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Drilling is the most widely used machining process in manufacturing holes in many industrial applications. Optimizing the drilling process is a key to improve the hole quality. Therefore, numerical modeling is an effective method that gives an idea about the cutting process to optimize the drilling parameters. This paper emphasizes the sensitivity of the thrust force, the torque and the machining-induced damage to the hole saw tool geometry using a 3D Finite Element (FE) model developed using ABAQUS/Explicit. A Johnson cook model associated with a ductile damage law is used to predict the failure mechanism of a random chopped glass fiber reinforced polyester. It is found that the thrust force, the torque and the damage around the hole obtained from the FE model are in good agreement with the experimental data. Differences of about 2% for the thrust force, 2.4% for the torque and 3% for the damage around the hole are observed. The results of the numerical model also indicated that the thrust force as well as the drilled workpiece quality are improved by choosing the suitable rake angle. A decrease of about 61% in the thrust force is observed when varying the rake angle from 0° to 20°. However, the latter has an insignificant effect on the thrust force. Furthermore, it can be concluded that this parameter highly influences the material removal process.

Isolation and utilization of proteins from seaweeds have been a novel trend in the world at present due to the increasing demand for healthy non-animal proteins. The attention of scientific community has been paid on the protein derived from seaweed Undaria pinnatifida due to their high nutritional quality and bioactivity. This article aims to provide an integrated overview on methods of extraction, isolation and purification of U. pinnatifida-derived proteins and composition, nutritional value and potential nutraceutical and food applications with an interest to stimulate further research to optimize the utilization. Potential food applications of U. pinnatifida derived proteins are nutritional components in human diet, food ingredients and additives, alternative meat and meat analogues and animal and fish feed. Excellent antioxidant, antihypertension, anticoagulant, anti-diabetes, antimicrobial and anti-cancer activities possessed by proteins of U. pinnatifida enable the use of these proteins in various nutraceutical applications. A number of studies have been carried out on antioxidant and antihypertensive activities of U. pinnatifida proteins, whereas other bioactivites are yet to be further studied. Hence, more research works are crucial to be done in order to facilitate and promote the emerging novel foods and nutraceuticals, using proteins from seaweed U. pinnatifida.

Unsuitable surface quality is frequently observed in the machining of composites due to their heterogeneity and anisotropic properties. Thus, minimizing the machining damages requires a thorough understanding of the machining process. In this study, two different finite element models were developed using Abaqus/Explicit to simulate the cutting process of unidirectional carbon fiber-reinforced polymer: (i) a macromechanical model based on the homogenization approach and (ii) a micromechanical model in which the composite constituents were treated separately. The effects of CFRP mechanical properties, the energy of breaking and hourglass control were analyzed using a macromechanical model. The results revealed that CFRP properties and the numerical parameters highly influenced the cutting process. A comparative study was also performed between the macromechanical and the micromechanical models to study the mechanisms of chip formation. It was demonstrated that the material removal mechanisms for both models are in good agreement with the experimental observations for different fiber orientation angles.

Trastuzumab (Trz) is a humanized monoclonal antibody targeting epidermal growth factor receptor 2 (HER2; ErbB2). The combined administration of Trz and doxorubicin (DOX) has shown potent anti-cancer efficacy; however, this regimen may be accompanied by severe cardiac toxicity. Mesenchymal stem cells (MSCs)-derived exosomes are nanosized vesicles that play a crucial role in cell–cell communication and have shown efficacy in the treatment of various diseases. In this study, we aim to investigate the cardioprotective effects of MSCs-derived exosomes in a DOX/Trz- mediated cardiotoxicity model, and the possible mechanisms underlying these effects are elucidated. Forty-nine male rats were randomly assigned into four groups: Group I (control); Group II (Dox/Trz); Group III (protective group); and Group IV (curative group). Cardiac hemodynamic parameters, serum markers of cardiac injury, oxidative stress indices, and cardiac histopathology were investigated. Further, transcript profile of specific cardiac tissue injury markers, apoptotic markers, and fibrotic markers were analyzed using qRT-PCR, while the protein expressions of pAkt/Akt, pERK/ERK, pJNK/JNK, pJNK/JNK, and pSTAT3/STAT3 were evaluated by ELISA. Additionally, cardiac mirR-21 and miR-26a were assessed. A combined administration of DOX/Trz disrupted redox and Ca2+ homeostasis in cardiac tissue induced myocardial fibrosis and myofibril loss and triggered cardiac DNA damage and apoptosis. This cardiotoxicity was accompanied by decreased NRG-1 mRNA expression, HER2 protein expression, and suppressed AKT and ERK phosphorylation, while triggering JNK phosphorylation. Histological and ultra-structural examination of cardiac specimens revealed features typical of cardiac tissue injury. Moreover, a significant decline in cardiac function was observed through biochemical testing of serum cardiac markers and echocardiography. In contrast, the intraperitoneal administration of MSCs-derived exosomes alleviated cardiac injury in both protective and curative protocols; however, superior effects were observed in the protective protocol. The results of the current study indicate the ability of MSCs-derived exosomes to protect from and attenuate DOX/Trz-induced cardiotoxicity. The NRG-1/HER2, MAPK, PI3K/AKT, PJNK/JNK, and PSTAT/STAT signaling pathways play roles in mediating these effects.

