxicant that triggers liver damage through hepatic exacerbation of oxidative stress. Geraniol (GRL) is a natural bioactive acyclic monoterpene with several pharmacological effects. We thus explored whether GRL could prevent CCl4-triggered hepatic toxicity. Rats were divided and administered GRL (100 mg/kg) and/or CCl4 (1 ml/kg of 1:1 v/v CCl4: olive oil) in Control group, GRL group, CCl4 group, GRL + CCl4 groups 2 times per week for 4 consecutive weeks. CCl4 caused significantly (p < 0.05) elevated serum activities of alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TB), whereas the albumin (ALB) and total protein (TP) levels were significantly (p < 0.05) reduced relative to the control group. The liver activities of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) decreased significantly (p < 0.05), while malondialdehyde (MDA) level evidently elevated in comparison to the control group. The CCl4 exposure caused significant increases in proinflammatory interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), apoptotic caspase-3 and caspase-9 levels, whereas the anti-inflammatory interleukin-4 (IL-4) and interleukin-10 (IL-10) were reduced in consistent with histopathological changes compared to the control. On the contrary, the GRL administration prevented the hepatic toxicity and lesions through restoration of liver status markers, antioxidant enzyme activities, MDA, cytokines and apoptosis in comparison to the CCl4 group. Altogether, the findings reveal that GRL could abrogate CCl4-provoked hepatic toxicity via inhibition of hepatic oxidative stress, inflammation and apoptosis in rats.

Capric Acid Behaves Agonistic Effect on Calcitriol to Control Inflammatory Mediators in Colon Cancer Cells.

Inflammation prompts cancer development and promotes all stages of tumorigenesis. Calcitriol is a nutraceutical essential regulator for host health benefits. However, the influence of calcitriol on inflammatory mediators involved in cancer cells is not clear. This study aimed to assess the sensitivity of calcitriol alone and combined with capric acid, and identify the possible influence of calcitriol on inflammatory mediators. The colorectal cancer cell line (HCT116) was induced by LPS/TNF-α and the inflammation and metastatic mediators (IL-1ß, IL-6, IL-17) were quantified in calcitriol and capric acid supplemented colon cancer cells. The mRNA and protein expression of MMP-2, NF-κB and COX-2 were quantified. The significant reduction in MMP-2 expression was confirmed at combination treatment by zymogram analysis. Our findings demonstrated the anti-inflammatory and anti-metastatic potentials of capric acid and calcitriol in individual exposure in a combination of human colon cancer cell lines (HCT116). These abilities may be due to the inhibition of COX-2 mediators and NF-κB transcription factor and reciprocally regulated MMP-2 and MMP-9 signaling pathways. These findings elucidate the activation of COX-2 and NF-κB via disruption of the cellular outer matrix could be considered a novel molecular target suitable for colorectal cancer therapy. This study confirmed that capric acid activates calcitriol sensitization in colon cancer cells and could be used as a successful supplement for intestinal diseases and colon aberrations.

Synthesis, Anticancer, Antioxidant, Anti-Inflammatory, Antimicrobial Activities, Molecular Docking, and DFT Studies of Sultams Derived from Saccharin.

