The Relation of VEGFA, VEGFR2, VEGI, and HIF1A Genetic Variants and Their Serum Protein Levels with Breast Cancer in Egyptian Patients.

Breast cancer is the most common type of cancer in Egyptian females. Polymorphisms in the angiogenesis pathway have been implicated previously in cancer risk and prognosis. The aim of the current study was to determine whether certain polymorphisms in the genes of vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), vascular endothelial growth inhibitor (VEGI), and hypoxia-inducible factor-1α (HIF1A) associated with breast cancer development. The study included 154 breast cancer patients and 132 apparently healthy age-matched females as a control group. VEGFA rs25648 genotyping was performed using (ARMS) PCR technique; while VEGFR2 rs2071559, VEGI rs6478106, and HIF-1α rs11549465 were genotyped by the PCR-RFLP method. Serum levels of VEGF, VEGFR2, VEGI, and HIF1A proteins in breast cancer patients and controls were measured by ELISA. There was a significant association between the VEGFA rs25648 C allele and breast cancer risk (OR 2.5, 95% CI 1.7-3.6, p < 0.001). VEGFA rs25648 C/C genotype was statistically significantly higher in breast cancer patients vs. control (p < 0.001). Participants with the T/T and T/C VEGFR2 rs2071559 genotypes had 5.46 and 5 higher odds, respectively, of having breast cancer than those with the C/C genotype. For the VEGI rs6478106 polymorphism, there was a higher proportion of C allele in breast cancer patients vs. control (p = 0.003). Moreover, the C/C genotype of VEGI rs6478106 was statistically significantly higher in breast cancer patients vs. control (p = 0.001). There was no significant difference in genotypes and allele frequencies of HIF1A rs11549465 polymorphism between breast cancer cases and control individuals (p > 0.05). Serum levels of VEGFA, VEGI, and HIF1A were considerably greater in women with breast cancer than in the control (p < 0.001). In conclusion, the genetic variants VEGFA rs25648, VEGFR2 rs2071559, and VEGI rs6478106 revealed a significant association with increased breast cancer risk in Egyptian patients.

Relation of STAT3 rs1053005 Variation and miR-452-3p with Osteoarthritis Susceptibility and Severity and the Clinical Response to High-Molecular-Weight Hyaluronic Acid Injection in Osteoarthritis Patients.

Polymorphisms in the 3' untranslated region of STAT3 mRNA can derange STAT3 gene expression via modifying the microRNA-binding site. This study aimed to examine the impact of STAT3 rs1053005 variation and miR-452-3p expression on osteoarthritis (OA) susceptibility and severity and the efficacy of intra-articular high-molecular-weight hyaluronic acid (HMW-HA) injection as a therapy option for knee OA. Two hundred and fifty-eight OA patients and 200 healthy controls were enrolled in the study. STAT3 genotyping and STAT3 and miR-452-3p expression were carried out using allelic-discrimination PCR and quantitative real-time PCR. Functional assessment and pain evaluation were performed for all patients. Eighty-three patients received HMW-HA injections, and multiple follow-up visits were performed. STAT3 mRNA was upregulated, and expression was positively associated with plasmin, TNF-α, MMP-3, and STAT3 serum levels, whereas miR-452-3p was downregulated and negatively associated with the previously mentioned parameters in OA patients. Osteoarthritis patients had a lower prevalence of the minor allele of the rs1053005 variant (p < 0.001). Plasmin, TNF, MMP-3, and STAT3 mRNA and protein levels were significantly decreased, and miR-452-3p expression was significantly increased in the GG genotype compared to AG and AA genotypes. HMW-HA injection improved OA patients' clinical scores with concomitant decreased STAT3 levels and enhanced expression of miR-452-3p. More efficient improvement was observed in rs1053005 AG + GG genotype carriers vs. AA genotype carriers. The G allele of STAT3 rs1053005 (A/G) polymorphism was associated with decreased OA susceptibility and severity and enhanced clinical response to HMW-HA injection, possibly via enhancing miR-452-3p binding and a subsequent decrease in STAT3 expression.

