Predictive significance of pretreatment 18F-FDG PET volumetric parameters on survival outcomes in pediatric patients with locally advanced undifferentiated nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a rare pediatric cancer. Most children are first diagnosed with advanced locoregional disease. Identification of patients at higher risk of treatment failure is crucial as they may benefit from more aggressive initial treatment approaches. 18Fluorine-labeled fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET) has shown promise as a prognostic tool for predicting outcomes. METHODS: Retrospective study of pediatric patients with locally advanced undifferentiated NPC who underwent 18F-FDG PET/CT prior to intial treatment. Predictive significance of metabolic PET parameters on survival outcomes were estimated. RESULTS: Thirty-two children were included, age range was 7.1-18 years at the time of diagnosis. The median follow-up duration was 46.1 months. Three patients (9.4%) were classified as AJCC stage IIb, 13 patients (40.6%) as stage IIIa, eight patients (25%) as stage IIIb, and eight patients (25%) as stage IVa. Our findings revealed that high whole-body metabolic tumor volume at the threshold of hepatic reference SUVmean (WB-MTV-HR) (>135 mL) was associated with significantly lower event-free survival (EFS) compared to the low WB-MTV-HR group (≤135 mL) (3-year EFS: 50% ± 18% vs. 82% ± 8%; p = .015). Additionally, the 3-year overall survival (OS) rates differed significantly between the high whole-body metabolic tumor volume at the threshold of an SUV of 2.5 isocontour (WB-MTV-2.5) group (MTV >74 mL) and the low WB-MTV-2.5 group (MTV ≤74 mL) (63% ± 18% vs. 100%; p = .021). CONCLUSION: Our study suggests that WB-MTV parameters could serve as significant prognostic factors for disease progression in pediatric patients with locally advanced undifferentiated NPC. However, further prospective studies with larger sample sizes are needed to validate these findings.

Development of certain aminoquinazoline scaffolds as potential multitarget anticancer agents with apoptotic and anti-proliferative effects: Design, synthesis and biological evaluation.

Newly designed 4 - aminoquinazoline derivatives (5a-f, 6a, b, 7, 8, 9, 10a-c, 11a, b, 12a, b and 13a, b) have been synthesized and evaluated for their potential multitarget anticancer activities, apoptotic and anti-proliferative effects. Thereupon, in vitro cytotoxic activities of all the synthesized compounds were screened against NCI 60 human cancer cell lines (nine subpanels) at NCI, USA. Successfully, 2-morpholino-N-(quinazolin-4-yl) acetohydrazide 5e was granted an NSC code, owing to its significant potency and broad spectrum of activity against various cancer cell lines; leukemia K-562, non-small cell lung cancer NCI-H522 cells, colon cancer SW-620, melanoma LOX IMVI, MALME-3M, renal cancer RXF 393, ACHN and breast cancer MDA-MB231/ATCC (GI% = 99.6, 161, 126.03, 90.22, 174.47, 139.7, 191 and 97, respectively). Compound 5e showed the best inhibitory activity (GI50 = 1.3 µM) against melanoma LOX IMVI, when tested at five doses against NCI 60 cell lines. Furthermore, compound 5e showed comparable EGFR and CDK2 inhibitory activity results (IC50 = 0.093 ± 0.006 µM and 0.143 ± 0.008 µM, respectively) to those of lapatinib and ribociclib (IC50 = 0.03 ± 0.002 µM and 0.067 ± 0.004 µM, respectively). Western blotting analysis of compound 5e against melanoma LOX IMVI marked out significant reduced EGFR and CDK2 protein expression percentages, up to 32.97% and 34.09%, respectively, if compared to lapatinib (31.18%) and ribociclib (29.66%). Moreover, compound 5e caused clear cell cycle arrests at S phase of renal UO-31 cells and at G1 phase of both breast cancer MCF7 and ovarian cancer IGROV1, associated with remarkable increase of DNA content of the controls. In accordance, it demonstrated promising anti- proliferative and apoptotic activities, showing a significant increase in total apoptotic percentages of renal cancer UO-31, breast cancer MCF7 and ovarian IGROV1 cancer cell lines, if compared to the control untreated cells (from 1.79% to 46.72%, 2.19% to 39.02% and 1.66 to 42.51%, respectively). Molecular modelling and dynamic simulation study results supported the main objectives of the present work.