A series of N-substituted saccharins namely 2-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl) acetonitrile (2) and (alkyl 1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl) acetate (3a-g) were synthesized, in moderate to excellent yields, from commercially available starting materials by two different approaches and their chemical structures were characterized by spectroscopic techniques (1H-NMR, 13C-NMR, IR, and MS). All the synthesized compounds were evaluated for their anti-inflammatory toward IL-6 and TNF-α, antioxidant, as well as their anticancer activities against hepatic cancer cells. In addition, their anti-fungal and antibacterial activities against both Gram-positive and Gram-negative bacteria were tested. All the tested compounds have exhibited excellent (3a, d, e) to moderate anti-inflammatory activity. Additionally, esters (3b, f) and nitrile (2) showed excellent antioxidant activity. Furthermore, ester 3f, with isopropyl ester, exhibited the highest cytotoxic activity compared to the other esters. Moreover, all compounds were evaluated as selective inhibitors of the human COX-1 enzyme using molecular docking by calculating the free energy of binding, inhibition constant, and other parameters to find out the binding affinity. The molecular study showed that esters (3d, f) and nitrile (2) revealed the highest binding affinities, hence enhancing the inhibition activity with the active site of the COX-1 enzyme. All the tested compounds have more negative Gibbs free, electrostatic, and total intermolecular energies than the standard inhibitor ASA. These results indicate that, all the tested sultams are potent anti-inflammatory drugs as compared to standard inhibitors. Finally, the chemical properties and the quantum factors of synthesized sultams were calculated based on density functional theory (DFT) to predict reactivity, and then correlated with the experimental data. Ester 3f showed the lowest ionization potential and lowest energy gap (Egap = 7.5691 eV), which was correlated with its cytotoxic activity. Furthermore, the spatial electron distribution of HOMO, LUMO were computed and it clearly indicates the electron donation ability of all the tested compounds.

Ruscogenin Protects Against Deoxynivalenol-Induced Hepatic Injury by Inhibiting Oxidative Stress, Inflammation, and Apoptosis Through the Nrf2 Signaling Pathway: An In vitro Study.

Background: Deoxynivalenol (DON) is a trichothecene mycotoxin with demonstrated cytotoxicity in several cell lines and animals, primarily owing to inflammation and reactive oxygen species accumulation. Ruscogenin (RGN), a steroidal sapogenin of Radix Ophiopogon japonicus, has significant anti-thrombotic/anti-inflammatory effects. Objective: The aim of this study was to assess the protective role of RGN against DON-induced oxidative stress, which occurs through the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and is regulated by phosphoinositide 3-kinases/protein kinase B (PI3K/AKT). Methods: The effects were examined using the HepG2 cell line. RGN and DON were suspended in serum-free medium. Cells were seeded onto plates, and then RGN, DON, or both were added over 24 h in triplicates for each group. Results: RGN conferred protection against DON-exhibited cytotoxicity against HepG2 cells. RGN pretreatment downregulated the expression of DON-induced TNF-α and COX-2 and the formation of reactive oxygen species in a dose-dependent manner. RGN upregulated the expression of Nrf2 and its antioxidant proteins as well as mRNA levels of HO-1/NQO-1/HO-1/Nrf2. Similarly, treatment with DON + RGN resulted in upregulation of the pI3K/pAKT signaling pathway in a dose-dependent manner. Finally, RGN was also found to inhibit the DON-induced apoptosis by upregulating the levels of cleaved proteins and downregulating the expression of Bcl2. Conclusion: The study demonstrates that RGN suppresses hepatic cell injury induced by oxidative stress through Nrf2 via activation of the pI3K/AKT signaling pathway.

Acacetin Inhibits Cell Proliferation and Induces Apoptosis in Human Hepatocellular Carcinoma Cell Lines.

Human hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of death across the world. Recent evidence suggests that STAT3 regulates proliferative, survival, metastasis, and angiogenesis genes in HCC. Novel agents that suppress STAT3 activation can be used to prevent or treat HCC. We used a functional proteomics tumor pathway technology platform and multiple HCC cell lines to investigate the effects of acacetin (ACN) on STAT3 activation, protein kinases, phosphatases, products of STAT3-regulated genes, and apoptosis. ACN was found to inhibit STAT3 activation in a dose- and time-dependent manner in HCC cells. Upstream kinases c-Src, Janus-activated kinase 1, and Janus-activated kinase 2 were also inhibited. The ACN inhibition of STAT3 was abolished by vanadate treatment, suggesting the involvement of tyrosine phosphatase activity. ACN was found to suppress the protein expression of genes involved in proliferation, survival, and angiogenesis via STAT3 inhibition. ACN appears to be a novel STAT3 inhibitor and may be a promising therapeutic compound for application in the treatment of HCC and other cancers.

