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Cryptosporidiosis is a global health problem threats life of immunocompromised patients. Allium sativum (A. sativum) is one of the therapeutic options for cryptosporidiosis. This study develops green synthesized ZnO‐NPs based on A. sativum extract, and assesses its therapeutic application in treating experimental cryptosporidiosis in immunosuppressed mice. FTIR, scanning electron microscopy, and zeta analyzer were used for characterization of bio ZnO‐NPs. The morphology of prepared materials appeared as sponge with many pores on the whole surface that allows the feasibility of bio ZnO‐NPs for different biological activities. Its structural analysis was highly stabilized with negative charge surface which indicated for well distribution into the parasite matrix. Twenty‐five immunosuppressed Cryptosporidium parvum infected mice, classified into 5 groups were sacrificed at 21th day after infection with evaluation of parasitological, histopathological, oxidative, and proinflammatory biomarkers. Treated mice groups with 50 and 100 mg/kg of AS/ZnO‐NPs showed a highly significant decline (79.9% and 83.23%, respectively) in the total number of expelled oocysts. Both doses revealed actual amelioration of the intestinal, hepatic, and pulmonary histopathological lesions. They also significantly produced an increase in GSH values and improved the changes in NO and MDA levels, and showed high anti‐inflammatory properties. This study is the first to report green synthesis of ZnO/A. sativum nano‐composite as an effective therapy in treating cryptosporidiosis which gave better results than using A. sativum alone. It provides an economical and environment‐friendly approach towards novel delivery synthesis for antiparasitic applications. Research Highlights: Green synthesis of ZnO‐NPs was developed using A. sativum extract.The morphology of prepared ZnO‐NPs appeared as sponge with many pores on SEMThe study evaluates its therapeutic efficacy against murine cryptosporidiosisThe green synthesized ZnO‐NPs significantly reduced percent of oocyst shedding, improved the pathological changes, and showed high antioxidant and anti‐inflammatory potentials. [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF)‐β and toll‐like receptors (TLRs) have been shown to independently modulate the proliferation of hepatocellular carcinoma (HCC). Since a direct cross‐talk between these two signalling pathways in HCC has not been clearly described before, we aimed here to explore the possibility of such interaction. A human HCC tissue array (n = 20 vs. four control samples), human HCC samples (n = 10) and steatohepatitis‐driven murine HCC samples (control, NASH and HCC; n = 6/group) were immunostained for TGFβR1, pSMAD2, TRAF6, IRAK1 and PCNA. The results were confirmed by immunoblotting. Effects of constant activation of the SMAD pathway by constitutive expression of ALK5 or knockdown of mediators of TLR signalling, IRAK1 and MyD88, on HCC proliferation, were investigated in the HCC cell line (HUH‐7) after treatment with TGFβ1 cytokine or TGFβR1 kinase inhibitor (LY2157299) using PCNA and MTS assay. TGFβR1 expression is decreased in human and murine HCC and associated with downregulated pSMAD2, but increased IRAK1, TRAF6 and PCNA staining. TGFβR1 kinase inhibition abolished the cytostatic effects of TGFβ1 and led to the induction of IRAK1, pIRAK1 and elevated mRNA levels of TLR‐9. Overexpression of ALK5 and knockdown of MyD88 or IRAK1 augmented the cytostatic effects of TGFβ1 on HUH‐7. In another epithelial HCC cell line, that is, HepG2, TGFβR1 kinase inhibitor similarly elevated cellular proliferation. There is a balance between the canonical SMAD‐driven tumour‐suppressing arm and the non‐canonical tumour‐promoting arm of TGFβ signalling. Disruption of this balance, by inhibition of the canonical pathway, induces HCC proliferation through TLR signalling. [ABSTRACT FROM AUTHOR]

New chromene derivatives were synthesized based on 4‐(3,4‐dimethoxy)‐4H‐chromene scaffold. All target compounds exhibited cytotoxic activity against HepG2 cells (IC50 = 2.40–141.22 μM). Chromens 5 and 9 showed superior cytotoxicity over staurosporine (IC50 = 18.27 μM) and vinblastine (IC50 = 5.20 μM). c‐Src kinase inhibition assay of compounds 5 and 9 displayed the dominant c‐Src inhibitory activity of 5 (IC50 = 0.184 μM) over 9 (IC50 = 0.288 μM). The safety of the most potent compound 5 against normal WI‐38 cells was confirmed via its IC50 of 115.75 μM comparable with 5‐FU (IC50 = 16.28 μM). Moreover, the promising chromene 5 displayed potent cytotoxicity against resistant HepG2 cells with IC50 of 26.03 μM comparable with 5‐FU (IC50 = 42.68 μM). The most active chromene 5 arrested the HepG2 cell cycle at the S phase and induced a 29‐fold increase in the total number of apoptotic cells indicating pre‐G1 apoptosis. The ability of compound 5 to induce apoptosis was supported via elevation of caspase‐3, caspase‐7, caspase‐9 and proapoptotic Bax protein levels in addition to downregulation of the antiapoptotic Bcl2 protein. Molecular docking studies of compound 5 showed good binding interaction pattern inside c‐Src kinase enzyme active site. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading causes of mortality worldwide, making it a public health concern. A novel series of pyrrolidine‐carboxamide derivatives 7a‐q were developed and examined in a cell viability assay utilizing a human mammary gland epithelial cell line (MCF‐10A), where all the compounds exhibited no cytotoxic effects and more than 85% cell viability at a concentration of 50 μM. Antiproliferative activity was evaluated in vitro against four panels of cancer cell lines A‐549, MCF‐7, Panc‐1, and HT‐29. Compounds 7e, 7g, 7k, 7n, and 7o were the most active as antiproliferative agents capable of triggering apoptosis. Compound 7g was the most potent of all the derivatives, with a mean IC50 of 0.90 μM compared to IC50 of 1.10 μM for doxorubicin. Compound 7g inhibited A‐549 (epithelial cancer cell line), MCF‐7 (breast cancer cell line), and HT‐29 (colon cancer cell line) more efficiently than doxorubicin. EGFR inhibitory assay results of 7e, 7g, 7k, 7n, and 7o demonstrated that the tested compounds inhibited EGFR with IC50 values ranging from 87 to 107 nM in comparison with the reference drug erlotinib (IC50 = 80 nM). 7e, 7g, 7k, 7n, and 7o inhibited CDK2 efficiently in comparison to the reference dinaciclib (IC50 = 20 nM), with IC50 values ranging from 15 to 31 nM. The results of inhibitory activity assay against different CDK isoforms revealed that the tested compounds had preferential inhibitory activity against the CDK2 isoform. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?What is the impact and drawbacks of subcutaneous lipectomy on body metabolism?What is the main finding and its importance?Subcutaneous lipectomy resulted in deterioration of hepatic functions, atherosclerotic lipid profile and disturbed redox state. While the results support lipectomy as an effective treatment for obesity, lipectomy induces unfavourable changes in health. The number of obese older adults is on the rise, but data about proper treatment of obesity in the elderly is controversial. The present study was designed to investigate the effectiveness and consequences of partial subcutaneous lipectomy, as a rapid medical intervention against increased accumulation of body fat, in adult obese rats. The study was conducted on adult (9–12 months) female rats, in which obesity was induced by bilateral surgical ovariectomy. They were randomized into two main groups: short term (5 weeks) and long term (10 weeks). Both groups were subdivided into control, ovariectomized (OVX) and ovariectomized lipectomized groups. Body weight (BW) was measured and body mass index (BMI) calculated. Fasting blood glucose, lipid profile and plasma levels of total proteins, albumin, liver enzymes, malondialdehyde (MDA), leptin and adiponectin were determined. The content of both blood and hepatic tissue of reduced glutathione was estimated. In addition, histological study of the liver, aorta and peri‐renal fat was performed. Compared to controls, OVX rats showed significant increase in BW, BMI and plasma levels of liver enzymes, MDA and leptin. Histological study revealed vacuolated ballooned hepatocytes and enlarged irregular visceral adipocytes with atherosclerotic changes in the wall of aorta. Following subcutaneous lipectomy, rats exhibited significant fasting hyperglycaemia, dyslipidaemia, lowered plasma albumin and disturbed redox state with aggravation of the histological changes. The findings indicate that although subcutaneous lipectomy appears to be effective in combating obesity in older females, it has unfavourable effects on both metabolic and hepatic functions. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammation in adipose tissue may play a substantial role in the pathogenesis of obesity‐related metabolic disorders. The present study aims to evaluate the changes in adipocytokines, bile acids, fibroblast growth factor 19 (FGF‐19) and pro‐inflammatory cytokines 6 months after laparoscopic sleeve gastrectomy (LSG). Methods: This prospective study included 75 obese patients with body mass index >35 kg/m2 who underwent LSG. All patients were recruited preoperatively and followed up post‐operatively at 6 months, with laboratory assessment of their cytokines including adiponectin, leptin, resistin, bile acid, interleukin (IL)‐6, IL‐8, tumour necrosis factor‐α, monocyte chemotactic protein‐1, high‐sensitivity C‐reactive protein, plasminogen activator inhibitor‐1, serum amyloid‐A and FGF‐19. Results: There were statistically highly significant changes regarding