Background. Liver transplantation remains the only viable therapy for liver failure but has a severely restricted utility. Here, we aimed to decellularize rat livers to form acellular 3D bio-scaffolds suitable for seeding with induced pluripotent cells (iPSCs) as a tool to investigate the role of Wnt/β-catenin signaling in liver development and generation. Methods. Dissected rat livers were randomly divided into three groups: I (control), II (decellularized scaffolds) and III (recellularized scaffolds). Liver decellularization was established via an adapted perfusion procedure and assessed through the measurement of extracellular matrix (ECM) proteins and DNA content. Liver recellularization was assessed through histological examination and measurement of transcript levels of Wnt/β-catenin pathway, hepatogenesis, liver-specific microRNAs and growth factors essential for liver development. Adult rat liver decellularization was confirmed by the maintenance of ECM proteins and persistence of growth factors essential for liver regeneration. Results. iPSCs seeded rat decellularized livers displayed upregulated transcript expression of Wnt/β-catenin pathway-related, growth factors, and liver specification genes. Further, recellularized livers displayed restored liver-specific functions including albumin secretion and urea synthesis. Conclusion. This establishes proof-of-principle for the generation of three-dimensional liver organ scaffolds as grafts and functional re-establishment.

The application of next-generation sequencing (NGS) in routine clinical analysis is still limited. The significance of NGS in the identification of pathogens of lower respiratory tract infection should be assessed as part of routine clinical bacterial examinations and chest imaging results. In the present study, the alveolar lavage fluid samples of 30 patients (25 males and 5 females, aged 19-92 years old, with a median age of 62) were examined by routine bacterial culture and NGS, and the results of pathogen detection and identification were compared. Chest imaging showed consolidation in all 30 patients (100%), and pleural effusion in 13 of the 30 patients (43.33%). The routine bacterial culture of the lavage solution was only positive in 14 of the 30 patients (46.6%), and negative in 16 patients (53.33%). However, the positive rate of NGS test results of the lavage fluid was 100%. A total of 12 cases (40%) were completely consistent with the routine bacterial culture test, with 56 other pathogens of mixed infection detected, accounting for the short comings of the routine bacterial examination. Although NGS cannot distinguish between live and dead bacteria, it is still a useful detection technology for accurate diagnosis of clinical infectious diseases. It is worthy of adaptation in the clinic for more effective clinical management and treatment of the lower respiratory airway infection in addition to the routine bacterial culture testing.

Diabetic retinopathy (DR) is a serious microvascular complication of diabetes mellitus. Mesenchymal stem cells are currently studied as therapeutic strategy for management of DR. Exosomes, considered as a promising cell-free therapy option, display biological functions similar to those of their parent cells. In retinal development, Wnt/b-catenin signaling provides key cues for functional progression. The present study aimed to evaluate the potential efficacy of bone marrow-derived mesenchymal stem cell-derived exosomes (BM-MSCs-Ex) in diabetes-induced retinal injury via modulation of the Wnt/ b-catenin signaling pathway.Eighty-one rats were allocated into 6 groups (control, DR, DR + DKK1, DR + exosomes, DR + Wnt3a and DR + exosomes+Wnt3a). Evaluation of each group was via histopathological examination, assessment of gene and/or protein expression concerned with oxidative stress (SOD1, SOD2, Nox2, Nox4, iNOS), inflammation (TNF-α, ICAM-1, NF-κB) and angiogenesis (VEGF, VE-cadherin).Results demonstrated that exosomes blocked the wnt/b-catenin pathway in diabetic retina concomitant with significant reduction of features of DR as shown by downregulation of retinal oxidants, upregulation of antioxidant enzymes, suppression of retinal inflammatory and angiogenic markers. These results were further confirmed by histopathological results, fundus examination and optical coherence tomography. Additionally, exosomes ameliorative effects abrogated wnt3a-triggered retinal injury in DR.Collectively, these data demonstrated that exosomes ameliorated diabetes-induced retinal injury via suppressing Wnt/ b-catenin signaling with subsequent reduction of oxidative stress, inflammation and angiogenesis.