Novel Organoselenium Redox Modulators with Potential Anticancer, Antimicrobial, and Antioxidant Activities.

Novel organic selenides were developed in good yields (up to 91%), and their chemical entities were confirmed by IR, MS, and 1H- and 13C-NMR spectroscopy. Their anticancer and antimicrobial properties were estimated against different human cancer (MCF-7 and HepG2) and healthy (WI-38) cell lines, as well as several microbial strains (Escherichia coli, Staphylococcus aureus, and Candida albicans). Furthermore, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) bioassays were used for the estimation of the antioxidant activities. Generally, cytotoxicity results were more pronounced against the MCF-7 cells than HepG2 cells. Compound 2-((4-((1-hydroxynaphthalen-2-yl)diazenyl)phenyl)selanyl)-N-phenylacetamide (9) was the most cytotoxic, even more than doxorubicin, with IC50 of 3.27 ± 0.2 against 4.17 ± 0.2 µM and twelve-times more selective, respectively. Interestingly, compound 9 exhibited similar antimicrobial potential to reference antibacterial and antifungal drugs and comparable antioxidant activity to vitamin C. These results point to selective cytotoxicity against MCF-7 cells and interesting antimicrobial and antioxidant properties of some newly synthesized organic selenides, which in turn needs further in vitro studies.

Colour-switchable and photoluminescent polyvinyl chloride for multifunctional smart applications.

Recycled polyvinyl chloride (PVC) waste was used to prepare transparent materials with long-lasting phosphorescence, photochromic activity, hydrophobicity, strong optical transmission, ultraviolet (UV) light protection, and stiffness. Lanthanide-activated aluminate (LaA) microparticles were prepared using a high temperature solid-state procedure, and were subjected to top-down grinding technology to produce lanthanide-aluminate nanoparticles (LaAN). Laminated PVC bottles were shredded into a transparent plastic matrix, which was combined with LaAN and drop casted to produce smart materials for various applications. Smart windows and photochromic film for smart packaging can be made from recycled PVC waste by immobilizing it with various ratios of LaAN. Long-lasting phosphorescent translucent PVC smart windows and films need LaAN to be evenly dispersed in PVC without clumping. Different analytical methods were used to assess the material's morphological structure and chemical composition. Photoluminescence and decay spectra were all used to investigate the luminescence characteristics. In addition, the mechanical performance was studied. According to Commission Internationale de l'Éclairage laboratory colour measurements, this transparent PVC smart material becomes bright green under UV rays and turns a greenish-yellow in the dark. The PVC luminescence was observed to exhibit apparent emission bands at 429 and 513 nm when excited at 367 nm. Improvements were monitored in UV shielding and hydrophobicity when increasing the phosphor concentration. LaAN-immobilized PVC exhibited reversible photochromism. The present approach can be applied to various applications such as anticounterfeiting films for smart packaging, smart windows, and warning light marks.

Beneficial role of naringin against methotrexate-induced injury to rat testes: biochemical and ultrastructural analyses.

BACKGROUND: Methotrexate (MTX) is a commonly used chemotherapeutic drug that has adverse toxic effects on germ cells. Naringin (NG) is a natural flavanone glycoside, with different phytotherapeutic applications, and its possible protective effects against MTX-induced testicular tissue damage were investigated in this study. METHODS: Low and high doses of NG (40 and 80 mg/kg/day) were given for 10 days by intraperitoneal (i.p.) injection and MTX (20 mg/kg i.p.) was given at the 4th day of the experiment, with or without NG in rats. RESULTS: The obtained results showed that exposure to MTX increased malondialdehyde (MDA) levels and nitric oxide (NO) production compared with the control. In the meantime, MTX depleted catalse (CAT), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), and reduced glutathione (GSH) in the testicular tissue. Further, serum testosterone levels were significantly decreased in the MTX group. NG significantly counteracted the aforementioned effects of MTX; however, NG80 was more effective in restoring SOD, GR, MDA and NO. Interestingly, NG80 achieved a better improvement in the ultrastructural pattern of the testicular cells in MTX-exposed rats. CONCLUSION: These results indicated, for the first time, that NG could be a potential candidate therapy against MTX-reprotoxic impacts.

