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.

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.

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.

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.

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.

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.

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.

The expression of zinc finger 804a (ZNF804a) and cyclin-dependent kinase 1 (CDK1) genes is related to the pathogenesis of rheumatoid arthritis.

CONTEXT: ZNF804a and CDK1 genes code for proteins involved in inflammatory pathways. OBJECTIVE: This study aimed to investigate the correlation of ZNF804a and CDK1 expression profiles in RA with the activity and the severity of the disease and to assess their association with inflammatory reactions in the Egyptian RA patients. METHODS: ZNF804a and CDK1 expression profiles were assessed using quantitative PCR (qRT-PCR). Clinical and laboratory parameters were evaluated. RESULTS: ZNF804a expression was down-regulated by 0.177-fold while CDK1 expression was up-regulated to 3.29-fold in RA patients compared with healthy controls (p < .001). ZNF804a down-regulation was negatively correlated with CRP, RF, disease activity score of 28 joints (DAS) using CRP (DAS-CRP) and TNF-α. CDK1 overexpression was correlated with IFN-1 and ACPA in RA patients. CONCLUSION: ZNF804a and CDK1 genes are implicated in RA pathogenesis due to their influences on TNF-α and IFN-1 which contribute to inflammation in RA patients.

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.

Anti-oxidant, anti-apoptotic, and mitochondrial regulatory effects of selenium nanoparticles against vancomycin induced nephrotoxicity in experimental rats.

AIM: Nephrotoxicity is the major limiting factor for the clinical use of vancomycin (VCM) for treatment against multi-resistant Gram-positive bacteria. The present research aimed to investigate the ability of selenium nanoparticles (SeNPs) to protect against VCM-induced nephrotoxicity in rats. MAIN METHODS: Experimental rats were divided into five groups; the first was the normal control, the second was treated with VCM (200 mg/kg twice/day, i.p.) for 7 days. The third, fourth, and fifth groups were treated orally with SeNPs (0.5, 1, and 2 mg/kg/day); respectively. SeNPs were administered for 12 days before VCM, 1 week simultaneously with VCM, and for another 1 week after its administration. KEY FINDINGS: Levels of malondialdehyde (MDA), inducible nitric oxide synthase (iNOS), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and kidney injury molecule-1 (KIM-1) were significantly increased in kidney tissue after VCM administration. Expression of adenosine 5'-monophosphate-activated protein kinase (AMPK), Bcl-2 associated X protein (Bax), caspase 3 and caspase 9 in kidney tissue was significantly increased, while the antioxidant enzymes, mitochondrial complexes, the ATP levels and B-cell lymphoma protein 2 (Bcl-2) were decreased in kidney in the VCM-treated rats compared to the normal control group. Treatment with SeNPs significantly decreased levels of MDA, iNOS, NO, TNF-α, and KIM-1 in the kidney tissue. Administration of SeNPs also downregulated the expression of the proapoptotic agents and enhanced the activities of the antioxidant enzymes and the mitochondrial enzyme complexes in the kidney. SIGNIFICANCE: SeNPs alleviated VCM-induced nephrotoxicity through their anti-oxidant, anti-inflammatory, anti-apoptotic and mitochondrial protective effects.

Hypothyroidism affect progression and worse outcomes of breast cancer but not ovarian cancer.

Some studies suggest that thyroid hormones and disorders can influence breast (BC) and ovarian (OC) cancers risks. However, studies regarding their effect on these tumors progression are limited. Thyroid-stimulating hormone (TSH), T4, free T4 (FT4), T3, and free T3 (FT3) were detected in patients with BC, OC, benign breast and ovary diseases, and healthy controls using highly sensitive chemiluminescence assay. In contrast to OC, hypothyroidism prevalence was associated with BC late stage (11/24 vs. 2/46), high grade (11/23 vs. 4/47), lymph node invasion (11/42 vs. 0/28), positive distant metastasis (11/25 vs. 1/45), and large tumor size (14/25 vs. 1/45) compared to tumor early stages, low grades, negative lymph node, and distant metastasis and small size, respectively. Patients with late stage, high grade, large tumor size, positive lymph nodes, or positive distant metastasis were significantly (P < 0.05) associated with elevated levels of TSH and decreased levels of T4, FT4, T3, and FT3. There were both significant positive correlation of serum TSH and significant inverse correlation of T4, FT4, T3, and FT3 with these tumor worse outcomes. In conclusion, our results identify hypothyroidism as potentially important prognostic factor in BC not in OC that is associated with poor outcomes of BC patients.