Background Diabetic foot ulceration is a serious chronic complication of diabetes mellitus characterized by high disability, mortality, and morbidity. Platelet-rich plasma (PRP) has been widely used for diabetic wound healing due to its high content of growth factors. However, its application is limited due to the rapid degradation of growth factors. The present study aimed to evaluate the efficacy of combined adipose-derived mesenchymal stem cells (ADSCs) and PRP therapy in promoting diabetic wound healing in relation to the Notch signaling pathway. Methods Albino rats were allocated into 6 groups [control (unwounded), sham (wounded but non-diabetic), diabetic, PRP-treated, ADSC-treated, and PRP+ADSCs-treated groups]. The effect of individual and combined therapy was evaluated by assessing wound closure rate, epidermal thickness, dermal collagen, and angiogenesis. Moreover, gene and protein expression of key elements of the Notch signaling pathway (Notch1, Delta-like canonical Notch ligand 4 (DLL4), Hairy Enhancer of Split-1 (Hes1), Hey1, Jagged-1), gene expression of angiogenic marker (vascular endothelial growth factor and stromal cell-derived factor 1) and epidermal stem cells (EPSCs) related gene (ß1 Integrin) were assessed. Results Our data showed better wound healing of PRP+ADSCs compared to their individual use after 7 and 14 days as the combined therapy caused reepithelialization and granulation tissue formation with a marked increase in area percentage of collagen, epidermal thickness, and angiogenesis. Moreover, Notch signaling was significantly downregulated, and EPSC proliferation and recruitment were enhanced compared to other treated groups and diabetic groups. Conclusions These data demonstrated that PRP and ADSCs combined therapy significantly accelerated healing of diabetic wounds induced experimentally in rats via modulating the Notch pathway, promoting angiogenesis and EPSC proliferation.

Background Diabetic foot ulceration is a serious chronic complication of diabetes mellitus characterized by high disability, mortality and morbidity. Platelet-rich plasma (PRP) has been widely used for diabetic wound healing due to its high content of growth factors. However, its application is limited due to rapid degradation of growth factors. The present study aimed to evaluate the efficacy of combined adipose derived mesenchymal stem cells (ADSCs) and PRP therapy in promoting diabetic wound healing in relation to the Notch signaling pathway. Methods Albino rats were allocated into 6 groups (control, sham, diabetic, PRP-treated, ADSCs-treated and PRP+ADSCs-treated groups). The effect of individual and combined therapy was evaluated by assessing wound closure rate, epidermal thickness, dermal collagen and angiogenesis. Moreover, gene and protein expression of key elements of Notch signaling pathway (Notch1, Delta like canonical Notch ligand 4 (DLL4), Hairy Enhancer of Split-1 (Hes1), Hey1, Jagged-1), gene expression of angiogenic marker (Vascular endothelial growth factor & stromal cell-derived factor 1) and epidermal stem cells (EPSCs) related gene (ß1 Integrin) were assessed. Results Our data showed a strong wound-healing effect of PRP+ADSCs compared to their individual use after 7 and 14 days. Combined therapy caused marked increase in area percentage of collagen, epidermal thickness and angiogenesis. Moreover, Notch signaling was significantly down-regulated, EPSCs proliferation and recruitment was enhanced compared to other treated groups and diabetic group. Conclusions These data demonstrated that PRP and ADSCs combined therapy significantly accelerated healing of diabetic wounds induced experimentally in rats via modulating Notch pathway, promoting angiogenesis and EPSCs proliferation.

Isolation and utilization of proteins from seaweeds have been a novel trend in the world at present due to the increasing demand for healthy non-animal proteins. The attention of scientific community has been paid on the protein derived from seaweed

Background Very small embryonic-like stem cells (VSELs) are a rare population within the ovarian epithelial surface. They contribute to postnatal oogenesis as they have the ability to generate immature oocytes and resist the chemotherapy. These cells express markers of pluripotent embryonic and primordial germ cells. Objective We aimed to explore the capability of VSELs in restoring the postnatal oogenesis of chemo-ablated rat ovaries treated with bone marrow-derived mesenchymal stem cells (BM-MSCs) combined with pregnant mare serum gonadotropin (PMSG). Methods Female albino rats were randomly assigned across five groups: I (control), II (chemo-ablation), III (chemo-ablation + PMSG), IV (chemo-ablation + MSCs), and V (chemo-ablation + PMSG + MSCs). Postnatal oogenesis was assessed through measurement of OCT4, OCT4A, Scp3, Mvh, Nobox, Dazl4, Nanog, Sca-1, FSHr, STRA8, Bax, miR143, and miR376a transcript levels using qRT-PCR. Expression of selected key proteins were established as further confirmation of transcript expression changes. Histopathological examination and ovarian hormonal assessment were determined. Results Group V displayed significant upregulation of all measured genes when compared with group II, III or IV. Protein expression confirmed the changes in transcript levels as group V displayed the highest average density in all targeted proteins. These results were confirmed histologically by the presence of cuboidal germinal epithelium, numerous primordial, unilaminar, and mature Graafian follicles in group V. Conclusion VSELs can restore the postnatal oogenesis in chemo-ablated ovaries treated by BM-MSCs combined with PMSG.