Design, Synthesis, and Biological Evaluations of Novel Azothiazoles Based on Thioamide.

Herein we studied the preparation of different thiazoles via the reaction of 2-(3,4-dimethoxybenzylidene)hydrazine-1-carbothioamide (1) with hydrazonoyl halides under base-catalyzed conditions. The reactions proceed through nucleophilic substitution attack at the halogen atom of the hydrazonoyl halides by the thiol nucleophile to form an S-alkylated intermediate. The latter intermediate undergoes cyclization by the loss of water to afford the final products. The structures of the azo compounds were confirmed by FTIR, MS, NMR, and elemental analyses. Indeed, the newly synthesized azo compounds were estimated for their potential anticancer activities by an MTT assay against different human cancer cells, such as lung adenocarcinoma (A549) and colorectal adenocarcinoma (DLD-1). The caspase-3 levels were also estimated using Western blotting and the dual staining technique to evaluate the potency of the titled compounds to promote apoptosis.

Silymarin abrogates acrylamide-induced oxidative stress-mediated testicular toxicity via modulation of antioxidant mechanism, DNA damage, endocrine deficit and sperm quality in rats.

Acrylamide (ACR) is a toxic chemical formed in foods processed at high temperature; it is a food-borne toxicant with increasing public health attention due to its carcinogenic, neurotoxic and reproductive toxicities. However, till date, it is unknown whether silymarin (SIL) could attenuate ACR testicular toxicity. Therefore, the present study investigated the effect of SIL on ACR testiculotoxicity in rats. Rats were randomly divided and administered respective agents in Control group, ACR group, SIL group and ACR + SIL group for consecutive 14 days. Rat exposure to ACR resulted in significant reduction in the level of serum testosterone, whereas FSH and LH levels prominently increased compared to control. Acrylamide induced marked decreases in sperm count and sperm motility followed by a considerable increase in sperm abnormality percentage in the ACR-exposed rats in comparison to control. The testicular activities of glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) were significantly diminished, whereas malondialdehyde (MDA) level considerably increased. Additionally, ACR induced marked DNA fragmentation and histopathological lesions compared to control. Interestingly, the co-treatment of SIL with ACR attenuated the altered reproductive indices and restored antioxidant balance and DNA integrity. Overall, SIL prevents ACR-induced testicular reproductive deficits via modulation of antioxidant mechanism in rats.

Antidiabetic Wound Dressing Materials Based on Cellulosic Fabrics Loaded with Zinc Oxide Nanoparticles Synthesized by Solid-State Method.

The current study aims for the use of the solid-state technique as an efficient way for the preparation of zinc oxide nanoparticles (ZnONPs) as an antimicrobial agent with high concentration using sodium alginate as stabilizing agent. ZnONPs were prepared with three different concentrations: ZnONPs-1, ZnONPs-2, and ZnONPs-3 (attributed to the utilized different concentrations of zinc acetate, 1.5, 3 and 4.5 g, respectively). The as-fabricated ZnONPs (ZnONPs-1, ZnONPs-2, and ZnONPs-3) were used for the treatment of cellulosic fabrics as dressing materials for the diabetic wounds. DLS findings illustrated that the as-prepared ZnONPs exhibited average particle size equal to 78, 117, and 144 nm, respectively. The data also showed that all the formulated ZnONPs were formed with good stability (above -30 mv). The topographical images of cellulosic fabrics loaded with ZnONPs that were obtained by SEM confirmed the deposition of nanoparticles onto the surface of cellulosic fabrics with no noticeable agglomeration. The findings also outlined that the treated cellulosic fabrics dressings were proven to have enhanced bactericidal characteristics against the pathogenic microorganisms. The finding of wound contraction for the diabetic rats was measured after 21 days and reached 93.5% after treating the diabetic wound with cotton fabrics containing ZnONPs-2. Ultimately, the generated wound dressing (cellulosic fabrics loaded with ZnONPs) offers considerable promise for treating the wound infections and might be examined as a viable alternative to antibiotics and topical wound treatments.