Anti-Oxidant and Anti-Inflammatory Effects of Lipopolysaccharide from Rhodobacter sphaeroides against Ethanol-Induced Liver and Kidney Toxicity in Experimental Rats.

This study aimed to investigate the protective effects of lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) against ethanol-induced hepatotoxicity and nephrotoxicity in experimental rats. The study involved an intact control group, LPS-RS group, two groups were given ethanol (3 and 5 g/kg/day) for 28 days, and two other groups (LPS-RS + 3 g/kg ethanol) and (LPS-RS + 5 g/kg ethanol) received a daily dose of LPS-RS (800 µg/kg) before ethanol. Ethanol significantly increased the expression of nuclear factor kappa B (NF-κB) and levels of malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in the liver tissue and decreased anti-oxidant enzymes. Hepcidin expression was downregulated in the liver, with increased serum levels of ferritin and iron. Prior-administration of LPS-RS alleviated the increase in oxidative stress and inflammatory markers, and preserved iron homeostasis markers. In the kidney, administration of ethanol caused significant increase in the expression of NF-κB and the levels of TNF-α and kidney injury markers; whereas LPS-RS + ethanol groups had significantly lower levels of those parameters. In conclusion; this study reports anti-oxidant, anti-inflammatory and iron homeostasis regulatory effects of the toll-like receptor 4 (TLR4) antagonist LPS-RS against ethanol induced toxicity in both the liver and the kidney of experimental rats.

Plicosepalus acacia Extract and Its Major Constituents, Methyl Gallate and Quercetin, Potentiate Therapeutic Angiogenesis in Diabetic Hind Limb Ischemia: HPTLC Quantification and LC-MS/MS Metabolic Profiling.

Plicosepalus acacia (Fam. Loranthaceae) has been reported to possess hypoglycemic, antioxidant, antimicrobial, and anti-inflammatory effects. Liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) analysis revealed the presence of a high content of polyphenolic compounds that are attributed to the therapeutic effects of the crude extract. In addition, methyl gallate and quercetin were detected as major phytomedicinal agents at concentrations of 1.7% and 0.062 g%, respectively, using high-performance thin layer chromatography (HPTLC). The present study investigated the effect of the P. acacia extract and its isolated compounds, methyl gallate and quercetin, on hind limb ischemia induced in type 1 diabetic rats. Histopathological examination revealed that treatment with P. acacia extract, methyl gallate, and quercetin decreased degenerative changes and inflammation in the ischemic muscle. Further biochemical assessment of the hind limb tissue showed decreased oxidative stress, increased levels of nitric oxide and endothelial nitric oxide synthase (eNOS), and enhancement of the levels of heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) in the groups treated with methyl gallate and quercetin. Expression levels of hypoxia inducible factor-1 alpha (HIF-1α), VEGF, fibroblast growth factor-2 (FGF-2), and miR-146a were upregulated in the muscle tissue of methyl gallate- and quercetin-treated groups along with downregulation of nuclear factor kappa B (NF-κB). In conclusion, P. acacia extract and its isolated compounds, methyl gallate and quercetin, mediated therapeutic angiogenesis in diabetic hind limb ischemia.

The Antioxidant Carrichtera annua DC. Ethanolic Extract Counteracts Cisplatin Triggered Hepatic and Renal Toxicities.

