Hepatoprotective impact of Nigella sativa silver nanocomposite against genotoxicity, oxidative stress, and inflammation induced by thioacetamide.

Protection from liver damage and the repercussion of that harm is thought to be crucial for reducing the number of deaths each year. This work was developed to evaluate the possible role of silver nanocomposite prepared using Nigella sativa (N. sativa) aqueous extract against the hepatic damage brought on by thioacetamide (TAA), with particular attention to how they affect the NF-κß, TNF-α, IL-1ß, and COX-2 signaling pathways. There were seven groups of male Wistar rats used as follows: control, saline, N. sativa aqueous extract (NSAE; 200 mg/kg/d), N. sativa silver nanocomposite (NS-AgNC; 0.25 mg/kg/d), TAA (100 mg/kg; thrice weekly), NSAE + TTA, and NS-AgNC + TAA, respectively. The experiment continued for six weeks. The results showed that NS-AgNPs significantly enhanced liver functions (p<0.05) (albumin, ALP, LDH, AST, total protein, ALT, and globulin) and oxidant/antioxidant biomarkers (p<0.05) (H2O2, MDA, PCC, NO, SOD, CAT, GPx, GR, GST and, GSH), contrasted with TAA group. Moreover, a significant (p<0.05) downregulation of the gene expressions (COX-2, TNF-α, IL-1ß, and NF-κß) was also achieved by using silver nanocomposite therapy. These findings have been supported by histological analysis. Collectively, NS-AgNC exhibits more prominent and well-recognized protective impacts than NSAE in modulating the anti-inflammatory, genotoxicity and oxidative stress effects against TAA-induced liver injuries.

Synergistic effect of spermidine and ciprofloxacin against Alzheimer's disease in male rat via ferroptosis modulation.

Alzheimer's disease (AD) is a prevalent form of neurodegenerative disease with a complex pathophysiology that remains not fully understood, and the exact mechanism of neurodegeneration is uncertain. Ferroptosis has been linked to the progression of degenerative diseases observed in AD models. The present study is designed to investigate the protective effects of spermidine, a potent antioxidant and iron chelator, and its synergistic interactions with ciprofloxacin, another iron chelator, in modulating ferroptosis and mitigating AD progression in rats. This study investigated AD-related biomarkers like neurotoxic amyloid beta (Aß), arginase I, and serotonin. Spermidine demonstrated an anti-ferroptotic effect in the AD model, evident from the modulation of ferroptosis parameters such as hippocampus iron levels, reduced protein expression of transferrin receptor 1 (TFR1), and arachidonate 15-lipoxygenase (ALOX15). Additionally, the administration of spermidine led to a significant increase in protein expression of phosphorylated nuclear factor erythroid 2-related factor 2 (p-Nrf2) and upregulation of Cystine/glutamate transporter (SLC7A11) gene expression. Moreover, spermidine notably decreased p53 protein levels, acrolein, and gene expression of spermidine/spermine N1-acetyltransferase 1 (SAT1). Overall, our findings suggest that spermidine and/or ciprofloxacin may offer potential benefits against AD by modulating ferroptosis. Furthermore, spermidine enhanced the antioxidant efficacy of ciprofloxacin and reduced its toxic effects.

Mechanistic role of quercetin as inhibitor for adenosine deaminase enzyme in rheumatoid arthritis: systematic review.

Rheumatoid arthritis (RA) is an autoimmune disease involving T and B lymphocytes. Autoantibodies contribute to joint deterioration and worsening symptoms. Adenosine deaminase (ADA), an enzyme in purine metabolism, influences adenosine levels and joint inflammation. Inhibiting ADA could impact RA progression. Intracellular ATP breakdown generates adenosine, which increases in hypoxic and inflammatory conditions. Lymphocytes with ADA play a role in RA. Inhibiting lymphocytic ADA activity has an immune-regulatory effect. Synovial fluid levels of ADA are closely associated with the disease's systemic activity, making it a useful parameter for evaluating joint inflammation. Flavonoids, such as quercetin (QUE), are natural substances that can inhibit ADA activity. QUE demonstrates immune-regulatory effects and restores T-cell homeostasis, making it a promising candidate for RA therapy. In this review, we will explore the impact of QUE in suppressing ADA and reducing produced the inflammation in RA, including preclinical investigations and clinical trials.