In vivo evaluation of the protective effects of arjunolic acid against lipopolysaccharide-induced septic myocardial injury.

Lipopolysaccharide (LPS) is a glycolipid component of the cell wall of Gram-negative bacteria, which induces multiple organ dysfunctions, eventually leading to septic shock and death. Arjunolic acid (AA) has been shown to have therapeutic benefits against various organ pathophysiologies, although its role in sepsis remains unclear. Here, we evaluated the effects of AA on LPS-induced free radical production and cardiotoxicity. Male albino mice were allocated to four groups: normal, 1.5 µg/30 g b.w. of LPS (LPS), 20 mg/kg b.w. AA with LPS (AA+LPS) and 20 mg/kg b.w. of AA (AA). Subsequently, blood and heart samples were harvested for biochemical and histopathological examinations. Pretreatment with AA attenuated LPS-induced increased serum levels of cardiac troponin I, lactate dehydrogenase and creatine kinase. In the meantime, AA pretreatment before LPS resulted in a significant increase in endogenous antioxidants (superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione) and a significant decrease in the level of lipid peroxidation product (malondialdehyde) in the heart as compared to the LPS group, while cardiac cytochrome c activity were significantly increased. In addition, in the AA-pretreated mice, C-reactive protein and proinflammatory cytokines (interlukin-1 and tumor necrosis factor-alpha) were significantly reduced, and anti-inflammatory cytokines (interleukin-4 and -10) were significantly increased in cardiac tissues as compared to the LPS-treated animals. Furthermore, prior administration of AA to LPS exposed mice led to a significant a significant decrease in heart caspase-3, -8, and -9 as compared to the LPS group. Interestingly, AA was also able to improve LPS-induced histopathological changes in the cardiomyocytes. In conclusion, these in vivo findings indicate that AA may be a promising cardioprotective agent against LPS-stimulated cardiotoxicity, at least in part, through upregulation of cardiac antioxidants, reduction of lipid peroxidation, and inhibition of inflammation and cardiac cell death.

Nephroprotective effect of naringin in methotrexate induced renal toxicity in male rats.

The current work aims to study the nephroprotective potential of naringin (NG), a flavanone derived from citrus fruits, in methotrexate (MTX)-induced renal toxicity. Thirty male rats were divided into five groups; control group (IP saline), MTX group (IP single dose, 20 mg/kg), and three groups co-treated with MTX and naringin (IP daily dose; 20, 40, and 80 mg/kg, respectively). Kidney tissues were used to investigate renal function, oxidative stress, lipid peroxidation, and caspase-3 activity. Biochemical cytokine analysis was performed in addition to ultrastructural examinations of kidney tissue. When compared to the MTX-treated rats, MTX+NG significantly reduced the levels of urea, creatinine, MDA, NO, TNFα, IL-6, and caspase-3 activity. A significant increase in the levels of the antioxidant enzymes and GSH were also noted. Additionally, naringin ameliorated the apparent ultrastructural changes observed in the glomeruli and renal tubules of MTX-intoxicated rats. Noticeable structural improvements of glomerular lesions, proximal, and distal convoluted tubular epithelium were observed in MTX+NG treated animals, including podocytes with regular foot processes, perfectly organized filtration barrier, no signs of GBM thickening, organized brush border, and normal architecture of microvilli. Naringin (80 mg/kg) had the maximum amelioration effect. To the best of our knowledge, this is the first study to investigate the ultrastructural manifestations of naringin and/or MTX on the kidney of rats. Taken all, naringin has a potent therapeutic effect and can be used in adjuvant therapy to prevent MTX-induced nephrotoxicity. Nevertheless, the molecular mechanism underlying the nephroprotective capacity of naringin needs further investigation.