Impacts of selenium nanoparticles and spirulina alga to alleviate the deleterious effects of heat stress on reproductive efficiency, oxidative capacity and immunity of doe rabbits.

Effects of dietary inclusion of spirulina platensis (SP) and selenium nanoparticles (SeNPs) combination (SP-SeNPs) on the reproductive performance in vivo and in vitro, reproductive and metabolic hormones, hemato-bichemical parameters, oxidative stress, and immunity of heat-stressed doe rabbis were evaluated. All supplements significantly increased live litter size at birth and weaning, viability rate at birth, hemoglobin and red blood cells, and plasma T3, T4, insulin, total proteins and albumin compared with control. Plasma estradiol 17-ß (pre-mating), progesterone (mid-pregnancy), and prolactin (day -7 postpartum) were significantly increased only by SeNPs (0.3, 0.4, and 0.5 mg/kg). All dietary supplements significantly reduced WBCs, cortisol, lipid profile, and improved liver and kidney functions. Immunoglobulins levels, antioxidants capacity were significantly increased, superoxide dismutase was increased by SeNPs (0.4 and 0.5 mg/kg), while malondialdehyde was reduced by 0.3, 0.4 and 0.5 SeNPs mg/kg. Sexual receptivity, pregnancy rate, viability rate at weaning, ovulation rate, and embryo quality were significantly increased by increasing SeNPs above 0.1 mg, while embryo yield was increased by >0.2 mg SeNPs/kg. A combination of SP and SeNPs, could be potentially used as a strong antioxidant to enhance heat regulation and doe rabbit reproduction via improving reproductive and metabolic hormones, antioxidant status and immunological parameters.

Nifuroxazide mitigates doxorubicin-induced cardiovascular injury: Insight into oxidative/NLRP3/GSDMD-mediated pyroptotic signaling modulation.

Doxorubicin (DOX) is a widely used powerful anthracycline for treatment of many varieties of malignancies; however its cumulative and dose-dependent cardio-toxicity has been limited its clinical use. In the current study, in vivo and in vitro (neonatal rat's cardiomyocytes) experiments were conducted to identify the impact of nifuroxazide (NIFU) on DOX-induced cardiomyopathy, vascular injury, and hemato-toxcity and plot the underlying regulatory mechanisms. Cardiovascular injury was induced in vivo by I.P. injection of an overall dose of DOX (21 mg/kg) administered (3.5 mg/kg) twice weekly for 21 days. NIFU (10 and 30 mg/kg) was administered orally once daily for 21 days, 1 week after DOX injection initiation. In vivo experiments confirmed NIFU to restore blood cells counts and hemoglobin concentration. Moreover, NIFU normalized the myocardial functional status as confirmed by ECG examination and myocardial injury markers; CK-MB, LDH, and AST. NIFU restored the balance between TAC and both of ROS and MDA and down-regulated the protein expression of TLR4, NF-kB, TXNIP, NLR-family pyrin domain containing 3 (NLRP3), caspase-1, IL-1ß, and GSDMD-N terminal, with inhibition of the up-stream of NLRP3 and the down-stream DOX-induced pyroptosis. The in vitro assay confirmed well preserved cardiomyocytes' architecture, amelioration of NLRP3/IL-1 ß-mediated cell pyroptosis, enhanced cell viability, and improved spontaneous beating. Moreover, NIFU normalized the disturbed aortic oxidant-antioxidant balance; enhanced eNOS- mediated endothelial relaxation, and down regulated IL-1ß expression. Thus, NIFU may be proposed to serve as a cardioprotective agent to attenuate DOX-induced cardio-toxicity and vascular injury.

Canagliflozin interrupts mTOR-mediated inflammatory signaling and attenuates DMBA-induced mammary cell carcinoma in rats.

BACKGROUND: Breast cancer prevalence has been globally increasing, therefore, introducing novel interventions in cancer treatment is of a significant importance. The present study was designed to investigate the anti-cancer effect of Canagliflozin (CNG) in an experimental model of DMBA-induced mammary carcinoma in female rats. METHODS: 18 female rats were divided into three experimental groups: Normal control, DMBA control, DMBA+ CNG treated group. DMBA (7.5 mg/kg) was injected subcutaneously in the mammary cells twice weekly for 4 weeks and CNG (10 mg/kg) was orally administered daily for an additional 3 weeks while DMBA control rats only received the vehicle for 3 weeks. Tumors' weight and volume were measured, BRCA-1 and TAC were quantified in serum samples, mTOR, caspase-1, NFκB, IL-1ß, NLRP3, GSDMD and MDA were quantified in tumors' homogenates. RESULTS: CNG treatment increased the BRCA-1 expression, suppressed mTOR inflammatory pathway, attenuated tumor inflammatory mediators; NLRP3, GSDMD, NFκB, IL-1ß, suppressed the oxidative stress and inhibited tumor expression of the proliferation biomarker; Ki67. CONCLUSION: CNG modulated mTOR-mediated signaling pathway and attenuated pyroptotic, inflammatory pathways, suppressed oxidative stress and eventually inhibited DMBA-induced mammary carcinoma proliferation.