The synergistic effect of nanocurcumin and donepezil on Alzheimer's via PI3K/AKT/GSK-3ß pathway modulating.

Alzheimer's disease (AD) hallmarks include amyloid-ßeta (Aß) and tau proteins aggregates, neurite degeneration, microglial activation with cognitive impairment. Phosphatidylinositol-3-kinase/protein kinase B/Glycogen synthase kinase-3-beta (PI3K/AKT/GSK-3) pathway is essential for neuroprotection, cell survival and proliferation by blocking apoptosis. This study aimed to assess protective role of nanocurcumin (NCMN) as strong antioxidant and anti-inflammatory agent with elucidating its synergistic effects with Donepezil as acetylcholinesterase inhibitor on AD in rats via modulating PI3K/AKT/GSK-3ß pathway. The experiment was performed on 70 male Wistar albino rats divided into seven groups (control, NCMN, Donepezil, AD-model, Donepezil co-treatment, NCMN only co-treatment, and NCMN+Donepezil combined treatment). Behavioral and biochemical investigations as cholinesterase activity, oxidative stress (malondialdehyde, reduced glutathione, nitric oxide, superoxidedismutase, and catalase), tumor necrosis factor-alpha, Tau, ß-site amyloid precursor protein cleaving enzyme-1 (BACE-1), Phosphatase and tensin homolog (Pten), mitogen-activated protein kinase-1 (MAPK-1), Glycogen synthase kinase-3-beta (GSK-3ß) and toll-like receptor-4 were evaluated. Treatment with NCMN improved memory, locomotion, neuronal differentiation by activating PI3K/AKT/GSK-3ß pathway. These results were confirmed by histological studies in hippocampus.

Caffeine-folic acid-loaded-chitosan nanoparticles combined with methotrexate as a novel HepG2 immunotherapy targeting adenosine A2A receptor downstream cascade.

BACKGROUND: Methotrexate (MTX) is a common chemotherapeutic drug that inhibits DNA synthesis and induces apoptosis. Treatment with MTX increased CD73 expression, which leads to higher levels of extracellular adenosine. Adenosine levels are also high in the tumor microenvironment through Cancer cells metabolism. That promotes the survival of cancer cells and contributes to tumor immune evasion through the Adenosine 2a Receptor. A2A receptor antagonists are an emerging class of agents that treat cancers by enhancing immunotherapy, both as monotherapy and in combination with other therapeutic agents. Caffeine is an adenosine receptor antagonist. Herein, we demonstrate the ability of a novel well prepared and characterized nano formula CAF-FA-CS-NPs (D4) for A2aR blockade when combination with MTX to improve its antitumor efficacy by enhancing the immune system and eliminating immune suppression. METHODS: CAF-FA-CS-NPs (D4) were prepared and characterized for particle size, loading efficiency, and release profile. Molecular docking was used to validate the binding affinity of caffeine and folic acid to A2A receptor. The effects of the nano formula were evaluated on human liver cancer cells (HepG2), breast cancer cells (MCF-7), and MDA-MB-231, as well as normal human cells (WI-38). Different combination ratios of MTX and D4 were studied to identify the optimal combination for further genetic studies. RESULTS: Molecular docking results validated that caffeine and folic acid have binding affinity to A2A receptor. The CS-NPs were successfully prepared using ionic gelation method, with caffeine and folic acid being loaded and conjugated to the nanoparticles through electrostatic interactions. The CAF loading capacity in D4 was 77.9 ± 4.37% with an encapsulation efficiency of 98.5 ± 0.37. The particle size was optimized through ratio variations. The resulting nanoparticles were fully characterized. The results showed that (D4) had antioxidant activity and cytotoxicity against different cancer cells. The combination of D4 with MTX (IC50 D4 + 0.5 IC50 MTX) resulted in the downregulation of Bcl-2, FOXP3, CD39, and CD73 gene expression levels and upregulation of Bax and A2AR gene expression levels in HepG2 cells. CONCLUSIONS: This study suggests that CAF-FA-CS-NPs (D4) in combination with MTX may be a promising candidate for cancer immunotherapy, by inhibiting A2aR signaling and leading to improved immune activation and anti-tumor activity of MTX.