The Safety and Efficacy of Combining Saxagliptin and Pioglitazone Therapy in Streptozocin-Induced Diabetic Rats.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic progressive disease due to insulin resistance. Oxidative stress complicates the etiology of T2DM. Saxagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, while Pioglitazone is a thiazolidinedione insulin sensitizer. This study aimed to assess the effect of Saxagliptin and Pioglitazone monotherapy and combination therapy on the biochemical and biological parameters in streptozotocin (STZ)-induced diabetic rats. METHODS: The study included thirty-five male albino rats. Diabetes mellitus was induced by intraperitoneal STZ injection (35 mg/kg). For a 1-month duration, rats were divided into five groups. Glucose homeostasis traits, lipid profiles, kidney functions, liver enzymes, and oxidative stress markers were measured. Gene expression of miRNA-29a, phosphoenolpyruvate carboxykinase (PEPCK), phosphoinositide-3-kinase (PI3K), and interleukin 1 beta (IL-1ß) was assessed using qRT-PCR. RESULTS: At a 1-month treatment duration, combination therapy improves oxidative stress markers more than either drug alone. The combination therapy had significantly higher levels of SOD, catalase, and GSH and lower levels of MDA compared to the monotherapy. Additionally, the diabetic group showed a significant increase in the expression levels of miRNA-29a, PEPCK, and IL-1ß and a significant decrease in PI3K compared to the normal control group. However, combination therapy of Saxagliptin and Pioglitazone was more effective than either Saxagliptin or Pioglitazone alone in reversing these results, especially for PEPCK and IL-1ß. CONCLUSIONS: Our findings revealed that combining Saxagliptin and Pioglitazone improves glycemic control and genetic and epigenetic expression profiles, which play an essential regulatory role in normal metabolism.

Empagliflozin suppresses hedgehog pathway, alleviates ER stress, and ameliorates hepatic fibrosis in rats.

Worldwide mortality from hepatic fibrosis remains high, due to hepatocellular carcinoma and end stage liver failure. The progressive nature of hepatic fibrosis from inflammation to cicatrized tissues warrants subtle intervention with pharmacological agents that hold potential. Empagliflozin (Empa), a novel hypoglycemic drug with antioxidant and anti-inflammatory properties, has lately been proposed to have additional antifibrotic activities. In the current study, we examined the antifibrotic effect of the Empa through modulating the activity of hepatic stellate cells by hedgehog (Hh) pathway. We also assessed the markers of inflammatory response and endoplasmic reticulum (ER) stress. Male Albino rats were treated with either CCl4 (0.4 mg/kg twice/week) and/or Empa (10 mg/kg/day) for eight weeks. In this study, CCl4 rats had active Hh signaling as indicated by overexpression of Patched 1, Smoothened and Glioblastoma-2. CCl4 induced ER stress as CHOP expression was upregulated and ERAD was downregulated. CCl4-induced inflammatory response was demonstrated through increased levels of TNF-α, IL-6 and mRNA levels of IL-17 while undetectable expression of IL-10. Conversely, Empa elicited immunosuppression, suppressed the expression of Hh markers, and reversed markers of ER stress. In conclusion, Empa suppressed CCl4-induced Hh signaling and proinflammatory response, meanwhile embraced ER stress in the hepatic tissues, altogether provided hepatoprotection.

Leptin Rs7799039 polymorphism is associated with type 2 diabetes mellitus Egyptian patients.

BACKGROUND: Leptin (LEP) is an anti-obesity hormone that regulates food intake, energy expenditure, and glucose metabolism. The genetic variants in LEP and the LEP receptor (LEPR) gene may play an important role in the pathogenesis of type 2 diabetes mellitus (T2DM) and obesity. The current study aimed to investigate the association of serum LEP levels, and LEP polymorphisms in LEP (rs7799039, 2548 G/A) with T2DM in Egyptian patients. METHODS: A total of 205 subjects were included in the present case-control study, consisting of 100 T2DM patients and 105 healthy controls. The anthropometric, psychometric, and biochemical measurements were taken from all the subjects. The genotyping of LEP gene variants was carried out by polymerase chain reaction TaqMan technology. Serum LEP levels were measured by the ELISA technique. RESULTS: T2DM patients had significantly elevated levels of glycated haemoglobin (HbA1c), fasting blood sugar (FBS), postprandial blood sugar (PPBS), international normalisation ratio (INR), creatinine, urea, cholesterol, triglyceride (TG), and low-density lipoproteins (LDL) and significantly decreased high-density lipoprotein (HDL) compared to healthy subjects. serum LEP levels were significantly decreased p (<0.001) as compared to the control group. LEP gene SNP rs7799039 was associated with an increased diabetic risk with A allele being more frequent in T2DM patients than control subjects. The distribution of the AA genotype and GA genotype of LEP SNP rs7799039 was higher in the diabetic group than control one. In addition, AA + GA genotype carriers had significantly elevated HbA1c, FBS, PPBS, TG, and LDL levels and on the contrary, decreased serum LEP levels compared to GG homozygotes. CONCLUSION: The genetic polymorphism rs7799039 showed a highly significant correlation with blood LEP. The co-dominant and dominant models of the LEP genetic polymorphism (rs7799039, 2548 G/A) were shown to have a significant correlation with complicated and uncomplicated diabetes individuals, but we have found that serum LEP levels were inversely related with control and diabetes patients. A positive significant association was found between LEP genetic polymorphism (rs7799039, 2548 G/A) and serum LEP in patients and controls. LEP levels and its rs7799039 genetic variant may play a vital role in increasing T2DM susceptibility.