Effect of Diacerein on HOTAIR/IL-6/STAT3, Wnt/ß-Catenin and TLR-4/NF-κB/TNF-α axes in colon carcinogenesis.

Colorectal cancer (CRC) is a common malignancy with high mortality and poor prognosis. Diacerein (DIA) is an anti-inflammatory used for treatment of osteoarthritis. We delineated some underlying molecular mechanisms of DIA's anti-carcinogenic effect in CRC using in vivo and in vitro models. Human Caco-2 cells were treated with DIA followed by MTT and Annexin V assays and CRC was experimentally induced using 1,2-dimethylhydrazine. DIA (50 mg/kg/day, orally) was administrated for 8 weeks. The MTT assay confirmed cytotoxic effect of DIA in vitro and Annexin V confirmed its apoptotic effect. DIA resulted in regression of tumour lesions with reduced colonic TLR4, NF-κB and TNF-α protein levels and down-regulated VEGF expression, confirming anti-angiogenic impact. DIA triggered caspase-3 expression and regulated Wnt/ß-Catenin pathway, by apparently interrupting the IL-6/STAT3/ lncRNA HOTAIR axis. In conclusion, DIA disrupted IL-6/STAT3/ lncRNA HOTAIR axis which could offer an effective therapeutic strategy for the management of CRC.

Dose-dependent renoprotective impact of Lactoferrin against glycerol-induced rhabdomyolysis and acute kidney injury.

Acute kidney injury (AKI) is a clinical disorder with a serious impact on the quality of patients' lives. Considering its increased worldwide prevalence, investigating novel therapeutic approaches for the management of AKI has been inevitable. Lactoferrin (LF), a glycoprotein belonging to the transferrin family, is known to play an important role in regulating iron homeostasis. This study aimed to evaluate the renoprotective effect of LF (30, 100, and 300 mg/kg orally) against glycerol (GLY)-induced rhabdomyolysis (RM) in rats. RM was induced by a single intramuscular injection of GLY 50% (10 mL/kg) after 24-h water deprivation in male Sprague-Dawley rats. LF administration conferred significant dose-dependent renoprotective impact against GLY-induced RM as evidenced by the decreased renal/somatic index and the significant improvement in renal functions as confirmed by the significant increase in creatinine clearance, decrease in serum creatinine and blood urea nitrogen, and improvement in albuminuria and proteinuria. Redox homeostasis was significantly restored in a dose-dependent manner as well. Moreover, serum interleukin-1ß (IL-1ß) was significantly decreased with a parallel significant decrease in renal NOD-like receptor family pyrin domain containing 3 (NLRP3) and thioredoxin interacting protein (TXNIP), kidney injury molecule-1 (KIM-1), caspase-3 expression, nuclear factor kappa B (NF-κB), cluster of differentiation (CD68) expression, and a significant increase in renal nuclear factor erythroid 2-related factor 2 (NRF2) expression. Ultimately, LF administration was associated with a significant amelioration of GLY-induced renal necrotic and inflammatory alterations. In conclusion, the observed dose-dependent nephroprotective effect of LF can be attributed to its modulatory impact on inflammatory/apoptotic/oxidative signaling.

Tranexamic Acid Microinjection Alone Versus Its Combination With Fractional Carbon Dioxide Laser in Melasma Treatment: A Dermoscopic Evaluation.