Fucoidan is a multifunctional marine carbohydrate polymer that differs in its chemical composition and bioactivity both between seaweed species and within species from different locations across the globe. In this study, fucoidan was extracted from the sporophyll of Undaria pinnatifida grown in Weihai, Shandong Province, China. Fucoidan fractions with molecular weight cutoffs (MWCO) of >300 kDa and 300 kDa fraction (300k) and

Carbon Fiber Reinforced Polymer (CFRP) composites are heavily used for advanced structural applications owing to their special mechanical properties like high strength, corrosion resistance and slight weight, etc. The intrinsic characteristics of these materials generate several defects during machining such as fiber pull-out, matrix crack and burr. The understanding of the machining operation of these materials are essential to eliminate the workpiece damage and to achieve a good surface quality. In this work, the effect of the fiber orientation angle and the cutting speed on the chip formation mechanisms has been analyzed. For this reason, a finite element model with equivalent homogeneous material (EHM) was developed using Abaqus/Explicit code. A hashin criterion was adopted to predict the damage of CFRP. The results revealed that the numerical and experimental findings are in good agreement. The fiber orientation angle and the cutting speed have a notable effect on the chip formation mechanisms.

The pathophysiological function of the forkhead transcription factor FOXN3 remains to be explored. Here we report that FOXN3 is a transcriptional repressor that is physically associated with the SIN3A repressor complex in estrogen receptor–positive (ER+) cells. RNA immunoprecipitation–coupled high-throughput sequencing identified that NEAT1, an estrogen-inducible long noncoding RNA, is required for FOXN3 interactions with the SIN3A complex. ChIP-Seq and deep sequencing of RNA genomic targets revealed that the FOXN3-NEAT1-SIN3A complex represses genes including GATA3 that are critically involved in epithelial-to-mesenchymal transition (EMT). We demonstrated that the FOXN3-NEAT1-SIN3A complex promotes EMT and invasion of breast cancer cells in vitro as well as dissemination and metastasis of breast cancer in vivo. Interestingly, the FOXN3-NEAT1-SIN3A complex transrepresses ER itself, forming a negative-feedback loop in transcription regulation. Elevation of both FOXN3 and NEAT1 expression during breast cancer progression corresponded to diminished GATA3 expression, and high levels of FOXN3 and NEAT1 strongly correlated with higher histological grades and poor prognosis. Our experiments uncovered that NEAT1 is a facultative component of the SIN3A complex, shedding light on the mechanistic actions of NEAT1 and the SIN3A complex. Further, our study identified the ERα-NEAT1-FOXN3/NEAT1/SIN3A-GATA3 axis that is implicated in breast cancer metastasis, providing a mechanistic insight into the pathophysiological function of FOXN3.

The effects of epigallocatechin-3-gallate (EGCG) and metformin single treatment have been tested against hepatocellular carcinoma (HCC). This study aimed to assess the combination effects of EGCG and metformin on proliferation and apoptosis of HepG2cells and identified new potential molecular targets. The effect of EGCG and metformin against cell proliferation in HepG2 was determined using MTT assay. Reverse transcription polymerase chain reaction was applied to examine the gene expression of cyclin D1, lncRNA-AF085935, caspase-3, survivin and VEGF. The level of protein expression of glypican-3 was assessed by western blot. In HepG2 cells, EGCG and metformin combination treatment exhibited high significant effect against tumor proliferation. It significantly reduced cyclin D1, lncRNA-AF085935, glypican-3 and promoted apoptosis through increasing caspase3 and decreasing survivin compared to control cells. Moreover, EGCG and metformin treated cells showed decreased expression levels of VEGF. Our study provided new insights of the anticarcinogenic effects of EGCG and metformin on HCC through their effects on glypican-3 and lncRNA-AF085935.

Human trophoblast invasion and differentiation are essential for successful pregnancy outcome. The molecular mechanisms, however, are poorly understood. Interleukin (IL)-11, a cytokine, regulates endometrial epithelial cell adhesion. Leukemia inhibitory factor (LIF) is one of the key cytokines in the embryo implantation regulation. The present study aimed to assess the levels of LIF, IL-11, and IL-11 α receptor gene expression in the endometrium of women undergoing IVF and correlate their levels with the IVF pregnancy outcome. Also, the study aimed to detect any mutation in these three genes among IVF pregnant and non-pregnant women versus control menstrual blood of fertile women. Endometrial tissue biopsies were taken from 15 women undergoing IVF on the day of oocyte retrieval. The quantitative expression of IL-11, IL-11Rα, and LIF genes was assessed by real-time PCR and PCR products were sequenced. Menstrual blood from 10 fertile women was used as control to compare the DNA sequence versus DNA sequence of the studied genes in endometrial biopsies. LH, FSH, and E2 were assessed for enrolled patients by ELISA. Endometrial thickness was also assessed by pelvic ultrasonography. No significant difference was detected between quantitative expression of the three studied genes and pregnancy IVF outcome. Although DNA sequence changes were found in IL-11 and LIF genes of women with negative pregnancy IVF outcome compared to women with positive pregnancy IVF outcome, no DNA sequence changes were detected for IL-11Rα. Other studied parameters (e.g., age, LH, FSH, E2, and endometrial thickness) showed no significant differences or correlation of quantitative expression of the three studied involved genes. Data suggested that there were no significant differences between quantitative expression of IL-11, IL-11Rα, and LIF genes and the IVF pregnancy outcome. The present study may reveal that changes in IL-11 and LIF genes sequence may contribute in pregnancy IVF outcome.