The present study revealed a positive significant association between the leptin (LEP) genetic polymorphism rs7799039, fasting blood sugar, and post-prandial blood sugar.LEP levels might be utilised to predict T2DM. The AA genotype of LEP rs7799039, 2548G/A (co-dominant model) raises the risk of diabetes compared to the GA genotype, and the A alle is considered a risk factor OR = 1.66.A positive significant association was found between LEP genetic polymorphism (rs7799039, 2548G/A) and serum LEP in patients and controls.

Effect of autologous bone marrow derived mesenchymal stem cells in treatment of rheumatoid arthritis.

INTRODUCTION: Chronic inflammation causes articular bone and cartilage degeneration in people with rheumatoid arthritis (RA). Despite recent advancements in the management of RA, adverse side effects and ineffective treatments remain a problem. Effective treatment is usually hampered by financial issues. As a result, less expensive medications that reduce both inflammation and bone resorption are required. Mesenchymal stem cells (MSCs) have recently been identified as a potential therapy for RA. AIM OF THE STUDY: This study aimed to examine the anti-arthritic effect of rat bone marrow-derived mesenchymal stem cells (rBM-MSCs), oligosaccharides (Os), and human placental extract (HPE), individually and combined, on an RA model, using Complete Freund's adjuvant (CFA)-induced arthritis in rats. MATERIALS AND METHODS: In female rats, RA was induced by injecting CFA in the paw of the hind limb. Rat bone marrow-MSCs, oligosaccharides, and human placental extract (HPE) were given individually and in combination via the intraperitoneal route. A complete blood count (CBC), erythrocyte sedimentation rate (ESR), serum cortisol, urea, uric acid, and other biochemical parameters were measured to determine the safety and efficacy of the different treatments. Histopathological analysis of bone sections was carried out. RESULTS: Combining oligosaccharides and HPE therapy with the infusion of rat-bone marrow MSCs had beneficial antiarthritic and anti-inflammatory effects in CFA-induced arthritis in rats: overall such triple therapy significantly reduced serum levels of IL-6, IL-10, and TNF-alpha in comparison with all other combinations (all P > 0.05). Meanwhile, the triple therapy did not have negative effects on levels of CBC, serum cortisol, ESR, and liver enzymes (all NS) as well as on renal functions (NS). Also, the histopathological analysis showed significant improvements in the healing and remodelling of osteoporotic lesions in arthritic rats. As shown by counting apoptotic cells as a histopathological substitute for measuring apoptotic or regeneration markers, the lowest count was found in the group treated with a triple therapy of rat bone marrow-derived mesenchymal stem cells (rBM-MSCs), oligosaccharides, and HPE. CONCLUSION: The combination of rat MSCs, oligosaccharides, and HPE has the potential to be an effective treatment for rheumatoid arthritis.

Serum Transforming Growth Factor ß1 and Its Genetic Variants Are Associated with Increased Macrophage Inflammatory Protein 1ß and Susceptibility to Idiopathic Carpal Tunnel Syndrome.

Carpal tunnel syndrome (CTS) is a common entrapment neuropathy in which one of the body's peripheral nerves becomes pinched or crushed. Transforming growth factor beta 1 (TGF-ß1) plays an important role in the pathogenesis of CTS. An association between TGF-ß1 polymorphisms and the susceptibility or progression of a number of diseases has been reported. In this study, three TGF-ß1 single nucleotide polymorphisms (SNPs), serum TGF-ß1, and macrophage inflammatory protein 1 beta (MIP-1ß) were investigated as potential diagnostic markers for the progression of CTS in Egyptian patients. One hundred CTS patients and 100 healthy controls were recruited for the study. TGF-ß1 SNPs +915G/C, -509C/T and -800G/A were determined by TaqMan genotyping assay. Serum TGF-ß1 and MIP-1ß levels were measured by ELISA. Serum TGF-ß1 and MIP-1ß levels increased significantly and were strongly correlated with the occurrence of CTS. The C allele of +915G/C, the T allele of -509C/T, and the G allele of -800G/A occurred more frequently in patients from CTS than in controls. The serum levels of TGF-ß1 and MIP-1ß in the group of carriers of the genotypes +915G/C GC and CC, the genotype -509C/T TT and the genotype -800G/A GA and AA were significantly higher in CTS patients. TGF-ß1 and its +915G/C, -509C/T, and -800G/A SNPs and MIP-1ß could be useful prognostic markers for the occurrence of CTS.

