Expanding the structure-activity relationships of alkynyl diphenylurea scaffold as promising antibacterial agents.

With the continuous and alarming threat of exhausting the current antimicrobial arsenals, efforts are urgently needed to develop new effective ones. In this study, the antibacterial efficacy of a set of structurally related acetylenic-diphenylurea derivatives carrying the aminoguanidine moiety was tested against a panel of multidrug-resistant Gram-positive clinical isolates. Compound 18 was identified with a superior bacteriological profile than the lead compound I. Compound 18 demonstrated an excellent antibacterial profile in vitro: low MIC values, extended post-antibiotic effect, refractory ability to resistance development upon extended repeated exposure, and high tolerability towards mammalian cells. Finally, when assessed in a MRSA skin infection animal model, compound 18 showed considerable healing and less inflammation, decrease in the bacterial loads in skin lesions, and it surpassed fusidic acid in controlling the systemic dissemination of S. aureus. Collectively, compound 18 represents a promising lead anti-MRSA agent that merits further investigation for the development of new anti-staphylococcal therapeutics.

Synergistic Antibacterial Potential of 6-Pentyl-α-pyrone Lactone and Zinc Oxide Nanoparticles against Multidrug-Resistant Enterobacterales Isolated from Urinary Tract Infections in Humans.

Urinary tract infection (UTI) is one of the most common bacterial infections in the world, which is associated with high morbidity and mortality rates. Enterobacterales species are considered the most causative agent for UTI, especially uropathogenic Escherichia coli (UPEC). Here, we investigated the antibacterial activity of the green fungal metabolite, 6-pentyl α pyrone lactone, alone or in combination with zinc oxide nanoparticles (ZnONPs) against multidrug-resistant Enterobacterales recovered from UTI. The results revealed that 57.27% of human urine samples were positive for Enterobacterales, where E. coli was the most prevalent bacterial pathogen (66.67%). Of note, 98.41% of Enterobacterales isolates were multidrug-resistant (MDR) with multiple antimicrobial resistance (MAR) indices ranged from 0.437 to 1. Fifty percent of the examined isolates were positive for the integrase gene; 60% out of them harbored class 2 integron, whereas the other 40% carried class 1 integrons. The broth microdilution assay ensured that the 6-pentyl-α-pyrone lactone had a reasonable antimicrobial effect against the examined isolates (Minimum inhibitory concentration (MIC) values of 16-32 µg/mL). However, ZnONPs showed a strong antimicrobial effect against the investigated isolates with MIC values ranging from 0.015 to 32 µg/mL. Interestingly, the MICs decreased 5-12 fold and 3-11 fold for 6-pentyl-α-pyrone lactone and ZnONPs, respectively, against examined isolates after their combination. This is the first report suggesting the use of 6-pentyl α pyrone lactone and ZnONPs combination as a promising candidate against MDR Enterobacterales recovered from UTI.

Bone Health Assessed by Calcaneal Quantitative Ultrasound among Cohort of Pregnant Egyptian Women.

AIM: The aim was to assess the risk of osteopenia and osteoporosis and to identify possible risk factors affecting bone density (BD) during pregnancy as parity, body mass index (BMI), Vitamin D, and calcium supplementation using quantitative ultrasound (QUS) of the calcaneus among first- and third-trimester pregnant women. METHODS: It is a case-control study conducted at Ain Shams Maternity Hospital, Egypt, from May 7 to December 14, 2015. One hundred and thirty-two women in the third trimester and 33 matched controls in the first trimester were screened for BD at the calcaneus by QUS. Stiffness index (SI), QUS-T, and Z scores were measured. RESULTS: Comparing both the groups regarding QUS-T score, Z score, and SI showed a statistically significant difference between both groups. Third-trimester participants had lower scores (-0.72 ± 1.0, -0.63 ± 0.99, and 88.53 ± 14.81, respectively) compared to their matched controls (1.05 ± 0.89, 1.16 ± 0.91, and 113.79 ± 12.49, respectively). According to QUS-T scores, 82 women (62.1%) in the third-trimester group were assessed as having normal BD, whereas 47 women (35.6%) were at risk of being osteopenic and 3 women (2.3%) were at risk of being osteoporotic. All women of the first trimester were assessed as having normal BD. Logistic regression was performed to identify possible risk factors affecting BD among third-trimester patients. BMI was the only statistically significant predictor for changes in bone health in those women (P = 0.001, odds ratio: 0.857, 95% confidence interval: 0.786-0.936). CONCLUSION: With one-unit rise in BMI, a 14% reduction in risk of decreased bone health is obtained.

