New nanodrug design for cancer therapy: Its synthesis,formulation, in vitro and in silico evaluations

The aim of this study was to develop a novel nanosize drug candidate for cancer therapy. For this purpose, (S)-methyl 2-[(7-hydroxy-2-oxo-4-phenyl-2H-chromen-8-yl)methyleneamino]-3-(1H-indol-3-yl)propanoate (ND3) was synthesized by the condensation reaction of 8-formyl-7-hydroxy-4-phenylcoumarin with l -tryptophan methyl ester. Its controlled release formulation was prepared and characterized by different spectroscopic and imaging methods. The cytotoxic effects of ND3 and its controlled release formulation were evaluated against MCF-7 and A549 cancer cell lines, and it was found that both of them have a toxic effect on cancer cells. For drug design and process development, the molecular docking analysis technique helps to clarify the effects of some DNA-targeted anticancer drugs to determine the interaction mechanisms of these drugs on DNA in a shorter time and at a lower cost. By using the molecular docking analysis and DNA binding assays, the interaction between the synthesized compound and DNA was elucidated and non-binding interactions were also determined. To predict the pharmacokinetics, and thereby accelerate drug discovery, the absorption, distribution, metabolism, excretion and toxicity values of the synthesized compound were determined by in silico methods.     

Serum indoleamine 2,3 dioxygenase and tryptophan and kynurenine ratio using the UPLC-MS/MS method,in patients undergoing peritoneal dialysis,hemodialysis, and kidney transplantation

Background: The level and activity of indoleamine 2,3-dioxygenase (IDO) and the concentrations of L-tryptophan and its metabolite L-kynurenine were determined in association with various renal diseases. However, there have been no data regarding these parameters in patients on peritoneal dialysis compared to those undergoing hemodialysis or kidney transplantation.

Methods: This study investigated the level and activity of IDO and determined oxidative balance by calculating the total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI). We enrolled 60 kidney disease patients, including 20 on peritoneal dialysis (PD group), 19 on hemodialysis (HD group), and 21 with kidney transplantation (KT group), as well as 21 control group.

Results: IDO levels were increased in the PD, HD, and KT groups compared to the control group. The concentration of kynurenine was significantly increased in the PD group compared to the other groups (p?p?p?Conclusion: The results showed that IDO levels were increased in peritoneal dialysis and hemodialysis patients and in renal transplant recipients, while oxidative stress was found to be related to IDO activity and was most increased in the patients on peritoneal dialysis.     

Vasculogenesis and angiogenesis in the early human placenta

Vasculogenesis and angiogenesis are two consecutive processes during blood vessel development in the human placenta. While vasculogenesis, which is the formation of first blood vessels, is achieved by differentiation of pluripotent mesenchymal cells into haemangiogenic stem cells. The subsequent step, angiogenesis, is characterized by development of new vessels from already existing vessels. In this review, we aim to give an overview of vasculogenesis and angiogenesis during the first trimester of human placental development. Recent studies have shown that at the very early stages of placental development, cytotrophoblasts trigger vasculogenesis and angiogenesis, whereas as pregnancy progresses Hofbauer and stromal cells take over the task of triggering blood vessel development. Important growth factors in this scenario are the vascular endothelial growth factor (VEGF) family and their receptors, as well as Tie-1 and Tie-2. This review depicts the molecular and morphological steps of vasculogenesis and angiogenesis, which can give further insights into human placental development and maturation disorders.     

Cellular diversity of human placental stem villi: an ultrastructural and immunohistochemical study

The aim of the study was to investigate the distribution and differentiation of cell types in the stroma of human placental stem villi (SV). A total of 14 human term placental tissues were studied. Double immunolabeling was performed for desmin-vimentin, desmin--smooth actin and vimentin--smooth actin. Cytokeratin 7, proliferating cell nuclear antigen immunolabeling was also performed. Parallel tissue samples were examined by transmission electron microscopy. HSCORE was performed for the semi-quantitative analysis of distribution of cells in the stroma of SV. Vimentin-labeled cells were mostly distributed in the subtrophoblastic area. Desmin-vimentin double immunolabeling was mainly localized in the triangular area and to a lesser degree in the perivascular area and vessel walls (p=<0.001). However, desmin- smooth actin labeling was observed predominantly in the vessel wall and perivascular area. Vimentin- smooth actin immunoreactivity was significantly stronger in the triangular and perivascular areas compared to the vessel walls (p=0.003).