Novel water-soluble curcumin derivatives have been developed to overcome low in vivo bioavailability of curcumin. The aim of this work is to assess the potential utility of certain downstream targets as bioavailability indicators of systemic activity of pure curcumin and two novel water-soluble curcumin derivatives (NCD) by constructing dose-dependent response curves and to prove whether this novel curcumin derivatives retained, improved, or abolished biological activity of pure curcumin when applied in vivo. Pure curcumin (CUR), curcumin-carboxy derivative (NCD-1), and curcumin protein conjugate (NCD-2) were administered orally to rats at escalating doses: 37, 74, 148, and 296 μM/kg body weight, respectively. Plasma levels of GST activity, cavernous tissue levels of cGMP, and enzymatic activity of both HO-1 and GST were assessed one and half and 24 hours after oral administration of curcumin formulae. This study showed that there was a progressive elevation of cavernous tissue levels of cGMP and enzymatic activity of both HO-1 and GST in a dose-dependent manner that was maintained for 24 h with CUR, NCD-1, and NCD-2. Plasma GST activity was decreased by the lowest doses on the curve. The three dose-dependent bioavailability indicators as surrogates of curcumin and two of its novel derivatives are valid in the studied range of concentration and extended time. The novel curcumin derivatives still conserve with improvement the biological activity of natural curcumin when applied in vivo. © 2013 BioFactors, 40(1):132–137, 2014

This study was conducted to evaluate the effect of mesenchymal stem cells (MSCs) and a novel curcumin derivative (NCD) on HepG2 cells (hepatoma cell line) and to investigate their effect on Notch1 signaling pathway target genes. HepG2 cells were divided into HepG2 control group, HepG2 cells treated with MSC conditioned medium (MSCs CM), HepG2 cells treated with a NCD, HepG2 cells treated with MSCs CM and NCD, and HepG2 cells treated with MSCs CM (CM of MSCs pretreated with a NCD). Expression of Notch1, Hes1, VEGF, and cyclin D1 was assessed by real-time, reverse transcription-polymerase chain reaction (RT-PCR) in HepG2 cells. In addition, HepG2 proliferation assay was performed in all groups. Notch1 and its target genes (Hes1 and cyclin D1) were downregulated in all treated groups with more suppressive effect in the groups treated with both MSCs and NCD. Also, treated HepG2 cells showed significant decrease in cell proliferation rate. These data suggest that modulation of Notch1 signaling pathway by MSCs and/or NCD can be considered as a therapeutic target in HCC.

Fucoidan, the complex fucose-containing sulphated polysaccharide varies considerably in structure, composition, and bioactivity, depending on the source, species, seasonality, and extraction method. In this study, we examined five fucoidans extracted from the same seaweed species Undaria pinnatifida but from different geological locations, and compared them to the laboratory-grade fucoidan from Sigma (S). The five products differed in molecular composition. The amount of over 2 kDa low molecular weight fraction (LMWF) of the New Zealand crude fucoidan (S1) was larger than that of S, and this fraction was unique, compared to the other four fucoidans. The difference of molecular compositions between S and S1 explained our previous observation that S1 exhibited different anticancer profile in some cancer cell lines, compared with S. Since we observed this unique LMWF, we compared the cytotoxic effects of a LMWF and a high molecular weight fucoidan (HMWF) in two breast cancer cell lines&mdash, MCF-7 and MDA-MB-231. Results indicated that the molecular weight is a critical factor in determining the anti-cancer potential of fucoidan, from the New Zealand U. pinnatifida, as the LMWF exhibited a dose-dependent inhibition on the proliferation of breast cancer cells, significantly better than the HMWF, in both cell lines. A time-dependent inhibition was only observed in the MCF-7. Induction of caspase-dependent apoptosis was observed in the MDA-MB-231 cells, through the intrinsic apoptosis pathway alone, or with the extrinsic pathway. LMWF stimulated a dose-dependent NOS activation in the MDA-MB-231 cells. In conclusion, the fucoidan extracted from the New Zealand U. pinnatifida contains a unique LMWF, which could effectively inhibit the growth of breast cancer cell lines. Therefore, the LMWF from New Zealand U. pinnatifida could be used as a supplement cancer treatment.