BACKGROUND: Melasma is a challenging pigmentation disorder. OBJECTIVE: To assess and compare the efficacy of tranexamic acid (TXA) intradermal microinjection alone versus its combination with low-power, low-density fractional CO2 laser in a sequential pattern in melasma. PATIENTS AND METHODS: This study included 29 patients with melasma. Half of the face was randomly assigned to fractional CO2 laser; the other half to TXA. This split-face session was repeated every 6 weeks for 3 sessions. In between, TXA was applied to the full face every 2 weeks. Treatment duration was 4 months. Dermoscopy, melanin index (M.I), and erythema index (E.I) were evaluated at baseline and 4 weeks after the last session. RESULTS: Melanin index, E.I, total dermoscopic score and different dermoscopic patterns of pigmentation, and vascular features showed significant reduction posttreatment on both sides of the face. No statistically significant difference was found regarding the degree and percentage of improvement in M.I, E.I, and total dermoscopic score between both sides. CONCLUSION: Tranexamic acid microinjection alone or combined with low-power, low-density fractional CO2 laser in a sequential pattern are comparatively effective and safe for melasma treatment; however, combined treatment is recommended. Dermoscopy is an essential noninvasive tool in the assessment of melasma and monitoring patients' response to treatment.

Downregulation of interleukin 36γ and its cleaver cathepsin G following treatment with narrow-band ultraviolet B phototherapy in psoriasis vulgaris.

BACKGROUND: Growing evidence suggests the important role of IL-36 in the pathogenesis of psoriasis. Cathepsin G is a neutrophil-derived protease that can activate IL-36γ. OBJECTIVE: To assess the expression of IL-36γ and cathepsin G in psoriasis and to quantify the impact of treatment with narrow-band ultraviolet B phototherapy (NB-UVB) on their levels. METHODS: This case-control study involved 26 patients with moderate-severe psoriasis and 25 healthy volunteers. Psoriasis patients eligible for phototherapy received 24 NB-UVB sessions. Punch skin biopsies were obtained from all participants at recruitment and after phototherapy from patients. Real-time PCR was utilized for quantitative assessment of IL-36γ and cathepsin G expression in tissue samples. RESULTS: The expression of IL-36γ and cathepsin G was significantly higher in psoriasis before NB-UVB therapy compared to controls (p < .001). Both proteins decreased significantly with clinical improvement following NB-UVB therapy compared to baseline (p < .001). However, their expression after treatment was still higher than controls (p < .001). CONCLUSION: IL-36γ and cathepsin G expression is upregulated in psoriatic lesions, supporting their role as mediators of inflammation in psoriasis. Downregulation of IL-36γ and cathepsin G is a possible mechanism for psoriasis improvement after NB-UVB therapy. IL-36 and cathepsin G can be considered as therapeutic targets for psoriasis.

Nanogold Particles Suppresses 5-Flurouracil-Induced Renal Injury: An Insight into the Modulation of Nrf-2 and Its Downstream Targets, HO-1 and γ-GCS.

The development of the field of nanotechnology has revolutionized various aspects in the fields of modern sciences. Nano-medicine is one of the primary fields for the application of nanotechnology techniques. The current study sheds light on the reno-protective impacts of gold nano-particles; nanogold (AuNPs) against 5-flurouracil (5-FU)-induced renal toxicity. Indeed, the use of 5-FU has been associated with kidney injury which greatly curbs its therapeutic application. In the current study, 5-FU injection was associated with a significant escalation in the indices of renal injury, i.e., creatinine and urea. Alongside this, histopathological and ultra-histopathological changes confirmed the onset of renal injury. Both gene and/or protein expression of nuclear factor erythroid 2-related factor 2 (Nrf-2) and downstream antioxidant enzymes revealed consistent paralleled anomalies. AuNPs administration induced a significant renal protection on functional, biochemical, and structural levels. Renal expression of the major sensor of the cellular oxidative status Nrf-2 escalated with a paralleled reduction in the renal expression of the other contributor to this axis, known as Kelch-like ECH-associated protein 1 (Keap-1). On the level of the effector downstream targets, heme oxygenase 1 (HO-1) and gamma-glutamylcysteine synthetase (γ-GCS) AuNPs significantly restored their gene and protein expression. Additionally, combination of AuNPs with 5-FU showed better cytotoxic effect on MCF-7 cells compared to monotreatments. Thus, it can be inferred that AuNPs conferred reno-protective impact against 5-FU with an evident modulatory impact on Nrf-2/Keap-1 and its downstream effectors, HO-1 and γ-GCS, suggesting its potential use in 5-FU regimens to improve its therapeutic outcomes and minimize its underlying nephrotoxicity.

Evaluation of nootropic activity of telmisartan and metformin on diazepam-induced cognitive dysfunction in mice through AMPK pathway and amelioration of hippocampal morphological alterations.