Novel diagnostic and therapeutic techniques reveal changed metabolic profiles in recurrent focal segmental glomerulosclerosis.

Idiopathic forms of Focal Segmental Glomerulosclerosis (FSGS) are caused by circulating permeability factors, which can lead to early recurrence of FSGS and kidney failure after kidney transplantation. In the past three decades, many research endeavors were undertaken to identify these unknown factors. Even though some potential candidates have been recently discussed in the literature, "the" actual factor remains elusive. Therefore, there is an increased demand in FSGS research for the use of novel technologies that allow us to study FSGS from a yet unexplored angle. Here, we report the successful treatment of recurrent FSGS in a patient after living-related kidney transplantation by removal of circulating factors with CytoSorb apheresis. Interestingly, the classical published circulating factors were all in normal range in this patient but early disease recurrence in the transplant kidney and immediate response to CytoSorb apheresis were still suggestive for pathogenic circulating factors. To proof the functional effects of the patient's serum on podocytes and the glomerular filtration barrier we used a podocyte cell culture model and a proteinuria model in zebrafish to detect pathogenic effects on the podocytes actin cytoskeleton inducing a functional phenotype and podocyte effacement. We then performed Raman spectroscopy in the < 50 kDa serum fraction, on cultured podocytes treated with the FSGS serum and in kidney biopsies of the same patient at the time of transplantation and at the time of disease recurrence. The analysis revealed changes in podocyte metabolome induced by the FSGS serum as well as in focal glomerular and parietal epithelial cell regions in the FSGS biopsy. Several altered Raman spectra were identified in the fractionated serum and metabolome analysis by mass spectrometry detected lipid profiles in the FSGS serum, which were supported by disturbances in the Raman spectra. Our novel innovative analysis reveals changed lipid metabolome profiles associated with idiopathic FSGS that might reflect a new subtype of the disease.

Impact of Ginkgo biloba extract and magnetized water on the survival rate and functional capabilities of pancreatic ß-cells in type 2 diabetic rat model.

INTRODUCTION: Type 2 diabetes (T2D) is a widely distributed disease that affects large population worldwide. This study aimed to verify the role of Ginkgo biloba (GB) extract and magnetized water (MW) on the survival rate and functional capabilities of pancreatic ß-cells in type 2 diabetic rats. MATERIALS AND METHODS: T2D was induced by feeding the rats on a high-fat diet (20% fat, 45% carbohydrate, 22% protein) for eight weeks followed by intra-peritoneal injection of a single low dose of streptozotocin (25mg/Kg). Forty rats were randomly assigned to four groups (n=10 rats) as follows: non treated control and three diabetic groups. One diabetic group served as a positive control (diabetic), while the other two groups were orally administered with water extract of GB leaves (0.11 g/kg/day) and MW (600 gauss) for four weeks, respectively. RESULTS: The ß-cell mass and insulin expression in these cells increased markedly after both treatments, particularly in GB treated group. In addition, the immune-expression of the two antioxidant enzymes; glutathione and superoxide dismutase 2 (SOD2) in the pancreatic tissue demonstrated a down-regulation in GB and MW treated groups as compared with the diabetic group. CONCLUSION: A four-week treatment of GB and MW protected pancreatic ß-cell cells and improved their insulin expression and antioxidant status in type 2 diabetic rats.

Protective effect of p53 knockout on 4-nonylphenol-induced nephrotoxicity in medaka (Oryzias latipes).