Analysis of silymarin-modulating effects against acrylamide-induced cerebellar damage in male rats: Biochemical and pathological markers.

BACKGROUND: Acrylamide (ACR) is a well-proven neurotoxin and potential food carcinogen in humans and rodent models. Silymarin (SIL) is a flavonoid mixture isolated from seeds, leaves, and fruits of Silymarin marianum (milk thistle) that possesses a free-radical scavenging effect. OBJECTIVE: In this work, the primary focus was to investigate the efficacy of SIL to mitigate ACR-induced subacute neurotoxic effects and oxidative changes in rat cerebellum. METHODS: Adult male rats were treated intraperitoneally with ACR (50 mg/kg) with or without SIL (160 mg/kg). The neuropathology and biochemical parameters viz. lipid peroxidation (measured as levels of malondialdehyde or MDA), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), serotonin (5-hydroxytryptamine; 5-HT), dopamine (DA), and cathepsin D (CTSD) in the cerebellum have been evaluated. RESULTS: The data showed that ACR induced redox disruptions as measured by increased MDA levels and inhibition of CAT, SOD, and GPx antioxidant enzyme activities. Besides, cerebellar monoamine neurotransmitters, 5-HT and DA, were depleted in ACR-treated rats. Furthermore, ACR administration caused a significant elevation of CTSD activity, indicating that ACR could trigger apoptosis or apoptosis-like death. At the tissue level, cerebellar cortex sections from ACR-treated animals were characterized by severe neuronal damage. The administration of SIL to ACR-treated rats remarkably alleviated all the aforementioned ACR-induced effects. CONCLUSION: SIL has a potent therapeutic effect against ACR-induced cerebellar neurotoxicity in experimental rats via the attenuation of oxidative/antioxidative responses and the inhibition of CTSD-activity.

Naringin alleviates methotrexate-induced liver injury in male albino rats and enhances its antitumor efficacy in HepG2 cells.

Methotrexate (MTX) is an efficient chemotherapeutic and immunosuppressant drug, but the hepatotoxicity of MTX limits its clinical use. Naringin (Nar) is a flavonoid derived from Citrus paradise, and has been shown to possess several pharmacological activities, including free-radical scavenging and antioxidant properties. In the present study, we first tested the possible protective effects of multiple doses of Nar against MTX-induced acute hepatotoxicity in rats, and then we investigated the growth inhibition and apoptotic effects of MTX and/or Nar against the HepG2 hepatocarcinoma cell line. Our in vivo results showed that Nar significantly reduced MTX-induced increases in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin levels. Nar also reduced MTX-induced oxidative stress by significantly reducing liver malondialdehyde (MDA) and nitric oxide (NO) content and increasing superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione (GSH). In addition, Nar significantly counteracted MTX-induced increases in hepatic interleukin-6 and tumor necrosis factor-α (TNF-α). Further, Nar greatly protected hepatocyte ultrastructure against MTX-induced injury. In contrast, in vitro MTX and/or Nar treatment of HepG2 cells for 48 h exhibited a cytotoxic effect and induced apoptosis in a dose-dependent manner mediated by a significant increase in the Bax/Bcl-2 protein expression ratio. Noticeably, Nar potentiated the MTX effect on the Bax/Bcl-2 ratio. In conclusion, Nar decreased MTX-induced functional and ultrastructural liver damage in a tumor-free animal model. Also, our data introduce MTX and Nar as promising antiproliferative agents with a distinctive mode of action, inducing apoptosis in HepG2 tumor cells through activation of Bax and down-regulation of Bcl-2 protein expression.

Somatic Cancer Mutations in the SUV420H1 Protein Lysine Methyltransferase Modulate Its Catalytic Activity.