Cognitive impairments such as dementia are considered the biggest challenges for public health. Benzodiazepines are often prescribed for treatment of anxiety disorder but they are associated with elevated risk of dementia. The present study has been designed to evaluate the neuroprotective effect of telmisartan and metformin on diazepam-induced cognitive dysfunction in mice. Piracetam was used as an established nootropic agent. Mice were divided into 8 groups, group1; control group which received normal saline. groups 2, 3 and 4 were received telmisartan 0.3 mg/kg/day, metformin 100 mg/kg/day and piracetam 200 mg/kg/day respectively. group 5; DZP group that injected with diazepam 2.5 mg/kg, groups 6, 7 and 8 were received diazepam 2.5 mg/kg + telmisartan 0.3 mg/kg/day, metformin 100 mg/kg/day and piracetam 200 mg/kg/day respectively. All drugs were administrated for 15 successive days. Cognitive skills of the animals were examined with Elevated plus maze and Passive Shock Avoidance tests. Investigations of oxidative stress markers were performed. Gene expression levels of TNF-α, NFκB, Caspase 3 and AMPK were analyzed using RT-PCR. Histological and immunohistochemical techniques were performed in hippocampus using H&E, cresyl violet stain, anti GFAP and anti COX-2 immunostain. The study revealed that administration of diazepam increased initial and retention transfer latency as well as it decreased step down latency that means it caused memory impairment. There was a significant increase in hippocampal expression levels of TNF-α, NFκB, and Caspase 3 and downregulation of AMPK expression levels associated with increased neurodegeneration, astrocytes activation and COX-2 immunohistochemical staining. This study indicates that diazepam caused a decline in cognitive function depending on hippocampal activity. Telmisartan, a common antihypertensive agent and metformin, a traditional antidiabetic drug improved this cognitive dysfunction through their anti-oxidant and anti-inflammatory effect as they decreased initial and retention transfer latency as well as it increased step down latency. Also they decreased TNF-α, NFκB, and Caspase 3 and upregulated AMPK expression, moreover they ameliorated the hippocampal morphological alterations, GFAP and COX-2 immunoexpression.

Nifuroxazide mitigates cholestatic liver injury by synergistic inhibition of Il-6/Β-catenin signaling and enhancement of BSEP and MDRP2 expression.

Cholestasis is a complex hepatic disorder underlined with retention of the highly toxic bile components within the hepatocytes. Nifuroxazide (NIF); a nitrofuran derivative, is widely used drug for treatment of acute and chronic diarrhea. The current study was performed to investigate the curative effect of NIF (25 and 50 mg/kg) on lithocholic acid (LCA)-induced cholestasis and compare the observed impact to that of ursodeoxycholic acid (UDCA). Intriguingly, NIF significantly attenuated LCA-induced cholestatic injury. NIF successfully reversed cholestatic injury to a similar extent compared to the mainstay drug, UDCA. NIF administration remarkably attenuated liver/body index and restored liver functions. Moreover, it restored the disrupted balance in oxidative homeostasis. On the other hand, NIF induced a marked improvement in histopathological and immuno-histochemical analysis of liver specimens. Ultimately, NIF mitigated inflammatory response and proliferative ability of hepatocytes with significant reduction in hepatic expression of proliferatingcellnuclearantigen(PCNA), cluster of differentiation 68 (CD68), interlukin-6 (Il-6) and ß-catenin. Interestingly, NIF successfully increased bile transformation with increased the hepatic expression of bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MDRP2). Nevertheless, molecular docking of NIF with ß-catenin and BSEP showed a better alignment inside the pocket with strong interaction for both protein binding sites. In conclusion, NIF attenuated experimentally-induced cholestatic dysfunction with an underlined synergistic inhibition of Il-6/Β-catenin pathways and direct enhancement of bile acids transporters gene expression.

Phenethyl isothiocyanate attenuates diabetic nephropathy via modulation of glycative/oxidative/inflammatory signaling in diabetic rats.