The long non-coding RNA ZFAS1 promotes colorectal cancer progression via miR200b/ZEB1 axis.

BACKGROUND: Colorectal cancer (CRC) is a common tumor worldwide. CRC is influenced by several types of miRNAs and long non-coding RNAs. This study aims to evaluate the correlation of lncRNA ZFAS1/ miR200b/ ZEB1 protein with presence of CRC. METHODS: Quantitative real-time polymerase chain reaction was used to measure serum expression of lncRNA ZFAS1 and microRNA-200b in 60 CRC patients and 28 control subjects. ZEB1 protein in serum was measured by ELISA. RESULTS: Lnc ZFAS1 and ZEB1 were up-regulated in CRC patients in compare to control subjects while miR-200b was down-regulated. There was a linear correlation between ZAFS1 expression and miR-200b and ZEB1 in CRC. CONCLUSION: ZFAS1 is a key player of CRC progression and could be a potential therapeutic target by sponging miR-200b. In-addition the association between ZFAS1, miR-200b and ZEB1 highlights their potential value as a novel diagnostic biomarker in human CRC.

Nano-melatonin and-histidine modulate adipokines and neurotransmitters to improve cognition in HFD-fed rats: A formula to study.

The established correlation between obesity and cognitive impairment portrays pharmacological products aimed at both disorders as an important therapeutic advance. Modulation of dysregulated adipokines and neurotransmitters is hence a critical aspect of the assessment of in-use drugs. At the cellular level, repairments in brain barrier integrity and cognitive flexibility are the main checkpoints. The aim of this study was to investigate whether melatonin and histidine, alone or in combination, could produce weight loss, meanwhile improve the cognitive processes. In this study, obese rat model was established by feeding high fat diet (HFD) composed of 25% fats (soybean oil) for 8 weeks, accompanied by melatonin (10 mg/kg), histidine (780 mg/kg), and combination of both in conventional form and nanoform. At the end of the study, adiposity hormones, neuronal monoamines and amino acids, brain derived neurotrophic factor (BDNF) and zonula occluden-1 (ZO-1) were assessed. HFD feeding resulted in significant weight gain and poor performance on cognitive test. Coadministration of histidine in the nanoform increased the level of ZO-1; an indicator of improving the brain barrier integrity, along with adjusting the adipokines and neurotransmitters levels, which had a positive impact on learning tasks. Cotreatment with melatonin resulted in an increase in the level of BDNF, marking ameliorated synaptic anomalies and learning disabilities, while reducing weight gain. On the other hand, the combination of melatonin and histidine reinstated the synaptic plasticity as well as brain barrier junctions, as demonstrated by increased levels of BDNF and ZO-1, positively affecting weight loss and the intellectual function.