Introduction Curcumin is an inducer of heme oxygenase enzyme-1 (HO-1) that is involved in erectile signaling via elevating cyclic guanosine monophosphate (cGMP)levels. Aim To assess the effect of oral administration of a water-soluble long-acting curcumin derivative on erectile signaling. Methods Two hundred and thirty six male white albino rats were divided into four groups; group 1 (N = 20) includes control. Group 2 (N = 72) was equally divided into four subgroups; subgroup 1 received pure curcumin (10 mg/kg), subgroup 2 received the long-acting curcumin derivative (2 mg/kg), subgroup 3 received the long-acting curcumin derivative (10 mg/kg), and subgroup 4 received sildenafil (4 mg/kg). Subgroups were sacrificed after the first, second, and third hour. Group 3 (N = 72) was equally divided into the same four subgroups already mentioned and were sacrificed after 24 hours, 48 hours, and 1 week. Group 4 (N = 72) was subjected to intracavernosal pressure (ICP) measurements 1 hour following oral administration of the same previous doses in the same rat subgroups. Main Outcome Measure Cavernous tissue HO enzyme activity, cGMP, and ICP. Results In group 2, there was a significant progressive maintained elevation of HO activity and cGMP tissue levels starting from the first hour in subgroups 3 and 4, whereas, the rise in HO activity and cGMP started from second hour regarding the other rat subgroups. Sildenafil effect decreased after 3 hours. In group 3, there was a significant maintained elevation of HO activity and cGMP tissue levels extended to 1 week as compared to controls for all rat subgroups that received both forms of curcumin. In group 4, long-acting curcumin derivative exhibited more significant potentiation of intracavernosal pressure as compared to control and to the pure curcumin. Conclusion Water-soluble long-acting curcumin derivative could mediate erectile function via upregulating cavernous tissue cGMP. Abdel Aziz MT, El Asmer MF, Rezq A, Kumosani TA, Mostafa S, Mostafa T, Atta H, Abdel Aziz Wassef M, Fouad HH, Rashed L, Sabry D, Hassouna AA, Senbel A, and Abdel Aziz A. Novel water-soluble curcumin derivative mediating erectile signaling

Curcumin exerts a hypoglycemic action and induces heme-oxygenase-1 (HO-1). We evaluated the effect of curcumin on isolated islets of Langerhans and studied whether its action on insulin secretion is mediated by inducible HO-1. Islets were isolated from rats and divided into control islets, islets incubated in different curcumin concentrations, islets incubated in hemin, islets incubated in curcumin and HO inhibitor, stannous mesoporphyrin (SnMP), islets incubated in hemin and SnMP, islets incubated in SnMP only, and islets incubated in 16.7 mmol/L glucose. Heme-oxygenase activity, HO-1 expression, and insulin estimation was assessed. Insulin secretion, HO-1 gene expression and HO activity were significantly increased in islets incubated in curcumin, hemin, and glucose compared with controls. This increase in insulin secretion was significantly decreased by incubation of islets in SnMP. The action of curcumin on insulin secretion from the isolated islets may be, in part, mediated through increased HO-1 gene expression.

Introduction Activation of the renin‐angiotensin system which is common in diabetes mellitus might affect heme oxygenase (HO‐1) gene expression. Aim Assessment of the effects of administration of angiotensin II (Ang II) receptor antagonist (losartan) with HO‐1 inducer or inhibitor on erectile signaling in diabetic rats. Materials and Methods Seventy male rats were divided equally into seven groups; healthy controls, streptozotocin‐induced diabetic rats, rats on citrate buffer, diabetic rats on losartan, diabetic rats on HO‐1 inducer (cobalt protoporphyrin [CoPP]), diabetic rats on losartan and CoPP, and diabetic rats on losartan and HO‐1 inhibitor (stannus mesoporphyrin [SnMP]). Main Outcome Measure HO enzyme activity, HO‐1 gene expression, cyclic guanosine monophosphate (cGMP) assay, intracavernosal pressure (ICP), and cavernous tissue sinusoids surface area. Results HO‐1 gene expression, HO enzymatic activity, and cGMP were significantly decreased in the cavernous tissue of diabetic rats. These parameters were significantly elevated with the use of CoPP that restored the normal control levels of HO enzyme activity. Administration of losartan exhibited a significant enhancing effect on these parameters compared with the diabetic group, but not restored to the control levels, whereas administration of CoPP combined with losartan led to the restoration of their normal levels. ICP demonstrated significant decline in diabetic rats. The use of CoPP and/or losartan led to its significant improvement compared with diabetic rats. Administration of either losartan and/or CoPP led to a significant increase in the cavernous sinusoids surface area of diabetic rats. Administration of losartan with SnMP significantly decreased the enhancing effect of losartan on the studied parameters. Conclusion The decline in erectile function in diabetes mellitus could be attributed to the downregulation of HO‐1 gene expression. HO‐1 induction added to Ang II receptor antagonist could improve erectile function. Abdel Aziz MT, El Asmer MF, Mostafa T, Atta H, Mahfouz S, Fouad H, Rashed L, Sabry D, Hassouna A, Abdel Aziz AT, Senbel A, and Demery A. Effects of losartan, HO‐1 inducers or HO‐1 inhibitors on erectile signaling in diabetic rats.