In the past few decades, environmental pollutants have become common because of misused nonionic surfactants and detergents. Nonylphenol ethoxylates (NPs) are one of the most important contaminants of water. Therefore, the present study aimed to investigate the protective blocking effect of apoptosis (deficient P53 gene) on 4-nonylphenol (4-NP)-induced nephrotoxicity of medaka (Oryzias latipes). We divided 36 fish into six groups: two different control groups of wild type (Wt; Hd-rR) control and p53 (-/-) control, and four different treated with 4-nonylphenol (50 µg/L and 100 µg/L) for 15 days. Histology, immunochemistry, and TUNEL assays confirmed that 4-NP causes nephrotoxicity. Our results showed that 4-NP administration significantly disturbed the kidney structure and function and 4-NP-treated fish showed dilated glomerular vessels, had less glomerular cellular content, decreased expression of glomerular proteins, and an increased level of apoptosis compared with a Wt control group (P < 0.05). As p53 is an apoptotic inducer, some protection in p53-deficient medaka was found as nephrotoxic effects of 4-NP were minimized significantly. Our study demonstrated for the first time to our knowledge that 4-NP induces apoptosis, causing nephrotoxicity in medaka. We found that blocking apoptosis blocking was able to protect the kidney from the toxic effects of 4-NP.

Histomorphometric analysis of the choroid of donkeys, buffalos, camels and dogs.

AIM: The present study was carried out to investigate the morphological and histomorphometric characters of choroid in donkeys, buffalos, camels and dogs. RESULTS: The findings of the study revealed that, macroscopically, the choroid was consisted of two areas in all studied animals, except in camel which consists of one area. Histologically, the choroid consists of five layers. Interestingly, the anterior borders of all investigated animals were free of pigments except in camel. Morphometric analysis revealed significant species differences in the mean total thickness of the choroid and its different layers. In addition, significant differences were also found between the ratios of the means of different layers to the total thickness of the choroid. CONCLUSION: In conclusion, these variations might be related to the different lifestyles and visual behavior of the investigated animals.

Corrigendum to "Protective Effect of Ginkgo biloba and Magnetized Water on Nephropathy in Induced Type 2 Diabetes in Rat".

[This corrects the article DOI: 10.1155/2018/1785614.].

BDNF: mRNA expression in urine cells of patients with chronic kidney disease and its role in kidney function.

Podocyte loss and changes to the complex morphology are major causes of chronic kidney disease (CKD). As the incidence is continuously increasing over the last decades without sufficient treatment, it is important to find predicting biomarkers. Therefore, we measured urinary mRNA levels of podocyte genes NPHS1, NPHS2, PODXL and BDNF, KIM-1, CTSL by qRT-PCR of 120 CKD patients. We showed a strong correlation between BDNF and the kidney injury marker KIM-1, which were also correlated with NPHS1, suggesting podocytes as a contributing source. In human biopsies, BDNF was localized in the cell body and major processes of podocytes. In glomeruli of diabetic nephropathy patients, we found a strong BDNF signal in the remaining podocytes. An inhibition of the BDNF receptor TrkB resulted in enhanced podocyte dedifferentiation. The knockdown of the orthologue resulted in pericardial oedema formation and lowered viability of zebrafish larvae. We found an enlarged Bowman's space, dilated glomerular capillaries, podocyte loss and an impaired glomerular filtration. We demonstrated that BDNF is essential for glomerular development, morphology and function and the expression of BDNF and KIM-1 is highly correlated in urine cells of CKD patients. Therefore, BDNF mRNA in urine cells could serve as a potential CKD biomarker.

Protective Effect of Ginkgo biloba and Magnetized Water on Nephropathy in Induced Type 2 Diabetes in Rat.