Time-dependent changes in the glycolytic pathway in activated T cells are independent of tumor burden or anti-cancer chemotherapy.

Although activated adoptive T cells therapy (ATC) is an effective approach for cancer treatment, it is not clear how modulation of T cell activation impacts their biochemical signature which significantly impacts the cell function. This study is aimed to investigate the impact of polyclonal activation on the metabolic signature of T cells from tumor-bearing mice under different settings of treatment with chemotherapy. Thirty female Swiss albino mice were divided into 5 groups (n = 6/each), Gp1(PBS), groups Gp2 were inoculated intraperitoneal (i.p) with 1 × 106 cells/mouse Ehrlich ascites carcinoma (EAC), Gp3-Gp5 were treated with cisplatin (20 mg/mice) which were represented as EAC/CIS/1wk Or EAC/CIS/2wk 3 times every other day. Splenocytes were cultured in or presence of concanavalin-A (Con-A) and IL-2 for 24 h or 72 h, then cells were harvested, and processed to determine the enzyme activities of hexokinase (HK), phosphofructokinase (PFK), lactate dehydrogenase (LDH) and glucose 6 phosphate dehydrogenase(G6PD) enzymes. The results showed that before culture, T cells harvested from EAC/PBS/1wk of mice or inoculated with EAC/CIS/1wk showed higher activity in HK, PFK, LDH, and G6PH as compared to naive T cells. After 24, and 72 h of culture and activation, the enzyme activities in T cells harvested from EAC/CIS/2wk mice or EAC/CIS/3wk mice decreased compared with their control. The late stage of the tumor without chemotherapy gives a low glycolic rate. In late activation, naive and early stages of the tumor with chemotherapy can give high glycolic metabolism. These results show great significance as an application of adoptive T-cell therapy.

Impairment of electron transport chain and induction of apoptosis by chrysin nanoparticles targeting succinate-ubiquinone oxidoreductase in pancreatic and lung cancer cells.

BACKGROUND: Flavonoids may help ameliorate the incidence of the major causes of tumor-related mortality, such as pancreatic ductal adenocarcinoma (PDAC) and lung cancer, which are predicted to steadily increase between 2020 to 2030. Here we compared the effect of chrysin and chrysin nanoparticles (CCNPs) with 5-fluorouracil (5-FLU) on the activity and expression of mitochondrial complex II (CII) to induce apoptosis in pancreatic (PANC-1) and lung (A549) cancer cells. METHODS: Chrysin nanoparticles (CCNPs) were synthesized and characterized, and the IC50 was evaluated in normal, PANC-1, and A549 cell lines using the MTT assay. The effect of chrysin and CCNPs on CΙΙ activity, superoxide dismutase activity, and mitochondria swelling were evaluated. Apoptosis was assessed using flow cytometry, and expression of the C and D subunits of SDH, sirtuin-3 (SIRT-3), and hypoxia-inducible factor (HIF-1α) was evaluated using RT-qPCR. RESULTS: The IC50 of CII subunit C and D binding to chrysin was determined and used to evaluate the effectiveness of treatment on the activity of SDH with ubiquinone oxidoreductase. Enzyme activity was significantly decreased (chrysin < CCNPs < 5-FLU and CCNPs < chrysin < 5-FLU, respectively), which was confirmed by the significant decrease of expression of SDH C and D, SIRT-3, and HIF-1α mRNA (CCNPs < chrysin < 5-FLU). There was also a significant increase in the apoptotic effects (CCNPs > chrysin > 5-FLU) in both PANC-1 and A549 cells and a significant increase in mitochondria swelling (CCNPs < chrysin < 5-FLU and CCNPs > chrysin > 5-FLU, respectively) than that in non-cancerous cells. CONCLUSION: Treatment with CCNPs improved the effect of chrysin on succinate-ubiquinone oxidoreductase activity and expression and therefore has the potential as a more efficient formulation than chemotherapy to prevent metastasis and angiogenesis by targeting HIF-1α in PDAC and lung cancer.