SUV420H1 is a protein lysine methyltransferase that introduces di- and trimethylation of H4K20 and is frequently mutated in human cancers. We investigated the functional effects of eight somatic cancer mutations on SUV420H1 activity in vitro and in cells. One group of mutations (S255F, K258E, A269V) caused a reduction of the catalytic activity on peptide and nucleosome substrates. The mutated amino acids have putative roles in AdoMet binding and recognition of H4 residue D24. Group 2 mutations (E238V, D249N, E320K) caused a reduction of activity on peptide substrates, which was partially recovered when using nucleosomal substrates. The corresponding residues could have direct or indirect roles in peptide and AdoMet binding, but the effects of the mutations can be overcome by additional interactions between SUV420H1 and the nucleosome substrate. The third group of mutations (S283L, S304Y) showed enhanced activity with peptide substrates when compared with nucleosomal substrates, suggesting that these residues are involved in nucleosomal interaction or allosteric activation of SUV420H1 after nucleosome binding. Group 2 and 3 mutants highlight the role of nucleosomal contacts for SUV420H1 regulation in agreement with the high activity of this enzyme on nucleosomal substrates. Strikingly, seven of the somatic cancer mutations studied here led to a reduction of the catalytic activity of SUV420H1 in cells, suggesting that SUV420H1 activity might have a tumor suppressive function. This could be explained by the role of H4K20me2/3 in DNA repair, suggesting that loss or reduction of SUV420H1 activity could contribute to a mutator phenotype in cancer cells.

Rutin ameliorates carbon tetrachloride (CCl4)-induced hepatorenal toxicity and hypogonadism in male rats.

Rutin, a food derived-polyphenolic bioflavonoid, has been acknowledged for several health benefits. This study aims to explore the ameliorative effects of rutin against carbon tetrachloride (CCl4) toxicity in male rats. Adult male rats were given either CCl4 (30% in olive oil, 3 ml/kg b.w. intraperitoneally) alone or in combination with rutin (70 mg/kg intragastrically) twice a week for 4 weeks. Our data showed that rutin mitigated CCl4 hepatorenal damage, as indicated by diagnostic markers (i.e., transaminases, alkaline phosphatase, total bilirubin, total protein, albumin, urea, uric acid and creatinine), and histopathological findings. In addition, CCl4 induced profound elevation of free radical generation and oxidative stress, as evidenced by increasing lipid peroxidation and reducing catalase, superoxide dismutase and glutathione peroxidase activities in liver, kidney and testicular tissues; these effects were suppressed by coexposure with rutin. Moreover, the increase in the levels of serum triglycerides, cholesterol, low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol induced by CCl4 was effectively counteracted by rutin. The decrease in the level of high-density lipoprotein cholesterol in the CCl4 group was also counteracted by rutin treatment. Interestingly, the decreased levels of hormonal mediators associated with sperm production, including serum testosterone, luteinizing hormone and follicle-stimulating hormone, and the impaired sperm quality induced by CCl4 were reversed by rutin. Data from the current study clearly demonstrated that rutin supplementation could at least partly overcome CCl4-induced hepatotoxicity, nephrotoxicity and reproductive toxicity by antioxidant and antidyslipidemic effects.

Protective effects of quercetin supplementation against short-term toxicity of cadmium-induced hematological impairment, hypothyroidism, and testicular disturbances in albino rats.

The aim of this study was to evaluate the probable protective effect of quercetin (QUE) against cadmium (Cd)-induced sub-chronic toxicity in rats. Adult male rats were given either Cd (as cadmium chloride; 5 mg/kg) alone or in combination with QUE (50 mg/kg) daily for 4 weeks by oral gavage. At the end of the experimental period, Cd accumulation, and selected hematological, thyroid, and reproductive markers were assessed. Results revealed that Cd treatment significantly increased Cd concentrations in blood, thyroid gland, and testicular tissue of rats. Cd also caused a decline in hemoglobin content, hematocrit value, and total erythrocyte and leucocyte counts. Further, significant suppressions in the blood levels of hormones related to thyroid gland function, and male reproductive hormones (i.e., testosterone, luteinizing hormone and follicle-stimulating hormone), were observed in Cd-treated rats compared to the control. In parallel, low sperm count and sperm motility, increased sperm abnormalities, and marked pathology occurred in testis. Combination with QUE recorded amelioration of the deleterious effects of Cd, involving regulation of hematological toxicity and thyroid hormonal levels and subsequently modulation of testicular function. In conclusion, it appears that dietary QUE can rescue from Cd-induced hematological dysfunctions and testicular damage by reversing the hypothyroid state.