We aimed in our current study to explore the protective effect of Ginkgo biloba (GB) and magnetized water (MW) against nephrotoxicity associating induced type 2 diabetes mellitus in rat. Here, we induced diabetes by feeding our lab rats on a high fat-containing diet (4 weeks) and after that injecting them with streptozotocin (STZ). We randomly divided forty rats into four different groups: nontreated control (Ctrl), nontreated diabetic (Diabetic), Diabetic+GB (4-week treatment), and Diabetic+MW (4-week treatment). After the experiment was finished, serum and kidney tissue samples were gathered. Blood levels of glucose, triglycerides, cholesterol, creatinine, and urea were markedly elevated in the diabetic group than in the control group. In all animals treated with GB and MW, the levels of urea, creatinine, and glucose were significantly reduced (all P < 0.01). GB and MW attenuated glomerular and tubular injury as well as the histological score. Furthermore, they normalized the contents of glutathione reductase and SOD2. In summary, our data showed that GB and MW treatment protected type 2 diabetic rat kidneys from nephrotoxic damages by reducing the hyperlipidemia, uremia, oxidative stress, and renal dysfunction.

The transcription factor Dach1 is essential for podocyte function.

Dedifferentiation and loss of podocytes are the major cause of chronic kidney disease. Dach1, a transcription factor that is essential for cell fate, was found in genome-wide association studies to be associated with the glomerular filtration rate. We found that podocytes express high levels of Dach1 in vivo and to a much lower extent in vitro. Parietal epithelial cells (PECs) that are still under debate to be a type of progenitor cell for podocytes expressed Dach1 only at low levels. The transfection of PECs with a plasmid encoding for Dach1 induced the expression of synaptopodin, a podocyte-specific protein, demonstrated by immunocytochemistry and Western blot. Furthermore, synaptopodin was located along actin fibres in a punctate pattern in Dach1-expressing PECs comparable with differentiated podocytes. Moreover, dedifferentiating podocytes of isolated glomeruli showed a significant reduction in the expression of Dach1 together with synaptopodin after 9 days in cell culture. To study the role of Dach1 in vivo, we used the zebrafish larva as an animal model. Knockdown of the zebrafish ortholog Dachd by morpholino injection into fertilized eggs resulted in a severe renal phenotype. The glomeruli of the zebrafish larvae showed morphological changes of the glomerulus accompanied by down-regulation of nephrin and leakage of the filtration barrier. Interestingly, glomeruli of biopsies from patients suffering from diabetic nephropathy showed also a significant reduction of Dach1 and synaptopodin in contrast to control biopsies. Taken together, Dach1 is a transcription factor that is important for podocyte differentiation and proper kidney function.

Impacts of fullerene C60 and virgin olive oil on cadmium-induced genotoxicity in rats.

Currently, cadmium is considered to be one of the major environmental pollutants. Environmentally, cadmium is released in various forms e.g. oxide, chloride and sulphide. The aim of the present study was to examine the genotoxic impact of fullerene nanoparticles C60 (C60) and virgin olive oil (VOO) on cadmium chloride (CdCl2)-induced genotoxicity in rats. To evaluate these effects on DNA damage and chromosomal frequency, 25 albino rats were randomly assigned to 5 groups (n=5 per group): Group 1 served as a control; Group 2 received a single intraperitoneal dose of CdCl2 (3.5mg/kg); Group 3 animals were treated with C60 (4mg/kg, orally) every other day for 20days; Group 4 received a single intraperitoneal dose of CdCl2 (3.5mg/kg) and an oral dose of C60 (4mg/kg); and Group 5 received a single intraperitoneal dose of CdCl2 (3.5mg/kg) and oral doses of VOO every other day for 20 consecutive days. Genotoxic and anti-genotoxic effects of C60 and VOO were evaluated in the liver, kidney and bone marrow using molecular and cytogenetic assays. As expected, CdCl2 and C60 administration was associated with band number alterations in both liver and kidney; however, C60 pretreatment recovered to approximately basal number. Surprisingly, C60 and VOO significantly attenuated the genotoxic effects caused by CdCl2 in livers and kidneys. In bone marrow, in addition to a reduction in the chromosomal number, several chromosomal aberrations were caused by CdCl2. These chromosomal alterations were also reversed by C60 and VOO. In conclusion, molecular and cytogenetic studies showed that C60 and VOO exhibit anti-genotoxic agents against CdCl2-induced genotoxicity in rats. Further studies are needed to investigate the optimal conditions for potential biomedical applications of these anti-genotoxic agents.