Post-irradiation physicochemical features of polymer composite for the removal of Co(II) and Nd(III) from aqueous solutions.

The scientific impact of this work is the protection of the environment from hazardous pollutants. Gamma irradiation was employed for the preparation of a new composite polymer by irradiating a mixture containing polyvinyl pyrrolidone (PVP), hydroxyethyl methacrylate (HEMA), and tannic acid (TA) to produce PVP-HEMA-TA. The sorption efficiency and capacity of PVP-HEMA-TA were evaluated by studying some factors affecting the sorption of Nd(III) and Co(II) from aqueous solutions. The results demonstrated that the maximum uptake was 92.4 and 75.3% for Nd(III) and Co(II), respectively. From the kinetic studies, the pseudo-second-order equation could better fit the data than the pseudo-first-order for the sorption of both ions. The sorption isotherm investigations illustrated that the Langmuir equation fits the gained data better than Freundlich equation. The Langmuir capacity was 64.5 and 60.8 mg/g for neodymium and cobalt ions, respectively. The applicability of Langmuir equation is strong evidence that the process is limited by a chemisorption mechanism. Findings of the work highlight the potential utilization of PVP-HEMA-TA as an effective and recyclable material for the elimination of Nd(III) and Co(II) from the aqueous phase.

Therapeutic potential of chrysin nanoparticle-mediation inhibition of succinate dehydrogenase and ubiquinone oxidoreductase in pancreatic and lung adenocarcinoma.

Pancreatic adenocarcinoma (PDAC) and lung cancer are expected to represent the most common cancer types worldwide until 2030. Under typical conditions, mitochondria provide the bulk of the energy needed to sustain cell life. For that inhibition of mitochondrial complex ΙΙ (CΙΙ) and ubiquinone oxidoreductase with natural treatments may represent a promising cancer treatment option. A naturally occurring flavonoid with biological anti-cancer effects is chyrsin. Due to their improved bioavailability, penetrative power, and efficacy, chitosan-chrysin nano-formulations (CCNPs) are being used in medicine with increasing frequency. Chitosan (cs) is also regarded as a highly versatile and adaptable polymer. The cationic properties of Cs, together with its biodegradability, high adsorption capacity, biocompatibility, effect on permeability, ability to form films, and adhesive properties, are advantages. In addition, Cs is thought to be both safe and economical. CCNPs may indeed be therapeutic candidates in the treatment of pancreatic adenocarcinoma (PDAC) and lung cancer by blocking succinate ubiquinone oxidoreductase.

Ellagic acid regulates hyperglycemic state through modulation of pancreatic IL-6 and TNF- α immunoexpression.