Ultrastructurally, cells in the stroma of SV were mesenchyme cells, reticulum cells, fibroblasts, myofibroblasts, smooth muscle cells, and Hofbauer cells, filamented and vacuolated cells. The differentiation of myofibroblasts in the triangular and perivascular areas may play a role in maturation of SV and villous contractility, modulation of the intervillous space and this may have effects on maternofetal placental circulation.     

Surgical and prosthodontic treatment using alveolar distraction osteogenesis and implant placement for a patient with mandibular prognathism: a clinical report

A 49-year-old patient presented with an Angle Class III malocclusion with a partially edentulous mandible, as diagnosed by orofacial examination and radiographic and cephalometric analyses. The patient refused orthognathic surgery; therefore, the treatment plan included the preparation of all teeth and fabrication of provisional restorations to reestablish optimal occlusion. To allow for the placement of 3 implants, the edentulous posterior mandibular ridge was improved via alveolar distraction. The patient was recalled 3, 6, 12, and 24 months after prosthodontic treatment. The oral situation was stable and patient satisfaction was reported as high.     

Importance of acylcarnitine profile analysis for disorders of lipid metabolism in adolescent patients with recurrent rhabdomyolysis: Report of two cases

Metabolic myopathies due to disorders of lipid metabolism are a heterogeneous group of diseases. Newborns may present with hypotonia and convulsions, while progressive proximal muscle weakness or recurrent episodes of muscle weakness accompanied by rhabdomyolysis/myoglobinuria may be seen in older ages. There is little knowledge on detection of disorders of lipid metabolism by acylcarnitine profile (ACP) analysis by tandem mass spectrometry outside the neonatal period particularly in cases with recurrent rhabdomyolysis first presenting in adolescence and adulthood. Two adolescent female cases presented with episodes of rhabdomyolysis and muscle weakness. A 13-year-old patient had five episodes of rhabdomyolysis triggered by infections. Tandem mass spectrometry was normal. A 16-year-old female patient was hospitalized eight times due to recurrent rhabdomyolysis. Increased levels of C14:2, C14:1, and C14 were determined in tandem mass spectrometry. Final diagnoses were carnitine palmitoyltransferase II (CPT II) deficiency and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Increased serum levels of long-chain acylcarnitine can guide to the diagnosis of lipid metabolism disorders. Serum ACP should be performed before enzyme assay and genetic studies.     

The effect of orlistat-induced weight loss on interleukin-6 and C-reactive protein levels in obese subjects

OBJECTIVE: Inflammation plays a major role in the pathogenesis of atherosclerosis. Obesity is an independent risk factor for cardiovascular disease, which may be mediated by increased secretion of proinflammatory cytokines by adipose tissue. The aim of this study is to investigate changes in the inflammatory markers interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) during weight reduction with orlistat treatment in obese patients. METHODS AND RESULTS: Thirty-six obese (BMI: 36.1 +/- 3.4 kg/m2) and II non-obese (BMI: 22.9 +/- 1.7 kg/m2) subjects were studied. IL-6 and hs-CRP levels were evaluated at baseline. In obese subjects after treatment of orlistat 120 mg three times daily for 6 months, IL-6 and hs-CRP levels were repeated. Levels of circulating IL-6 (p < 0.05) and hs-CRP (p < 0.01) were significantly higher in the obese group than in the non-obese group. Plasma IL-6 (r = 0.29 and p < 0.05) and CRP (r = 0.35 and p < 0.05) concentrations correlated positively with the level of obesity assessed by BMI at baseline. After 6 months of orlistat treatment in obese subjects, the mean weight of the patients decreased by 6.8 kg, the BMI by 3.2 kg/m2. Compared with baseline, weight loss was associated with significant reductions of IL-6 (p < 0.001) and hs-CRP (p < 0.001) levels. CONCLUSION: In summary plasma IL-6 and hs-CRP levels were increased in obese patients. Orlistat-induced weight reduction was associated with decreasing levels of both IL-6 and hs-CRP in obese subjects. Because inflammatory mediators may be directly involved in atherogenesis, this would suggest that interventions to reduce IL-6 and CRP levels could be cardioprotective.     