Integrating experimental model, LC-MS/MS chemical analysis, and systems biology approach to investigate the possible antidiabetic effect and mechanisms of Matricaria aurea (Golden Chamomile) in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a heterogeneous disease with numerous abnormal targets and pathways involved in insulin resistance, low-grade inflammation, oxidative stress, beta cell dysfunction, and epigenetic factors. Botanical drugs provide a large chemical space that can modify various targets simultaneously. Matricaria aurea (MA, golden chamomile) is a widely used herb in Middle Eastern communities for many ailments, including diabetes mellitus, without any scientific basis to support this tradition. For the first time, this study aimed to investigate the possible antidiabetic activity of MA in a type 2 diabetic rat model, identify chemical constituents by LC-MS/MS, and then elucidate the molecular mechanism(s) using enzyme activity assays, q-RTPCR gene expression analysis, network pharmacology analysis, and molecular docking simulation. Our results demonstrated that only the polar hydroethanolic extract of MA had remarkable antidiabetic activity. Furthermore, it improved dyslipidemia, insulin resistance status, ALT, and AST levels. LC-MS/MS analysis of MA hydroethanolic extract identified 62 compounds, including the popular chamomile flavonoids apigenin and luteolin, other flavonoids and their glycosides, coumarin derivatives, and phenolic acids. Based on pharmacokinetic screening and literature, 46 compounds were chosen for subsequent network analysis, which linked to 364 candidate T2DM targets from various databases and literature. The network analysis identified 123 hub proteins, including insulin signaling and metabolic proteins: IRS1, IRS2, PIK3R1, AKT1, AKT2, MAPK1, MAPK3, and PCK1, inflammatory proteins: TNF and IL1B, antioxidant enzymes: CAT and SOD, and others. Subsequent filtering identified 40 crucial core targets (major hubs) of MA in T2DM treatment. Functional enrichment analyses of the candidate targets revealed that MA targets were mainly involved in the inflammatory module, energy-sensing/endocrine/metabolic module, and oxidative stress module. q-RTPCR gene expression analysis showed that MA hydroethanolic extract was able to significantly upregulate PIK3R1 and downregulate IL1B, PCK1, and MIR29A. Moreover, the activity of the antioxidant hub enzymes was substantially increased. Molecular docking scores were also consistent with the networks' predictions. Based on experimental and computational analysis, this study revealed for the first time that MA exerted antidiabetic action via simultaneous modulation of multiple targets and pathways, including inflammatory pathways, energy-sensing/endocrine/metabolic pathways, and oxidative stress pathways.

Cyanidin-3-Glucoside Modulates hsa_circ_0001345/miRNA106b/ATG16L1 Axis Expression as a Potential Protective Mechanism against Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of malignancy in the liver. Autophagy was found to have a significant effect in controlling HCC. Anthocyanins, which are naturally occurring pigments in a variety of fruits and vegetables, have been thoroughly documented to be involved in a variety of bioactive activities and are widely employed for their antioxidant capabilities. Cyanidin-3-glucoside (C3G) extracted from Morus alba L. has promising antioxidant and anti-tumour activities. The current study aims to examine the protective action of C3G against hepatocellular carcinoma through the investigation of the autophagy protein ATG16L1 expression along with its related RNA molecules (hsa_circ_0001345 and miRNA106b) in Wistar rats. In vivo precancerous lesions (PCL) were induced using diethylnitrosamine (DEN) and acetamidofluorene (2-AAF). Rats were treated with C3G (10, 15, and 20 mg/kg; 4 times weekly) for 112 days (16 weeks). Liver function tests, alfa fetoprotein, ATG16L1 expression, hsa_circ_0001345, and miRNA106b differential expression were examined. Liver sections were examined by histological and immunohistochemical approaches. The current study's findings indicated that C3G administration protects against the negative effects of DEN-2-AAF on liver functions and liver histopathological sections, which nominated C3G as a potential prophylactic agent against HCC.

Pro-Neurotensin as a Potential Novel Diagnostic Biomarker for Detection of Nonalcoholic Fatty Liver Disease.

Background and Aims: Currently, liver biopsy is the gold standard method for diagnosis of non-alcoholic fatty liver severity. It is critical to develop non-invasive diagnostic method to diagnose nonalcoholic fatty liver rather than invasive techniques. Our case-control study was to address the value of circulating miRNA-122 and serum pro-neurotensin as a potential non-invasive biomarker for the diagnosis of non-alcoholic fatty acid diseases. Methods: Clinical assessment, laboratory investigations, and anthropometric measurements were reported for 157 patients with proven NAFLD. Apparently, healthy participants (n=100) were enrolled as a control group. Serum samples were tested for micro-RNAs-122 and pro-neurotensin. Results: Compared with the control subjects, both mi-RNA-122 and serum proneurotensin levels were increased in NAFLD (p<0.001) and at a cut-off ≥6.83, mi-RNA-122 had 51.0% sensitivity, 70.0% specificity to differentiate NAFLD from healthy controls, while serum proneurotensin had 80.0% sensitivity and 80.0% specificity at a cutoff ≥108. Conclusion: The circulating pro-neurotensin might be used as a novel biomarker for diagnosis of patients with NAFLD, wherefore the integration of a circulating mi-RNA-122 and serum pro-neurotensin could be beneficial to diagnose NAFLD cases. Large-scale studies are needed to investigate the possible role of mi-RNA-122 and pro-neurotensin in the development, progression, and prognosis of NAFLD and NASH.