A little is known about the relation of plasma cytokines with psychological risk factors, such as hopelessness, and the severityof depressive symptoms. The present work studied theeffect of depression onplasma interleukin (IL)-1β, IL-6 and high sensitivity C-reactive protein (hsCRP) in 40 subjects. Participants included two groups; patient group included 20 nonsmoking males (aged 20–40years), recruited from the psychiatry clinic at Kasr El-Ainy Hospital fulfilling the DSM-IV Axis I disorders criteria for major depression. Control group included 20 healthy, nonsmoking males (age matched with no current or past history of psychiatric disorders). After an overnight fast, blood samples were collected and plasma IL-6, IL-1β, and hsCRP were determined using enzymatic-linked immunosorbent assay (ELISA), also fasting total cholesterol (TC) and high density lipoprotein-cholesterol (HDL-C) were estimated on the same day that the BeckDepression Inventory (BDI), Hopelessness Scale (HS) and full psychiatric sheet were accomplished. The results of the study showed a significant increase in depressed patients compared to normal controls as regards mean scores of BDI, HS, IL-1β, IL-6 and hsCRP. There was, also, a significant increase in both patients withmoderate and severe depression compared to patients with mild depression asregards mean scores of BDI, IL-1β, IL-6 and hsCRP. There was, also, a significant difference between patients with mild hopelessness and those with moderate and severe hopelessness as regards mean scores of HS, IL-1β, IL-6 and hsCRP.Conclusion: Patients with major depression revealed high levels of IL-1β, IL-6 and hsCRP. That finding makes such patients more vulnerable to cerebrovascular accidents, where elevation of plasma cytokines and inflammatory markers are considered as risk factors for myocardial infarction

Estrogen (E(2)) and progesterone (P) hormones have a pro-inflammatory and an anti-inflammatory role under different conditions. The current study explored this phenomenon in the context of septic inflammation.This study involved 48 female albino rats. E(2) (4 mg/100 g body weight (b.w.) and P (5 mg/kg b.w.) were administered to ovariectomized (OVX) rats after systemic inflammation (SI) induced by puncturing the caecum I cm from its end with a single hole by using a 21-gauge needle. Key indices of inflammation and apoptosis were evaluated.OVX animals subjected to SI showed significantly increased levels of serum tumor necrosis factor-alpha (TNF-u), C reactive protein (CRP) and alanine aminotransferase (ALT). They also showed higher levels of expression of the enzyme inducible nitric oxide synthase (iN OS); 312 ± 43 mg/ml; in the liver, and the activity of both cyclooxygenase 2 (COX-2); 59.4 ± 3.2 U/ml; and caspase 3 enzymes; 6.3 ± 0.54 ng/ml; when compared to non-OVX animals subjected to (SI), (180 ± 3 mg/ml, 16.4 ± 1.69 U/ml, 0.98 ± 0.23 ng/ml respectively). Administration of E(2) resulted in a significant reduction of all serum and liver tissue parameters of inflammation (e.g.decreased iNOS; 193 ± 28 mg/ml and COX-2; 27.6 ± 3.91 U/ml) and decreased apoptosis (Caspase 3; 1.18 ± 0.21 ng/ml). In contrast, OVX animals injected with P before induction of SI showed a significant rise of all measured parameters.E(2) and Pin physiological levels have contrasting though complementary roles in regulation of the immune system possibly allowing a limited inflammatory response while preventing excessive damage to the tissues.