Background: Type 2 diabetes (T2DM) is a chronic metabolic disorder. Although therapeutic pharmaceutical agents continue to advance, herbal medicines are potential complementary treatments for the promotion of glucose homeostasis, with minimal adverse effects. Conventionally, ellagic acid (EA) has been utilized for the therapy of a range of pathologies owing to its anti-inflammatory and anti-diabetic actions. Objective: The aim of this study is to determine the activity of EA on serum α-amylase and lipase titers, and on pancreatic tumor necrosis factor-α (TNF-α), proliferating cell nuclear antigen (PCNA) and interleukin-6 (IL-6) concentrations using the streptozocin-induced T2DM rodent model. Methods: EA extract synthesized from fresh strawberry fruit was employed for therapy. 50 adults male Wistar rats were randomized into either control, EA, diabetic, co-treated or post- treated cohorts. Results: EA diminished fasting blood glucose levels, altered lipase, amylase, IL-6, PCNA and TNF- α expression and enhanced islet cell renewal, insulin, and immunoreactivities. Conclusion: Inflammatory indicators are elevated in the presence of T2DM. Extract of EA has overall tissue reparative and safeguarding properties, as indicated by the augmented ß- cell population and enhanced glucose homeostasis. Thus, EA may be an innovative treatment approach for the maintenance of normoglycemia in individuals with T2DM.

Gamma radiation crosslinking of PVA/myrrh resin thin film for improving the post-harvest time of lemon fruits.

Preparation of a thin film of polyvinyl alcohol (PVA)/myrrh natural resin using a low gamma irradiation dose (1 kGy) was investigated towards increasing the post-harvest time of lemon fruit. Different analytical techniques, such as Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), energy-dispersive X-ray (EDX) spectroscopy, and mapping techniques were used to characterize the prepared thin film. This investigation was carried out to evaluate the effect of different concentrations of myrrh as an edible coating in prolonging shelf life and preserving the quality of lemon fruits (Citrus aurantifolia). Lemons were immersed directly in PVA solution containing 1%, 2%, and 3% concentrations of myrrh and then stored at ambient (25 ± 1 °C) and low (4 ± 1 °C) temperatures. The disease severity, acidity, total soluble solids (TSS), and ascorbic acid contents were tested after the coating with the PVA/myrrh thin film at different temperatures (4 °C and 25 °C) for different storage times (7 and 14 days). The application of different concentrations of the synthesized PVA/myrrh thin film (1%, 2%, and 3%) significantly reduced green mold disease symptoms and disease severity in the lemon fruits. The acidity value (pH value) was the lowest for the 2% myrrh treatment after 7 °C days at 25 °C, followed by the 1% myrrh treatment under the same conditions. The highest TSS was observed after the treatment for 7 days at 25 °C, with a value of 8.1 g dL-1. A high ascorbic acid concentration (33.5 mg dL-1) was noted after coating the lemons with the 1% PVA/myrrh thin film for 7 days at 25 °C. The results show that the application of a PVA/myrrh thin film extends the shelf-life and maintains the quality of lemon fruits by decreasing the levels of evaporation from the fruits and loss of weight due to the delay of the complete ripening stage of the lemon fruits.

Quercetin mitigates rheumatoid arthritis by inhibiting adenosine deaminase in rats.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by synovial proliferation and bone destruction. Adenosine deaminase (ADA) is a key inflammatory enzyme that increases joint stiffness and pain in RA. In this study, we evaluated the in-silico, and in vivo inhibitory effect of quercetin isolated from Egyptian Fenugreek on ADA enzyme activity. We also determined the combinatorial effect of quercetin on methotrexate mediated anti-inflammatory efficacy and toxicity. In-silico molecular docking was conducted and confirmed in an in vivo RA rat model. The results showed that the inhibition constant of quercetin on joint ADA by docking and in-vitro was 61.9 and 55.5 mM, respectively. Therefore, quercetin exhibits anti-inflammatory effect in a rat RA model as evidenced by reducing the specific activity of ADA in joint tissues, lower jaw volume, enhance body weight, downregulate ADA gene expression, reduce levels of RA cytokines interleukin-1ß, interleukin-6, tumor necrosis factor-α, also, rheumatoid factor, C-reactive protein, and anti-cyclic citrullinated peptide RA biomarker levels. These findings demonstrate that the purified quercetin has a promising anti-inflammatory effect against RA disease through its inhibitory effects on the ADA enzyme. Furthermore, isolated quercetin improved the anti-inflammatory efficacy of methotrexate, reduced its toxic effects by increasing antioxidant enzymes and reducing oxidative stress.