Genetic variants of ALR (-106C → T /-12C → G) and serum PKC-δ are associated with peripheral neuropathy in Egyptian diabetic patients with impaired handwriting.

Purpose: Diabetic peripheral neuropathy can injure the hand median nerve and cause extensive nerve damage. PKC and ALR are associated with progression of diabetic complications. We hypothesized a genetic association between the ALR polymorphisms (-106C → T/-12C → G) and elevated serum PKC-δ levels in diabetic neuropathy and its adverse effects on handwriting in Egyptian population. Methods: One hundred DPN were compared with 100 DP and 100 healthy volunteers. ALR -106C → T/-12C → G variants were studied using the PCR-RFLP method. A routine set of standard laboratory markers was determined. Serum PKC-δ concentration was determined by ELISA. Logistic regression analysis and areas under the receiver characteristic curves (AUCs) were evaluated to investigate the predictors of diabetic neuropathy. Arabic handwriting was analyzed based on the recognition of functional features, word shape, and ascending/descending parts of letters. Results: Individuals carrying ALR-106C → C and -12G → G had a significantly higher risk of developing diabetic neuropathy than individuals with -106C → T and -12C → G genotypes (P = 0.01, P = 0.02). Carriers of the (-106C → T) CC and (-12C → G) GG genotypes had significantly increased serum levels of PKC-δ, FBG, TC, and LDL-c. PKC- δ serum levels were significantly correlated with glycemic and lipid indicators (P < 0.001). PKC-δ is a significant predictor of diabetes with or without neuropathy at a cutoff value of 16.6, sensitivity was 89%, and specificity 100%. All DPN showed complete deterioration of handwriting after the onset of diabetic neuropathy. Conclusion: The genetic variants ALR-106C → C / -12G → G and PKC-δ in serum may help in the detection and treatment of diabetic neuropathy in Egyptian population before writing performance is affected.

Selenium nanoparticles overcomes sorafenib resistance in thioacetamide induced hepatocellular carcinoma in rats by modulation of mTOR, NF-κB pathways and LncRNA-AF085935/GPC3 axis.

AIMS: The first-line treatment for advanced hepatocellular carcinoma (HCC) is the multikinase inhibitor sorafenib (SOR). Sofafenib resistance is linked to protein kinase B/ mammalian target of rapamycin (AKT/mTOR) and nuclear factor kappa B (NF-κB) activation, apoptosis inhibition and oxidative stress. This study investigated selenium nanoparticles (SeNps) to overcome SOR resistance in thioacetamide (TAA) induced HCC in rats. MATERIALS AND METHODS: TAA (200 mg/kg/twice weekly, i.p.) was administered for 16 weeks to induce HCC.s. Rats were treated with oral SOR (10 mg/Kg daily), selenium, and SeNps (5 mg/kg three times/week) alone or in combination, for two weeks. Apoptosis, proliferation, angiogenesis, metastasis and drug resistance were assessed. Cleaved caspase 3 (C. CASP3), mTOR, and NF-κB were determined by western blotting. Expression of p53 gene and long-noncoding RNA-AF085935 was determined by qRT-PCR. Expression of B- Cell Leukemia/Lymphoma 2 (Bcl2), Bcl associated X protein (Bax)and glypican 3 (GPC3) was determined by enzyme-linked immunosorbent assay. Liver functions, antioxidant capacity, histopathology and CD34 immunohistochemistry were performed. KEY FINDINGS: SOR/SeNps reversed TAA-induced HCC in rats, through reduction of oxidative stress, activation of p53, Bax and CASP3, and inhibition of Bcl2. SOR/SeNps ameliorated the HCC-induced effect on cell proliferation and drug resistance by targeting mTOR and NF-κB pathways. SOR/SeNps decreased CD34 immunostaining indicating a decrease in angiogenesis and metastasis. SOR/SeNps regulated HCC epigenetically through the lncRNA-AF085935/GPC3 axis. SIGNIFICANCE: SOR/SeNps are a promising combination for tumor suppression and overcoming sorafenib resistance in HCC by modulating apoptosis, AKT/mTOR and NF-κB pathways, as well as CD34 and lncRNA-AF085935/GPC3 axis.

Infliximab and/or MESNA alleviate doxorubicin-induced Alzheimer's disease-like pathology in rats: A new insight into TNF-α/Wnt/ß-catenin signaling pathway.