Cisplatin is a powerful anti-neoplastic drug that displays multi-organ toxicity, especially to the liver and kidneys. Consumption of phytomedicines is a promising strategy to overcome the side effects of chemotherapy. Carrichtera annua extract proved to possess potent antioxidant activity. Its protective potential against cisplatin-induced hepato-nephrotoxicity was scrutinized. Moreover, a phytochemical study was conducted on C. annua ethyl acetate fraction which led to the isolation of five known phenolic compounds. Structure determination was achieved utilizing 1H- and 13C-NMR spectral analyses. The isolated phytochemicals were trans-ferulic acid (1), kaempferol (2), p-coumaric acid (3), luteolin (4) and quercetin (5). Regarding our biological study, C. annua has improved liver and kidney deteriorated functions caused by cisplatin administration and attenuated the histopathological injury in their tissues. Serum levels of ALT, AST, blood urea nitrogen and creatinine were significantly decreased. C. annua has modulated the oxidative stress mediated by cisplatin as it lowered MDA levels while enhanced reduced-GSH concentrations. More importantly, the plant has alleviated cisplatin triggered inflammation, apoptosis via reduction of INFγ, IL-1ß and caspase-3 production. Moreover, mitochondrial injury has been ameliorated as remarkable increase of mtDNA was noted. Furthermore, the MTT assay proved the combination of cisplatin-C. annua extract led to growth inhibition of MCF-7 cells in a notable additive way. Additionally, we have investigated the binding affinity of C. annua constituents with caspase-3 and IFN-γ proteins using molecular simulation. All the isolated compounds exhibited good binding affinities toward the target proteins where quercetin possessed the most auspicious caspase-3 and IFN-γ inhibition activities. Our results put forward that C. annua is a promising candidate to counteract chemotherapy side effects and the observed activity could be attributed to the synergism between its phytochemicals.

Role of heme oxygenase-1, cytokines, and vascular endothelial growth factor in murine Schistosoma mansoni.

OBJECTIVES: Among tropical diseases, schistosomiasis caused by Schistosoma mansoni is the second major cause of morbidity and mortality worldwide. Inflammation was considered as an adverse event that contributes to the pathology associated with schistosomiasis. Heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) have been implicated in the process of angiogenesis. The current study aimed to evaluate the effect of S. mansoni infection on HO-1 gene expression, IL-4, IL-12, and VEGF to address the role of these factors in the pathogenesis of schistosomiasis. METHODS: Thirty mice divided equally into three groups comprised a non-infected control group and two S. mansoni-infected groups. Infected animals were studied at 8 and 12 weeks post-infection. Serum IL-4, IL-12, and VEGF were measured. HO-1 mRNA was detected by RT-PCR of liver homogenates and HO activity was assessed as percentage of carboxy hemoglobin. RESULTS: S. mansoni-infected mice showed a progressive increase in serum IL-4 and VEGF and decrease in IL-12 levels. In addition, HO-1 expression and activity were increased in infected mice compared to control group with the maximum increase at egg deposition stage. CONCLUSION: Our results suggested that the body response to acute stage of S. mansoni infection by elevating the expression of the stress gene HO-1 and that VEGF may serve as a new indicator of progression of S. mansoni associated angiogenesis which regulates granuloma and/or fibrosis development in the liver of infected mice. Understanding the role of HO-1 and VEGF in pathogenesis of S. mansoni may provide a new pharmacological target.

Ginger Extract Loaded into Chitosan Nanoparticles Enhances Cytotoxicity and Reduces Cardiotoxicity of Doxorubicin in Hepatocellular Carcinoma in Mice.

This study aimed to investigate the impact of ginger extract (GE) loaded into chitosan nanoparticles (CNPs) in enhancing cytotoxicity and reducing cardiotoxicity of doxorubicin (DXN) in hepatocellular carcinoma (HCC) induced mice. DXN and GE were loaded into CNPs and cytotoxicity of loaded and unloaded drugs against HepG2 cells was evaluated. HCC was induced in male albino mice by injection of diethylnitrosamine (DINA). Mice were divided into eight groups (n = 15): (1) normal control, (2) DINA, (3) CNPs, (4) free DXN, (5) CNPs DXN, (6) free GE, (7) CNPs GE, and (8) CNPs DXN + CNPs GE. Both GE and DXN loaded into CNPs showed a greater decline in cell viability of HepG2 cells than the unloaded forms. GE CNPs displayed pronounced anticancer activity In Vivo through apoptosis, greater down-regulation of multidrug resistance 1, enhancement of anti-oxidant activity and depletion of vascular endothelial growth factor content in liver tissues. GE CNPs in combination with DXN CNPs showed nearly normal hepatic lobule architecture and the greatest increase in apoptotic cell count. Co-treatment group had decreased cardiac malondialdehyde, tumor necrosis factor-α and serum activity of creatine kinase and lactate dehydrogenase. Combination of GE CNPs and DXN CNPs might be a potentially effective therapeutic approach for HCC.