Anticancer Effects of Combination of Indole-3-Carbinol and Hydroxychloroquine on Ehrlich Ascites Carcinoma via Targeting Autophagy and Apoptosis.

Indole-3-carbinol (I3C) is an active component of cruciferous vegetables which is considered a promising antineoplastic agent. This study aimed to assess I3C antineoplastic activity alone and with hydroxychloroquine (HCQ) on Ehrlich ascites carcinoma (EAC) model. Eighty female mice were divided into six groups wherein all groups except groups I and II received EAC cells (106 cells/mouse i.p.). Group I, served as control; group II served as I3C; group III served as EAC; groups IV and V received I3C (250 mg/kg body weight oral), and HCQ (60 mg/kg body weight i.p.) respectively; GVI received both I3C and HCQ. Antitumor response markers, serum, hepatic and renal biochemical parameters, histopathological changes, as well as autophagy and apoptosis markers in EAC cells were analyzed. The combination of I3C and HCQ showed the best antitumor responses with increased survival time and ameliorated biochemical parameters. Moreover, I3C upregulated LC3B and downregulated p62 gene expression in EAC cells. Furthermore, I3C combined with HCQ induced apoptosis by highly upregulating cleaved caspase-3 and Bax while downregulating Bcl-2 proteins expression in EAC cells in comparison with each drug alone. In conclusion, I3C combined with HCQ exhibited better antitumor activities than each drug alone via targeting autophagy and apoptosis.

Evaluation of MicroRNA92, MicroRNA638 in Acute Lymphoblastic Leukemia of Egyptian Children.

OBJECTIVE: miRNA considers a small non-coding RNA molecule that has tumor suppressor or oncogenic functions and regulates gene expression. miRNA may be involved in the pathogenesis of acute lymphoblastic leukemia (ALL).  miRNA was evaluated in patients with ALL to correlate their importance in the clinical prediction and the response to chemotherapy. SUBJECT AND METHODS: The study population included 30 healthy control and 71 children with ALL is divided into 4 groups: healthy, newly diagnosed, remitted, and relapsed groups. We quantify miRNA 92a, miRNA 638 expression using real-time PCR in childhood ALL. RESULTS: plasma miRNA 92a and miRNA 638 expressions were elevated in ALL cases at the time of diagnosis (2.51 and 2.19 folds), and relapsed (2.1 and 1.61 folds) than that of patients with remitted ALL. There was a positive correlation between miRNA 92a and miRNA 638 patients with ALL. Also, total leukocyte and blast correlated with miRNA 92a and miRNA 638 unlike hemoglobin, and platelets didn't correlate with miRNA 92a and miRNA 638. The sensitivity of miRNA 92a and miRNA 638 were 41.5% and 54.7% respectively while the specificity was 100 % of miRNA 92a and miRNA 638. CONCLUSION: miRNA 92a and miRNA 638 are recommended to be used as potential predictive and follow-up markers in children with ALL remitted and relapsed cases.

The synthetic opioid fentanyl enhances viral replication in vitro.

The US is in the midst of a major drug epidemic fueled in large part by the widespread recreational use of synthetic opioids such as fentanyl. Persons with opioid use disorder are at significant risk for transmission of injection-associated infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV). Commonly abused substances may antagonize immune responses and promote viral replication. However, the impact of synthetic opioids on virus replication has not been well explored. Thus, we evaluated the impact of fentanyl and carfentanil using in vitro systems that replicate infectious viruses. Fentanyl was used in cell lines replicating HBV or HCV at concentrations of 1 ng, 100 ng, and 10 ug. Viral protein synthesis was quantified by ELISA, while apoptosis and cell death were measured by M30 or MTT assays, respectively. HCV replicative fitness was evaluated in a luciferase-based system. RNAseq was performed to evaluate cellular gene regulation in the presence of fentanyl. Low dose fentanyl had no impact on HCV replication in Huh7.5JFH1 hepatocytes; however, higher doses significantly enhanced HCV replication. Similarly, a dose-dependent increase in HCV replicative fitness was observed in the presence of fentanyl. In the HepG2.2.15 hepatocyte cell line, fentanyl caused a dose-dependent increase in HBV replication, although only a higher doses than for HCV. Addition of fentanyl resulted in significant apoptosis in both hepatocyte cell lines. Cell death was minimal at low drug concentrations. RNAseq identified a number of hepatocyte genes that were differentially regulated by fentanyl, including those related to apoptosis, the antiviral / interferon response, chemokine signaling, and NFκB signaling. Collectively, these data suggest that synthetic opioids promote viral replication but may have distinct effects depending on the drug dose and the viral target. As higher viral loads are associated with pathogenesis and virus transmission, additional research is essential to an enhanced understanding of opioid-virus pathogenesis and for the development of new and optimized treatment strategies.