AIMS: The current study aimed to elucidate the neurotoxic potential of DOX to induce AD-like pathology paying attention to the role of wingless-integrated/ß-catenin (Wnt/ß-catenin) signaling pathway. A major aim was to evaluate the efficacy of infliximab (IFX) either individually or in combination with 2-mercaptoethane sulfonate sodium (MESNA) on the DOX-induced neurotoxicity in rats. METHODOLOGY: AD-like pathology was induced in adult male Wistar rats by intraperitoneal (i.p.) administration of DOX at a dose of 3.5 mg/kg twice a week for 3 weeks. DOX-injected rats were then treated with either INF at a single dose of 5 mg/kg i.p. (IFX group), MESNA at a dose of 160 mg/kg/day i.p. for 4 weeks (MESNA group) or their combination at the same specified doses (INF + MESNA group). At the end of the study period, behavioral assessment was performed and the brain tissue samples were harvested at sacrifice. KEY FINDINGS: DOX-treated rats significantly exhibited AD-like brain injury, increased amyloid burden, enhanced neuroinflammation and apoptosis, and multifocal histological injury in the cerebral cortex with widespread vacuolations. IFX and MESNA significantly reversed all the aforementioned detrimental effects in the DOX-treated rats. SIGNIFICANCE: The study has provided sufficient evidence of the potential of IFX and/or MESNA to ameliorate the DOX-induced neurotoxicity, with the best improvement observed with their combined administration. A new insight has been introduced into the critical role of Wnt/ß-catenin activation.

Antisecretory and antioxidative effects of the antidepressants fluvoxamine and mirtazapine on water immersion stress and pyloric ligation-induced gastric ulcer in rats.

Objectives: Although there are numerous drugs available for the treatment of gastric ulcers (GU), these drugs are not always effective. Antidepressant medications have been used for a variety of non-psychiatric indications, including antiulcer activity in various ulcer models. The purpose of this study was to compare the antiulcer effects of fluvoxamine and mirtazapine in two rat GU experimental models and to determine their relationship to antioxidant and antisecretory mechanisms. Materials and Methods: The antiulcer activities of various doses of fluvoxamine and mirtazapine on water immersion restraint stress (WIRS) and pyloric ligation-induced GU in rats have been studied against the positive control antiulcer drug famotidine. Various oxidative stress markers were evaluated. Results: Fluvoxamine and mirtazapine significantly protected against WIRS and pyloric ligation-induced gastric lesions, as evidenced by a dose-dependent decrease in ulcer index, myeloperoxidase (MPO) activity, lipid peroxidation, and an increase in prostaglandin E2, nitric oxide (NO), and reduced glutathione levels, as well as increased antioxidant enzyme activity. In the pyloric ligation model, fluvoxamine and mirtazapine improved GU more than famotidine. Furthermore, a 30 mg/kg dose of mirtazapine significantly improves both NO levels and MPO activity compared to famotidine. Conclusions: The results highlighted the relationship in correlating the antiulcer effect of drugs from different antidepressant classes across two animal GU models, implying that antidepressants that affected both norepinephrine and serotonin levels (mirtazapine) had a more potent antiulcer effect in WIRS-induced gastric model than drugs that only affected serotonin levels (fluvoxamine).

Prevalence of Occult Hepatitis C Virus Infection in Egyptian Patients with Lymphoma: A New Vision.

Occult hepatitis C virus infection (OCI) is the absence of HCV RNA in serum and the presence of actively replicating HCV RNA in hepatocytes and peripheral blood mononuclear cells (PBMCs), as evidenced by the presence of antigenomic negative sense single-stranded RNA. This study aimed to determine the prevalence of OCI in Egyptian lymphoma patients and assess changes in biochemical parameters in patients with confirmed OCI. The current study was conducted on 100 apparently healthy subjects as control group and 100 patients with lymphoma as a case group. HCV RNA was extracted and detected in both plasma and PBMCs using qRT-PCR. Total protein, albumin, ALT, AST, and total and direct bilirubin were measured in serum. OCI was detected in 6% of the patient group. OCI patients had lower levels of total protein and serum albumin and higher ALT and AST compared with lymphoma patients without OCI. Our study revealed that six out of 100 patients with lymphoma disorders had occult HCV infection (6%). Therefore, the possibility of this infection should be considered in patients with lymphoma.

Effect of gold nanoparticles shape and dose on immunological, hematological, inflammatory, and antioxidants parameters in male rabbit.