Background Hyperglycemia induces activation of the c-Jun N-terminal kinase (JNK) pathway, which suppresses insulin gene expression and reduces DNA binding of pancreatic and duodenal homeobox factor (PDX)-1. This study aims to investigate the effects of a novel curcumin derivative (NCD) on JNK signaling pathway on insulin synthesis and secretion in streptozotocin (STZ)-treated rat pancreatic islets in vitro. Methods Isolated rat pancreatic islets were divided into five groups: untreated control group; group treated with NCD (10 μM); group exposed to STZ (5 mM); group treated with NCD (10 μM) and then exposed to STZ (5 mM); and group exposed to STZ (5 mM) and then treated with NCD (10 μM). The pancreatic islets from all groups were used for DNA fragmentation assays and quantitative assessments of the JNK, Pdx1, glucose transporter-2 (GLUT2), heme oxygenase (HO)-1, transcription factor 7-like 2 (TCF7L2), and glucagon-like peptide (GLP)-1 gene expression levels. The intracellular calcium, zinc, and the phosphorylated and total JNK protein levels were assessed. The insulin (secreted/total) and C-peptide levels were examined in islet culture medium. Results NCD protected pancreatic islets against STZ-induced DNA damage, improved total insulin (P = 0.001), secreted insulin (P = 0.001), and C-peptide levels (P = 0.001), normalized mRNA expressions of insulin, Pdx1, and GLUT2 (P = 0.0001), and significantly elevated calcium and zinc levels (P = 0.0001). All effects were significant when islets were treated with NCD before STZ (P = 0.05). JNK gene overexpression and JNK protein levels induced by STZ were significantly inhibited after NCD treatment of islets ( P = 0.0001). NCD-treated islets showed significantly elevated gene expressions of HO-1, TCF7L2, and GLP-1 (P = 0.0001), and these upregulated gene expressions were more significantly elevated with NCD treatment before STZ than after STZ (P = 0.05). Conclusions NCD improved insulin synthesis and secretion in vitro in isolated pancreatic islets treated with STZ through inhibition of the JNK pathway, up-regulation of the gene expressions of HO-1, TCF7L2, and GLP-1 and enhancing effects on calcium and zinc levels.

Novel water-soluble curcumin derivatives have been developed to overcome low in vivo bioavailability of curcumin. The aim of this work is to assess the potential utility of certain downstream targets as bioavailability indicators of systemic activity of pure curcumin and two novel water-soluble curcumin derivatives (NCD) by constructing dose-dependent response curves and to prove whether this novel curcumin derivatives retained, improved, or abolished biological activity of pure curcumin when applied in vivo. Pure curcumin (CUR), curcumin-carboxy derivative (NCD-1), and curcumin protein conjugate (NCD-2) were administered orally to rats at escalating doses: 37, 74, 148, and 296 μM/kg body weight, respectively. Plasma levels of GST activity, cavernous tissue levels of cGMP, and enzymatic activity of both HO-1 and GST were assessed one and half and 24 hours after oral administration of curcumin formulae. This study showed that there was a progressive elevation of cavernous tissue levels of cGMP and enzymatic activity of both HO-1 and GST in a dose-dependent manner that was maintained for 24 h with CUR, NCD-1, and NCD-2. Plasma GST activity was decreased by the lowest doses on the curve. The three dose-dependent bioavailability indicators as surrogates of curcumin and two of its novel derivatives are valid in the studied range of concentration and extended time. The novel curcumin derivatives still conserve with improvement the biological activity of natural curcumin when applied in vivo.

Objective: Our aim was to determine whether the level of plasma total ghrelin varies with the menopause stage (pre-, peri-, and postmenopause). Participants and interventions: women were divided in three groups: premenopausal, perimenopausal and postmenopausal. All participants had bone mineral densitometry and blood assay of plasma ghrelin, estradiol E2. Correlation between plasma ghrelin levels, their reproductive status and BMD was done. Results: The mean plasma level of ghrelin was significantly decreased in the perimenopausal and postmenopausal groups in comparison to the premenopausal group. A significant positive correlation was found between ghrelin and each of E2 and BMD (at one or more of the three sites assessed) in all subjects, as well as, in peri- and postmenopausal women, whereas a significant negative correlation was found between ghrelin and FSH. Conclusion: It may be assumed that ghrelin can affect BMD. Whether ghrelin and estrogen work independent or through convergent mechanisms needs ...

Summary This work postulated that heme oxygenase (HO) is partly responsible for controlling phosphodiesterase-5 inhibitor actions by modulating cyclic guanosine monophosphate (cGMP) cavernous tissue levels. Five hundred and four male Sprague–Dawley rats, divided into five groups, were investigated. Group 1 (n = 72) included controls, group 2 (n = 72) received sildenafil citrate (ViagraR) orally, group 3 (n = 72) received vardenafil hydrochloride (LevitraR), group 4 (n = 72) received tadalafil (CialisR). Group 5 (n = 216), subdivided into three subgroups (A, B and C, 72 each), received the same dose of each drug with the HO inhibitor, Zn protoporphyrin. Eight rats from each group/subgroup were killed at 0.5, 1, 2, 3, 4, 6, 18, 24 and 36 h when cGMP levels in the cavernous tissues were estimated. Cavernous tissue cGMP levels increased significantly in sildenafil, vardenafil and tadalafil-treated rats compared to the controls with significant decreases after HO inhibition. It is concluded that the effects of these PDE-5 inhibitors in rat cavernous tissue are partly mediated through HO activity via the cGMP signalling pathway.