Diabetic nephropathy (DN) is a diabetic complication characterized by disruption of renal microvasculature, reactive oxygen species accumulation and increased inflammation, all of which contribute to renal injury. Phenethyl isothiocyanate (PEITC) is a naturally occurring isothiocyanate well known for its antioxidant and anti-inflammatory effects, yet its reno-preventive effects against DN has not been investigated. The current study looked into the in vivo reno-protective effects of PEITC in STZ-induced DN in rats. PEITC (3, 10 and 30 mg/kg) was administered orally for 8 weeks post DM establishment. PEITC treatment significantly improved kidney and liver functions, renal histopathological features, tissue fibrosis, macrophage infiltration and blood glucose levels compared to DN control. Mechanistically, PEITC treatment alleviated DN-induced renal damage via modulating glycation and oxidative stresses and inflammatory response. As such, PEITC activated glyoxalase 1 (GLO1) that induced a retraction in renal tissue expression of advanced glycation end products (AGEs) and its receptor (RAGE). PEITC activated nuclear erythroid 2-related factor 2 (Nrf2) and increased expression of its downstream targets, hemeoxygenase-1 (HO-1) and gamma glutamate-cysteine (γ-GCS). Additionally, PEITC treatment decreased the expression of Nrf2 repressor protein, keap1. The anti-inflammatory effect of PEITC was driven, at least in part, via reducing the NLRP3 inflammasome activation as indicated by down regulation of NLRP3, TXNIP, capsase-1 and IL-1ß, TNF-alpha and IL-6. In conclusion; PEITC attenuated DN progression in a dose dependent manner mainly via interruption of AGE/RAGE and NLPR3/TXNIP/NrF2 crosstalk.

Saxagliptin defers thioacetamide-induced hepatocarcinogenesis in rats: A novel suppressive impact on Wnt/Hedgehog/Notch1 signaling.

AIM: Hepatocellular carcinoma (HCC) is a highly invasive form of hepatic cancer. It is a highly intricate disease with multiple pathophysiological mechanisms underlying its pathogenesis. MATERIALS AND METHODS: The results of the current investigation shed light on the ability of saxagliptin (SAXA) (12.5 mg/kg) to defer HCC progression in an experimental model of thioacetamide (TAA)-induced hepatocarcinogenesis. RESULTS: SAXA administration improved liver function biomarkers, with a concomitant histopathological recovery. Mechanistically, the observed hepatoprotective impact was associated with significant suppression of the hepatic content of Wnt3a, ß-catenin, Notch1, Smo, and Gli2 and enhanced expression of GSK 3ß. Nevertheless, the hepatic expression of PCNA, P53, and cyclin D1 was significantly enhanced, with a parallel increase in the tumor expression of caspase-3. Thus, it appears that SAXA significantly enhanced tumor apoptosis, with concomitant suppression of HCC proliferation. CONCLUSION: SAXA deferred experimentally-induced HCC via suppressing Wnt/Hedgehog/Notch1 Signaling, with enhanced tumor apoptosis and suppressed proliferation.

Dasatinib mitigates renal fibrosis in a rat model of UUO via inhibition of Src/STAT-3/NF-κB signaling.

This research aimed to investigate the reno-protective impact of the tyrosine kinase inhibitor dasatinib (DAS) against renal fibrosis induced by unilateral ureteral obstruction (UUO) in rats. DAS administration improved renal function and mitigated renal oxidative stress with paralleled reduction in the ligated kidney mass index, significant retraction in renal histopathological alterations and suppression of renal interstitial fibrosis. Nevertheless, DAS administration attenuated renal expression of phosphorylated Src (p-Src), Abelson (c-Abl) tyrosine kinases, nuclear factor-kappaB (NF-κB) p65, and phosphorylated signal transducer and activator of transcription-3 (p-STAT-3)/STAT-3 with paralleled reduction in renal contents of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and monocyte chemoattractant protein-1 (MCP-1). DAS diminished interstitial macrophage infiltration and decreased renal profibrotic transforming growth factor-ß1 (TGF-ß1) levels and suppressed interstitial expression of renal α-smooth muscle actin (α-SMA) and fibronectin. Collectively, DAS slowed the progression of renal interstitial fibrosis, possibly via attenuating renal oxidative stress, impairing Src/STAT-3/NF-κB signaling, and reducing renal inflammation.

Nifuroxazide suppresses UUO-induced renal fibrosis in rats via inhibiting STAT-3/NF-κB signaling, oxidative stress and inflammation.