Background and Aim: Gold nanorods (AuNRs) have gained much attention recent years due to their promising optical and chemical properties and are hence used in applied research and industrial nanotechnology. This study was designed to investigate the effect of gold nanoparticle shape (Gold nanorods vs. gold nanosphere) on immune response in rabbit. Materials and Methods: Thirty New Zealand white rabbits were divided into six groups (n=5 rabbits). The first group is the control negative received an intravenous (IV) injection of normal saline 0.9%; the second group (vaccinated) is the control positive, and the other four groups were vaccinated and received a single-dose or repeated five consecutive IV doses of 300 mg/kg body weight 50 nm AuNRs or 50 nm gold nanosphere (50 nm AuNSs) dissolved in ultrapure water. Blood and serum were collected for the hematological and biochemical analysis. Results: White blood cells (WBCs) count, lymphocytes, monocytes, eosinophils, and basophils showed significantly (p<0.05) higher values with the repeated-dose AuNRs. g-globulin levels showed a significant difference after 15 days in the single-dose AuNSs. Single-dose AuNSs significantly (p<0.05) increased the immunoglobulin G (IgG) and significantly (p<0.05) decreased the tumor necrosis factor-alpha. In addition, it elicited a significant (p<0.05) decrease in the malondialdehyde levels and a significant (p<0.05) increase of the superoxide dismutase, glutathione peroxidase, and catalase levels. Moreover, evoked red blood cells count, mean corpuscular volume, and mean corpuscular hemoglobin were significantly (p<0.05) lower than the control group. The platelet count, lysozymes, and nitric oxide were significantly (p<0.05) higher in repeated-dose AuNRs. Conclusion: The effect of AuNPs is shape and dose-dependent. The repeated 5 days IV 50 nm AuNRs doses over 15 days showed a significant antioxidant effect, with no considerable toxicity or vascular reactions.

YWHAH Genetic Variants are Associated with Increased Hypoxia Inducible Factor-1α/Vascular Endothelial Growth Factor in Egyptian Rheumatoid Arthritis Patients.

The 14-3-3 Eta (14-3-3 η) biomarker platform is a relatively recent discovery with the potential to significantly address the diagnosis and prognosis of rheumatoid arthritis (RA) disease. Hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) have been implicated in inflammatory mechanisms in RA. We hypothesized a molecular association of the coding YWHAH gene and its expressed protein 14-3-3 η with hypoxia and angiogenesis in RA. One hundred healthy subjects and 100 RA patients were enrolled in the study. YWHAH gene expression was determined using quantitative PCR, and its gene polymorphism rs2858750 was assessed by Taqman genotyping assay. Serum levels of 14-3-3 η, HIF-1α, and VEGF were measured using the ELISA technique, and clinical parameters were routinely examined. In RA patients, significant positive correlations were found between 14-3-3 η, HIF-1α (r = 0.84), and VEGF (r = 0.85). YWHAH gene expression was upregulated 10.8 fold (CI 95% 10.1-11.5) in RA patients and significantly correlated with all disease activity parameters, ACPA, and levels of 14-3-3 η, HIF-1α, and VEGF. RA patients showed a higher frequency of YWHAH rs2858750 A allele than healthy subjects (p = 0.02). The risk A allele carriers showed higher disease activity parameters, ACPA, YWHAH gene expression, and increased serum levels of 14-3-3 η (p < 0.001), HIF-1α (p = 0.002), and VEGF (p = 0.001) than the G allele. Serum 14-3-3 η and its rs2858750 genetic variant are associated with increased hypoxia and angiogenesis in RA and activity, and severity of the disease.

Long non-coding RNA MEG3 and its genetic variant rs941576 are associated with rheumatoid arthritis pathogenesis in Egyptian patients.

BACKGROUND: Rheumatoid arthritis (RA) is a joint destructive disorder. This study aimed to assess lncRNA MEG3 expression and its variant rs941576 in Egyptian patients with RA. SUBJECTS AND METHODS: 100 RA patients and 100 healthy individuals were enrolled in the study. Quantitative PCR was used for expression analysis and allelic discrimination technology for genotyping. RESULTS: LncRNA MEG3 was down-regulated in RA patients and negatively associated with RA clinical features and HIF-1α and VEGF serum levels. On the contrary, it was positively associated with BAX serum levels in RA patients. The major A allele of rs941576 variant was associated with RA patients (p = .0003). AA genotype showed a significant decrease in lncRNA MEG3 expression and BAX and increase in HIF-1α and VEGF. CONCLUSIONS: Serum lncRNA MEG3 expression showed negative association with increased susceptibility to RA. MEG3 gene rs941576 (A/G) polymorphism was associated with increased severity of RA in the current population.