The Coumarin Derivative 5'-Hydroxy Auraptene Suppresses Osteoclast Differentiation via Inhibiting MAPK and c-Fos/NFATc1 Pathways.

The phytochemical substances, coumarin derivatives, have demonstrated antiresorptive bone effects by suppressing osteoclast differentiation in vitro and in vivo. Recently, we have identified 5'-hydroxy auraptene (5'-HA), a coumarin derivative isolated from Lotus lalambensis Schweinf, as a novel stimulator for osteoblast differentiation. In this study, we investigated the effect of 5'-HA on osteoclast differentiation of mouse bone marrow (BM) cells. The effect of 5'-HA on BM cell proliferation and osteoclast differentiation was determined by measuring cell viability and tartrate-resistant acid phosphatase (TRAP) enzyme activity, quantification of TRAP+ multinucleated cells (TRAP+MNCs), and quantitative real-time PCR (qPCR) of osteoclastic gene expression. Regulation of NF-κB, c-Fos/NFATc1, and MAPK signaling pathways by 5'-HA during osteoclastogenesis was measured by the NF-κB reporter assay and Western blot analysis. 5'-HA significantly suppresses the receptor activator of NF-κB ligand (RANKL) induced osteoclast differentiation of BM cells in a dose-dependent manner. Consistently, treatment of BM cells with 5'-HA significantly inhibited RANKL-induced activation of NF-κB and c-Fos/NFATc1 pathways in a dose-dependent manner. Furthermore, RANKL-induced phosphorylation of ERK1/2, p-38, and JNK was significantly inhibited by 5'-HA in BM cells. In conclusion, we identified 5'-HA as a novel coumarin derivative that suppresses RANKL-induced osteoclastogenesis via inhibiting c-Fos/NFATc1 and MAPK signaling pathways.

Biological potential of oxo-vanadium salicylediene amino-acid complexes as cytotoxic, antimicrobial, antioxidant and DNA interaction.

New series of oxo-vanadium N-salicyledieneamino acid Schiff base complexes are synthesized and characterized. They are synthesized from the reaction of sodium salicylaldehyde-5-sulfonate, some amino acids, alanine (VOHL1), leucine (VOHL2) or glycine (VOHL3) in an aqueous media, and leucine (VOHLpy1) or tryptophan (VOHLpy2) in pyridine with vanadyl acetylacetonate. The complexes are characterized by EA, TGA, IR, UV-Visible and mass spectra, conductivity and magnetic measurements. The biological activity of the VO-complexes shows that VOHL1, VOHL2 and VOHL3 exhibit anti-proliferative effect and may be used as anticancer drugs. VO-complexes manifest high toxicity, except VOHL2 is less toxic, and could be applied for the human being. VOHL1, VOHL2 and VOHL3 display remarkable SOD like potential and act as high inhibiting reagents. VOHLpy1 and VOHLpy2 show low inhibiting potentials. VO-complexes have good anti-oxidant effect, in which VOHL3 affords the best antioxidant activity. The interaction between VO-complexes and DNA is studied spectrophotometrically and by gel electrophoresis. Binding constants and spectrophotometric parameters indicate a strong interaction between VO-complexes and DNA. VO-complexes have respectable anti-bacterial and antifungal activities, where VOHL3 shows the maximum potential. DFT calculations of VOHL1 and VOHL3 were discussed in the light of their biological activity, which are convenient with the obtained results.