Effects of Spirulina platensis on DNA damage and chromosomal aberration against cadmium chloride-induced genotoxicity in rats.

Todays, bioactive compounds extracted from Spirulina platensis have been intensively studied for their therapeutical values. Therefore, in the present study, we aimed to evaluate the effects of S. platensis extract on DNA damage and chromosomal aberrations induced by cadmium in rats. Four groups of male albino rats (n = 7 rats) were used. The first group served as a control group and received distilled water. The second group was exposed intraperitoneally to cadmium chloride (CdCl2) (3.5 mg/kg body weight dissolved in 2 ml distilled water). The third group included the rats that were orally treated with S. platensis extract (1 g/kg dissolved in 5 ml distilled water, every other day for 30 days). The fourth group included the rats that were intraperitoneally and orally exposed to cadmium chloride and S. platensis, respectively. The experiment in all groups was extended for 60 days. The results of cadmium-mediated toxicity revealed significant genetic effects (DNA fragmentation, deletion or disappearance of some base pairs of DNA, and appearance of few base pairs according to ISSR-PCR analysis). Moreover, chromosomes showed structural aberrations such as reduction of chromosomal number, chromosomal ring, chromatid deletions, chromosomal fragmentations, and dicentric chromosomes. Surprisingly, S. platensis extract plus CdCl2-treated group showed less genetic effects compared with CdCl2 alone. Further, S. platensis extract upon CdCl2 toxicity was associated with less chromosomal aberration number and nearly normal appearance of DNA fragments as indicated by the bone marrow and ISSR-PCR analysis, respectively. In conclusion, the present novel study showed that co-treatment with S. platensis extract could reduce the genotoxic effects of CdCl2 in rats.

Protective effect of Nigella sativa on 4-nonylphenol-induced nephrotoxicity in Clarias gariepinus (Burchell, 1822).

The aim of this study was to examine the protective effects of Nigella sativa (N. sativa) on 4-Nonylphenol-induced nephrotoxicity in Clarias gariepinus. 30 fishes were divided into five groups: control, 4-nonylphenol-treated, 1% N. sativa treated, 2.5% N. sativa treated, and 5% N. sativa treated. N. sativa and 4-Nonylphenol were given for 3weeks. 4-NP and 4-NP-N. sativa treated fishes were compared with the control group. Kidney histology, immunochemistry, and electron microscope were assessed after 4-NP exposure. In the African catfish, 4-NP is mainly excreted through the kidney causing nephrotoxicity. Our results showed that 4-NP administration significantly disturbed the kidney structure and function. 4-NP treated fishes showed dilated glomerular vessels, fewer glomerular cells content, decreased expressions of glomerular proteins, and increased level of autophagy compared to control group (P<0.05). As N. sativa has different immunological and pharmacological effects such as anti-apoptotic and anti-oxidant, therefore, the administration of N. sativa with 4-Nonylphenol significantly minimize the nephrotoxic effect of 4-NP and maintain the normal kidney structure and function. Our novel study demonstrated for the first time that N. sativa could protect the kidney against 4-NP induced-nephrotoxicity.

Bony reconstruction of hip in cerebral palsy children Gross Motor Function Classification System levels III to V: a systematic review.

Hip dislocation is a common source of disability in cerebral palsy children. It has been remedied by various reconstructive procedures. This review aims at providing the best evidence for bony reconstructive procedures in cerebral palsy hip migration. The literature extraction process yielded 36 articles for inclusion in this review. There is fair evidence to indicate that the comparative effectiveness of femoral versus combined pelvifemoral reconstruction favours pelvifemoral reconstruction. All except one were retrospective articles with a significant degree of selection and performance bias and confounding variables that limited the validity and generalizability of the conclusions. The findings of this systematic review provide fair evidence for the use of adequate soft tissue and combined pelvifemoral reconstruction in the management of hip migration in none and minimally ambulatory cerebral palsy children in the short and long term. This has been shown in studies with a summed sizable patient population. There is limited evidence available that would support the use of soft-tissue and isolated femoral reconstruction. In the context of these retrospective and biased studies, it is extremely difficult to identify, with great precision, predictors of surgical success. Future studies should consider prospective designs that allow for bias control, strict patient selection criteria and incorporation of validated quality-of-life scales.