Tioconazole and Chloroquine Act Synergistically to Combat Doxorubicin-Induced Toxicity via Inactivation of PI3K/AKT/mTOR Signaling Mediated ROS-Dependent Apoptosis and Autophagic Flux Inhibition in MCF-7 Breast Cancer Cells.

Cancer is a complex devastating disease with enormous treatment challenges, including chemo- and radiotherapeutic resistance. Combination therapy demonstrated a promising strategy to target hard-to-treat cancers and sensitize cancer cells to conventional anti-cancer drugs such as doxorubicin. This study aimed to establish molecular profiling and therapeutic efficacy assessment of chloroquine and/or tioconazole (TIC) combination with doxorubicin (DOX) as anew combination model in MCF-7 breast cancer. The drugs are tested against apoptotic/autophagic pathways and related redox status. Molecular docking revealed that chloroquine (CQ) and TIC could be potential PI3K and ATG4B pathway inhibitors. Combination therapy significantly inhibited cancer cell viability, PI3K/AkT/mTOR pathway, and tumor-supporting autophagic flux, however, induced apoptotic pathways and altered nuclear genotoxic feature. Our data revealed that the combination cocktail therapy markedly inhibited tumor proliferation marker (KI-67) and cell growth, along with the accumulation of autophagosomes and elevation of LC3-II and p62 levels indicated autophagic flux blockage and increased apoptosis. Additionally, CQ and/or TIC combination therapy with DOX exerts its activity on the redox balance of cancer cells mediated ROS-dependent apoptosis induction achieved by GPX3 suppression. Besides, Autophagy inhibition causes moderately upregulation in ATGs 5,7 redundant proteins strengthened combinations induced apoptosis, whereas inhibition of PI3K/AKT/mTOR pathway with Beclin-1 upregulation leading to cytodestructive autophagy with overcome drug resistance effectively in curing cancer. Notably, the tumor growth inhibition and various antioxidant effects were observed in vivo. These results suggest CQ and/or TIC combination with DOX could act as effective cocktail therapy targeting autophagy and PI3K/AKT/mTOR pathways in MCF-7 breast cancer cells and hence, sensitizes cancer cells to doxorubicin treatment and combat its toxicity.

Doxorubicin, L-arginine, or their combination as a prophylactic agent against hepatic carcinoma in mice.

Hepatocellular carcinoma (HCC) is one of the ten most commonly diagnosed cancers. Doxorubicin is an antibiotic used in cancer treatment protocols that has several side effects. L-Arginine is a non-essential amino acid that is used as immune system activation and antitumor drugs. Therefore, the current study was designed to compare using doxorubicin, L-arginine, or their combination as a prophylactic agent against hepatic carcinoma induced by hepatocellular carcinoma cells (HepG2) injection in mice. The mice were divided into five groups: normal mice and mice that received HepG2, doxorubicin and HepG2, L-arginine and HepG2, and doxorubicin, L-Arginine, and HepG2, respectively. Liver function test as, aspartate transaminase (AST) and alanine transaminase (ALT), and alpha-fetoprotein (AFP), caspase 3, interleukin 6 (IL-6), tumor necrotic factor (TNF), lipid peroxidation (NDA), and some antioxidant parameters were determined. A significant increase in AST and ALT, α-fetoprotein, TNF-α, and cytokines IL6 and MDA and a significant decrease in the serum caspase and liver catalase were determined in HepG2-injected mice. Moreover, some large hyperchromatic heptocytes were observed and the percentage of the positive area/field of HepPar-1, the most specific HCC marker, was 9.56%. Interestingly, mice that received doxorubicin, L-arginine, or their combination showed an improvement in some of the previous parameters. The improvement was more prominent with L-arginine administration.