anthropometric parameters (weight, body mass index and waist‐to‐hip ratio), blood glucose and lipid profile as well as liver enzymes at 6 months post‐sleeve gastrectomy. The present study showed that the levels of serum adiponectin and FGF‐19 significantly increased at 6 months of follow‐up after surgery (P < 0.001), while the levels of serum leptin, resistin, high‐sensitivity C‐reactive protein, plasminogen activator inhibitor‐1 and serum amyloid‐A significantly decreased at 6 months of follow‐up after surgery (P < 0.001). There were no significant differences regarding serum bile acid, IL‐6, IL‐8, tumour necrosis factor‐α and monocyte chemotactic protein‐1. Conclusion: Weight loss after LSG is associated with significant improvement of the adipokine levels towards anti‐diabetic and anti‐inflammatory profiles. Future studies should use a larger sample size and longer follow‐up periods. [ABSTRACT FROM AUTHOR]

Abstract: Aim: The goal of this study is to investigate how urinary angiostatin, vascular cell adhesion molecule 1 (VCAM‐1) and established measures of renal function relate to specific histologic findings in paired kidney biopsy samples from patients with lupus nephritis (LN). Method: Urine samples were collected from 54 LN patients together with paired kidney biopsy samples and examined for urinary angiostatin and VCAM‐1 protein levels. Nonparametric tests were used to examine the association of both urinary biomarkers and established traditional laboratory markers of renal function with nine specific renal histologic features seen in LN, including glomerular leukocyte infiltration, endocapillary proliferation, cellular crescents, fibrinoid necrosis, wire loops, interstitial inflammation, glomerulosclerosis, fibrous crescents, tubular atrophy and interstitial fibrosis. Results: Compared to traditional renal disease metrics, both urinary angiostatin and VCAM‐1 exhibited outstanding potential (area under the curve 0.97, 0.98, respectively) to predict renal biopsy activity index score ≥ 7, which is associated with poor long‐term prognosis. Whereas urine VCAM‐1 was most significantly associated with fibrous crescents, urine angiostatin was most significantly associated with endocapillary proliferation, cellular crescents, fibrinoid necrosis and fibrous crescents in concurrent renal biopsies. Conclusion: Urinary angiostatin and VCAM‐1 are predictive of specific histological changes in concurrent LN renal biopsies. Both urinary biomarkers are good candidates for use as noninvasive measures of renal pathology activity changes in LN. [ABSTRACT FROM AUTHOR]

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Background & Aims Chronic liver disease is a predisposing factor for development of hepatocellular carcinoma ( HCC). Toll-like receptors play a crucial role in immunity against microbial pathogens and recent evidence suggests that they may also be important in pathogenesis of chronic liver disease. The purpose of this study was to determine whether TLR7 and TLR9 are potential targets for prevention and progression of HCC. Methods Tissue microarrays containing liver samples from patients with cirrhosis, viral hepatitis and HCC were examined for expression of TLR7 and TLR9 and the data obtained was validated in liver specimens from the hospital archives. Proliferation of human HCC cell lines was studied following stimulation of TLR7 and TLR9 using agonists (imiquimod and CpG- ODN respectively) and inhibition with a specific antagonist ( IRS-954) or chloroquine. The effect of these interventions was confirmed in a xenograft model and diethylnitrosamine ( DEN)/nitrosomorpholine ( NMOR)-induced model of HCC. Results TLR7 and TLR9 expression was up-regulated in human HCC tissue. Proliferation of HuH7 cells in vitro increased significantly in response to stimulation of TLR7. TLR7 and TLR9 inhibition using IRS-954 or chloroquine significantly reduced HuH7 cell proliferation in vitro and inhibited tumour growth in the mouse xenograft model. HCC development in the DEN/ NMOR rat model was also significantly inhibited by chloroquine ( P < 0.001). Conclusion The data suggest that inhibiting TLR7 and TLR9 with IRS-954 or chloroquine could potentially be used as a novel therapeutic approach for preventing HCC development and/or progression in susceptible patients. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this in vitro study was to evaluate the effects of four surface treatments and two resin cements on the repair bond strength of a ceramic primer. Materials and Methods Eighty-eight pairs of disks (10 and 5 mm in diameter, 3 mm thickness) were prepared from heat-pressed feldspar ceramics (GC Initial IQ). After being stored in mucin-artificial saliva for 2 weeks, the 10-mm disks were divided into four surface treatment groups (n = 22) and then treated as follows: (1) no treatment (control); (2) 40% phosphoric acid; (3) 5% hydrofluoric acid + acid neutralizer + 40% phosphoric acid; (4) silica coating (CoJet-sand) + 40% phosphoric acid. The 5-mm disks were treated with 5% hydrofluoric acid + 40% phosphoric acid. The two sizes of porcelain disks, excluding the control group, were primed with Clearfil Ceramic Primer. The specimens in each group were further divided into two subgroups of 11 each, and bonded with Clearfil Esthetic Cement (CEC) or Panavia F 2.0 Cement (PFC). The specimens were stored in distilled water at 37°C for 24 hours, thermocycled for 3000 cycles at 5 to 55°C, and stored at 37°C for an additional 7 days. Shear bond strength (SBS) was measured with a universal testing machine at a 0.5 mm/min crosshead speed until fracture. Statistical analysis of the results was carried out with a two-way ANOVA and Tukey HSD test (α = 0.05). Debonded specimen surfaces were examined under an optical microscope to determine the mode of failure. Results The statistical analysis showed that the SBS was significantly affected by surface treatment and resin cement ( p < 0.05). For treatment groups bonded with CEC, the SBS (MPa) values were (1) 2.64 ± 1.1, (2) 13.31 ± 3.6, (3) 18.88 ± 2.6, (4) 14.27 ± 2.7, while for treatment groups cemented with PFC, the SBS (MPa) values were (1) 3.04 ± 1.1, (2) 16.44 ± 3.3, (3) 20.52 ± 2.2, and (4) 16.24 ± 2.9. All control specimens exhibited adhesive failures, while mixed types of failures were observed in phosphoric acid-treated groups. The other groups revealed mainly cohesive and mixed failures. Conclusions Combined surface treatment of etching with hydrofluoric acid and phosphoric acid provides the highest bond strengths to porcelain. Also, PFC exhibited higher SBS than CEC did. [ABSTRACT FROM AUTHOR]

Background Patients with cirrhosis frequently develop renal dysfunction, a proportion of who do not fulfill criteria for hepatorenal syndrome ( HRS). We hypothesized that the kidneys in these patients would exhibit histological and biomarker evidence of kidney injury. We looked specifically for TLR expression as they may mediate kidney injury. Methods Sixty seven subjects (6); alcoholic cirrhosis: compensated (9), acute deterioration of alcoholic cirrhosis (52)] were included. Renal dysfunction was defined as a creatinine of >133 μmol/L and/or according to the AKI network criteria. Urinary biomarkers, KIM-1, π GST, α GST and a novel biomarker, urinary TLR4 were measured. Renal biopsies were also available from eight other alcoholic cirrhosis patients (three non- HRS renal dysfunction; five HRS) that were stained for TLR4 and caspase-3. Results Fourteen patients developed renal dysfunction, amongst these three had type 2 HRS. KIM-1, π GST and α GST were higher in patients with acute deterioration of cirrhosis compared with patients with compensated cirrhosis, but did not differ between those with and without renal dysfunction. Urinary TLR4 was significantly higher in patients with renal dysfunction associated with infection/inflammation. Kidney biopsies from non- HRS renal dysfunction patients showed tubular damage with evidence of increased tubular expression of TLR4, and caspase-3. Minor changes were observed in HRS patients. Conclusions The data provide proof of concept that renal dysfunction in patients with cirrhosis with superimposed inflammation is associated with significant tubular injury and apoptosis and with increased renal expression and urinary excretion of the TLR4, suggesting a potential role of TLR4 as mediator of renal injury. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis (OP) is a growing health problem not only in women but also in men. Subjects and methods: This study was carried out on 100 healthy men, age range 30–65 years (mean ± SD, 44.65 ± 8.3). All were randomly recruited from Assiut city during the period January 2005 to January 2006. Complete clinical history included occupational history, smoking habit, physical activity and calcium intake. Complete clinical examination and anthropometric measurments were done. Laboratory investigations for serum calcium, phosphorus and osteocalcin were performed. Bone mineral density (BMD) was measured by calcaneal ultrasound. Results: Sixty-three percent of participants had normal BMD, 37% had low BMD, (26% had quantitative bone ultrasound [QUS] T-score –1 to –2.5 and 11% had QUS T-score ≤ –2.5). Smoking and low physical activity were risk factors for low BMD. Significant positive correlations were found between BMD and body mass index, serum calcium, and osteocalcin and negative correlation with phosphorus. We concluded that low BMD occurs with high frequency in Egyptian men. Smoking, physical inactivity and low body index are significant risk factors. Low serum calcium, low serum osteocalcin and high serum phosphorus are biochemical risk factors of low BMD in males. [ABSTRACT FROM AUTHOR]