The current work explored the influences of nifuroxazide, an in vivo inhibitor of signal transducer and activator of transcription-3 (STAT-3) activation, on tubulointerstitial fibrosis in rats with obstructive nephropathy using unilateral ureteral obstruction (UUO) model. Thirty-two male Sprague Dawley rats were assigned into 4 groups (n = 8/group) at random. Sham and UUO groups were orally administered 0.5% carboxymethyl cellulose (CMC) (2.5 mL/kg/day), while Sham-NIF and UUO-NIF groups were treated with 20 mg/kg/day of NIF (suspended in 0.5% CMC, orally). NIF or vehicle treatments were started 2 weeks after surgery and continued for further 2 weeks. NIF treatment ameliorated kidney function in UUO rats, where it restored serum creatinine, blood urea, serum uric acid and urinary protein and albumin to near-normal levels. NIF also markedly reduced histopathological changes in tubules and glomeruli and attenuated interstitial fibrosis in UUO-ligated kidneys. Mechanistically, NIF markedly attenuated renal immunoexpression of E-cadherin and α-smooth muscle actin (α-SMA), diminished renal oxidative stress (↓ malondialdehyde (MDA) levels and ↑ superoxide dismutase (SOD) activity), lessened renal protein expression of phosphorylated-STAT3 (p-STAT-3), phosphorylated-Src (p-Src) kinase, the Abelson tyrosine kinase (c-Abl) and phosphorylated nuclear factor-kappaB p65 (pNF-κB p65), decreased renal cytokine levels of transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and monocyte chemoattractant protein-1 (MCP-1) and reduced number of cluster of differentiation 68 (CD68) immunolabeled macrophages in UUO renal tissues, compared to levels in untreated UUO kidneys. Taken together, NIF treatment suppressed interstitial fibrosis in UUO renal tissues, probably via inhibiting STAT-3/NF-κB signaling and attenuating renal oxidative stress and inflammation.

Tranilast ameliorated subchronic silver nanoparticles-induced cerebral toxicity in rats: Effect on TLR4/NLRP3 and Nrf-2.

Silver nanoparticles (AgNPs) are widely applied in various aspects of life. However, recent studies reported their potential toxicity both on environment and human health. The present study aimed to unravel the underlying molecular mechanisms involved in AgNPs-induced brain toxicity. Moreover, chemopreventive effect of tranilast, an analogue of tryptophan metabolite and a mast cell membrane stabilizer was evaluated. Thirty Sprague Dawley rats were enrolled equally into Normal control group, AgNPs-intoxicated group (50 mg/kg, 3 times/week) and tranilast (300 mg/kg, 3 times/week)+AgNPs group. AgNPs administration triggered brain oxidative stress as depicted by reduced Nrf-2 expression, decreased TAC and GSH as well as upregulated brain lipid peroxidation. The apparent brain oxidative damage was accompanied by elevated levels of inflammatory cytokines (IL-1ß, IL-6 and TNF-α). Moreover, brain levels of TLR4, NLRP3 and caspase-1 were up-regulated. Additionally, histological study indicated marked cellular injury in cerebrum and cerebellum specimens. This was concomitant with elevated serum CK activity and CK-BB level. On the other hand, tanilast administration remarkably alleviated AgNPs-induced brain toxicity. The present study shed the light on implication of TLR4/NLRP3 axis and NrF2 in AgNPs-induced brain toxicity. In addition, it explored the potential protective effect of tranilast on AgNPs-induced brain injury via antioxidant and anti-inflammatory efficacies.

Psoriatic arthritis among Egyptian patients with psoriasis attending the dermatology clinic: prevalence, comorbidities, and clinical predictors.

OBJECTIVES: Early diagnosis and treatment of psoriatic arthritis (PsA) help to prevent progressive joint involvement and disabilities. There is a problem in the early diagnosis of PsA worldwide, which may be attributed to the dermatologists missing PsA symptoms and signs and a lack of effective screening tools. AIM OF THE STUDY: The current study was designed to assess the prevalence, comorbidities, and clinical predictors associated with the development of PsA in psoriasis patients. MATERIAL AND METHODS: A cross-sectional observational study was performed. Screening questionnaires - the Psoriasis Epidemiology Screening Tool (PEST) and Early Arthritis for Psoriatic Patients (EARP) - were applied to 200 psoriasis patients; among them n = 22 (11% of all tested patients) were in developmental age. Those with positive questionnaires were classified as having PsA or not according to the classification for psoriatic arthritis criteria. Body surface area, psoriasis area and severity index, and psoriasis disability index tools were used for assessing psoriasis patients. A full rheumatological and dermatological evaluation were carried out for PsA patients. RESULTS: The prevalence of PsA was found to be 30%, with a mean age of 45.48 ±10.79 years. Further, psoriasis preceded the onset of PsA in 46 patients (76.6%), arthritis began before psoriasis in 6 individuals (10%), and both psoriasis and arthritis coincided in 8 (13.3%) patients. Obesity (OR 7.0, 95% CI: 2.61-18.85), nail psoriasis (OR 5.02, 95% CI: 2.02-12.476), and intergluteal cleft site (OR 12.659, 95% CI: 4.302-37.255) were associated with increased risk of PsA. However, classic plaque psoriasis (OR 0.149, 95% CI: 0.051-0.433) and flexure site (OR 0.238, 95% CI: 0.076-0.746) were linked with a decreased risk of PsA development. CONCLUSIONS: Screening for PsA in patients with psoriasis revealed a significant number of undiagnosed cases of PsA that should be treated early. Obesity, nail psoriasis, and psoriasis at the intergluteal sites can help predict the PsA development.