Withdrawal Notice: Role of Zinc Oxide Nanoparticles Synthesized by Fenugreek Seeds Extract as Anticancer Agent: In Vitro and In Vivo Studies

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Functional Assembly of Caenorhabditis elegans Cytochrome b-2 (Cecytb-2) into Phospholipid Bilayer Nanodisc with Enhanced Iron Reductase Activity.

Among seven homologs of cytochrome b561 in a model organism C. elegans, Cecytb-2 was confirmed to be expressed in digestive organs and was considered as a homolog of human Dcytb functioning as a ferric reductase. Cecytb-2 protein was expressed in Pichia pastoris cells, purified, and reconstituted into a phospholipid bilayer nanodisc. The reconstituted Cecytb-2 in nanodisc environments was extremely stable and more reducible with ascorbate than in a detergent-micelle state. We confirmed the ferric reductase activity of Cecytb-2 by analyzing the oxidation of ferrous heme upon addition of ferric substrate under anaerobic conditions, where clear and saturable dependencies on the substrate concentrations following the Michaelis-Menten equation were observed. Further, we confirmed that the ferric substrate was converted to a ferrous state by using a nitroso-PSAP assay. Importantly, we observed that the ferric reductase activity of Cecytb-2 became enhanced in the phospholipid bilayer nanodisc.

Induction of Apoptosis by Nano-Synthesized Complexes of H2L and its Cu(II) Complex in Human Hepatocellular Carcinoma Cells.

BACKGROUND: Chemotherapy is currently the most utilized treatment for cancer. Therapeutic potential of metal complexes in cancer therapy has attracted a lot of interest. The mechanisms of action of most organometallic complexes are poorly understood. OBJECTIVE: This study was designed to explore the mechanisms governing the anti-proliferative effect of the free ligand N1,N6-bis((2-hydroxynaphthalin-1-yl)methinyl)) adipohydrazone (H2L) and its complexes of Mn(II), Co(II), Ni(II) and Cu(II). METHODS: Cells were exposed to H2L or its metal complexes where cell viability determined by MTT assay. Cell cycle was analysed by flow cytometry. In addition, qRT-PCR was used to monitor the expression of Bax and Bcl-2. Moreover, molecular docking was carried out to find the potentiality of Cu(II) complex as an inhibitor of Adenosine Deaminase (ADA). ADA, Superoxide Dismutase (SOD) and reduced Glutathione (GSH) levels were measured in the most affected cancer cell line. RESULTS: The obtained results demonstrated that H2L and its Cu(II) complex exhibited a strong cytotoxic activity compared to other complexes against HepG2 cells (IC50=4.14±0.036µM/ml and 3.2±0.02µM/ml), respectively. Both H2L and its Cu(II) complex induced G2/M phase cell cycle arrest in HepG2 cells. Additionally, they induced apoptosis in HepG2 cells via upregulation of Bax and downregulation of Bcl-2. Interestingly, the activity of ADA was decreased by 2.8 fold in HepG2 cells treated with Cu(II) complex compared to untreated cells. An increase of SOD activity and GSH level in HepG2 cells compared to control was observed. CONCLUSION: The results concluded that Cu(II) complex of H2L induced apoptosis in HepG2 cells. Further studies are needed to confirm its anti-cancer effect in vivo.