Refractory Postinflammatory Hyperpigmentation Treated Fractional CO2 Laser

Objective: Postinflammatory hyperpigmentation is a reactive hypermelanosis of the skin that occurs as a consequence of an inflammatory process, such as acne, eczema, drug reactions, burns, chemical peelings, and laser applications. Although topical agents remain to be the first-line treatment of postinflammatory hyperpigmentation, treatment of recalcitrant cases is challenging. The Q-switched ruby laser, the low-dose Q-switched neodymium-doped yttrium aluminum garnet laser, and the fractional 1550nm erbium-doped fiber laser have been reported to improve postinflammatory hyperpigmentation. Design/setting/participants: The authors present a case of refractory postinflammatory hyperpigmentation successfully treated with two sessions of fractional CO₂ laser in a 24-year-old woman with Fitzpatrick skin type III. Results: After two treatment sessions with a one-month interval, the lesion totally cleared without any complications. Conclusion: Although many laser systems, including fractional CO₂ lasers, can cause postinflammatory hyperpigmentation, they also can be very efficacious tools by using conservative laser settings and by providing appropriate post-treatment care in recalcitrant postinflammatory hyperpigmentation treatment.Postinflammatory hyperpigmentation (PIH) is a reactive hypermelanosis of the skin. It appears as asymptomatic macules or patches that may be different in size and distribution depending on the causative pathology. Characteristically, it occurs as a consequence of an inflammatory process, such as acne, eczema, drug reactions, burns, chemical peelings, and laser applications. Increased amounts of arachidonic acid metabolites, cytokines, inflammatory mediators, and histamine in the inflammatory process may stimulate the melanocytes causing an increase in the melanin synthesis and transfer of pigment to the surrounding keratinocytes. In PIH, there is either excess melanin production or an abnormal distribution of melanin pigment deposited in the epidermis and/or dermis.1Treatment of PIH consists of a variety of medications and procedures. These include topical bleaching agents, such as hydroquinone, azelaic acid, kojic acid, retinoids, vitamin C, chemical peels, laser therapy, and sunscreens.1,2 The Q-switched ruby laser, the low-dose Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, and the fractional 1550nm erbium-doped fiber laser have been reported to improve PIH.1-4 Here, the authors present a case of refractory PIH treated with fractional CO₂ laser.     

The relationship of Prohepcidin levels with anemia and inflammatory markers in non-diabetic uremic patients: a controlled study

Introduction: Hepcidin, a small peptide hormone synthesized in the liver, plays central role in regulation of iron metabolism. Hepcidin generation in chronic kidney disease (CKD) is dependent on iron status, anemia, inflammation, and hypoxia and erythropoietin levels. In our study, the relationship between Prohepcidin levels and inflammation and iron indices in non-diabetic uremic patients was investigated. Methods: This study has a cross-sectional design which includes four groups: Non-diabetic 21 patients with stage 4 CKD (predialysis), 20 hemodialysis (HD) and 21 peritoneal dialysis (PD) patients and 17 healthy volunteers as the control group. Complete blood count, iron, total iron binding capacity (TIBC), ferritin, high-sensitive C-reactive protein (hsCRP), fibrinogen, parathyroid hormone, interleukin (IL)-6 and Prohepcidin levels were recorded. Results: Serum Prohepcidin levels in the predialysis, HD, PD and the control groups were 119.6?±?45.1?ng/mL, 140.2?±?41.8?ng/mL, 148.2?±?35.0?ng/mL and 93.8?±?21.9?ng/mL, respectively (p?r?=?0.345, p?=?0.002), creatinine (r?=?0.465, p?r?=?0.253, p?=?0.025), hsCRP (r?=?0.275, p?=?0.019), duration of dialysis treatment (r?=?0.443, p?r?=?0.467, p?r?=?0.615, p?r?=??0.286, p?r?=??0.573, p?r?=??0.473, p?r?=??0.351, p?=?0.002) and hematocrit (r?=??0.342, p?=?0.002) levels. Discussion: Prohepcidin levels increase with deepening anemia and show positive correlation with inflammatory markers. Therapeutic interventions regarding Prohepcidin action on inflammatory status may play a role in the treatment of anemia due to inflammation. Functional iron deficiency is frequent in uremic patients. It may be beneficial to measure Prohepcidin level together with ferritin among these patients.