Combined effect of hydrogen sulfide and mesenchymal stem cells on mitigating liver fibrosis induced by bile duct ligation: Role of anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-fibrotic biomarkers.

Objectives: Liver fibrosis eventually develops into cirrhosis and hepatic failure, which can only be treated with liver transplantation. We aimed to assess the potential role of hydrogen sulfide (H2S) alone and combined with bone marrow-derived mesenchymal stem cells (BM-MSCs) on hepatic fibrosis induced by bile-duct ligation (BDL) and to compare their effects to silymarin. Materials and Methods: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), and alkaline phosphatase (ALP) were investigated in serum. Gene expression levels of CBS (cystathionine ß-synthase), CSE (cystathionine γ-lyase), and alpha-smooth muscle actin (α- SMA) were measured in liver tissues using RT-PCR. Hepatic protein kinase (Akt) was assessed by Western blot assay. Liver oxidative stress markers, malondialdehyde (MDA), and reduced glutathione (GSH) were analyzed by the colorimetric method. Lipocalin-2 (LCN2) and transforming growth factor-ß (TGF-ß) were measured using ELIZA. Liver tissues were examined by H&E and Masson trichome staining for detection of liver necrosis or fibrosis. Caspase 3 expression was evaluated by immunohistochemistry. Results: H2S and BM-MSCs ameliorated liver function and inhibited inflammation and oxidative stress detected by significantly decreased serum ALT, AST, ALP, TB, and hepatic MDA, Akt, TGF-ß, LCN2, and α-SMA expression and significantly increased CBS and CSE gene expression levels. They attenuated hepatic apoptosis evidenced by decreased hepatic caspase expression. Conclusion: Combined treatment with H2S and BM-MSCs could attenuate liver fibrosis induced by BDL through mechanisms such as anti-inflammation, anti-oxidation, anti-apoptosis, anti-fibrosis, and regenerative properties indicating that using H2S and MSCs may represent a promising approach for management of cholestatic liver fibrosis.

Chemo-preventive effect of crocin against experimentally-induced hepatocarcinogenesis via regulation of apoptotic and Nrf2 signaling pathways.

The results of the current study investigated the chemo-preventive effect of crocin against hepatocarcinogenesis in rats with particular focus on the evaluation of the modulatory impact of crocin on apoptotic and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways. Thioacetamide (TAA) (200 mg/kg, I.P.) was used for experimental induction of hepatocarcinogenesis in rats. Crocin administration significantly attenuated TAA-induced cancerous lesions with concomitant attenuation of impaired liver functions. This was associated with significant enhancement in hepatic Nrf2 and heme oxygenase-1 (HO-1) expression with parallel suppression in Keap-1 expression. Inline, crocin induced a significant improvement in hepatic oxidative status with enhanced antioxidant batteries. Crocin administration significantly suppressed the hepatic content of c-Jun N-terminal kinase (c-JNK) with significant upregulation in TNF-related apoptosis-inducing ligand (TRAIL) and caspase-8 protein expression as well as p53 gene expression; biomarkers of apoptosis. Moreover, hepatic expression of the apoptotic BAX significantly increased and the anti-apoptotic Bcl-2 significantly decreased in the liver specimen; biomarkers of intrinsic apoptosis. In conclusion; crocin attenuates experimentally induced hepato-carcinogenesis via modulation of oxidative/apoptotic signaling. Namely, crocin induced hepatic expression of Nrf2 with downstream modulation of endogenous HO-1 and Keap-1 signaling with modulation of various key players of apoptosis including; c-JNK, p53, TRAIL, caspase-8, BAX, and Bcl-2.