A Heterologous Model of Thrombospondin Type 1 Domain-Containing 7A-Associated Membranous Nephropathy.

Thrombospondin type 1 domain-containing 7A (THSD7A) is a target for autoimmunity in patients with membranous nephropathy (MN). Circulating autoantibodies from patients with THSD7A-associated MN have been demonstrated to cause MN in mice. However, THSD7A-associated MN is a rare disease, preventing the use of patient antibodies for larger experimental procedures. Therefore, we generated antibodies against the human and mouse orthologs of THSD7A in rabbits by coimmunization with the respective cDNAs. Injection of these anti-THSD7A antibodies into mice induced a severe nephrotic syndrome with proteinuria, weight gain, and hyperlipidemia. Immunofluorescence analyses revealed granular antigen-antibody complexes in a subepithelial location along the glomerular filtration barrier 14 days after antibody injection, and immunohistochemistry for rabbit IgG and THSD7A as well as ultrastructural analyses showed the typical characteristics of human MN. Mice injected with purified IgG from rabbit serum that was taken before immunization failed to develop any of these changes. Notably, MN developed in the absence of detectable complement activation, and disease was strain dependent. In vitro, anti-THSD7A antibodies caused cytoskeletal rearrangement and activation of focal adhesion signaling. Knockdown of the THSD7A ortholog, thsd7aa, in zebrafish larvae resulted in altered podocyte differentiation and impaired glomerular filtration barrier function, with development of pericardial edema, suggesting an important role of THSD7A in glomerular filtration barrier integrity. In summary, our study introduces a heterologous mouse model that allows further investigation of the molecular events that underlie MN.

Effect of a bradykinin-potentiating factor isolated from scorpion venom (Leiurus quinquestriatus) on some blood indices and lipid profile in irradiated rats.

Bradykinin appears to be an important regulator of cardiovascular function. It is also being increasingly noted as a participant in actions of drugs that affect the liver, kidney, and circulation. In our previous studies, bradykinin-potentiating factor (BPF) isolated from scorpion venom (Leiurus quinquestriatus) has been shown to be protective against hepato- and nephrotoxicity as well as healing skin burns by reducing oxidative stress in hyperglycemic conditions. Therefore, we aim to evaluate the ability of BPF in treating irradiated rats. A group of rats was exposed to γ-irradiation and subsequently treated with BPF injections aiming to elucidate the possibility of BPF to rescue γ-irradiation harmful effects. As controls, we used γ-irradiation exposed, BPF-injected, and untreated rats. The data obtained showed that the irradiated animals suffered from marked changes of many important blood parameters including red blood cells, leukocytes, platelets, hemoglobin, packed cell volume, high-density cholesterol, total cholesterol, triglycerides, and low-density cholesterol. Interestingly, BPF was able to rescue the deleterious effects of irradiation in rats and normalized their blood parameters to the basal levels. We conclude that BPF could ameliorate irradiation damaging effects.

MDM2 prevents spontaneous tubular epithelial cell death and acute kidney injury.

Murine double minute-2 (MDM2) is an E3-ubiquitin ligase and the main negative regulator of tumor suppressor gene p53. MDM2 has also a non-redundant function as a modulator of NF-kB signaling. As such it promotes proliferation and inflammation. MDM2 is highly expressed in the unchallenged tubular epithelial cells and we hypothesized that MDM2 is necessary for their survival and homeostasis. MDM2 knockdown by siRNA or by genetic depletion resulted in demise of tubular cells in vitro. This phenotype was completely rescued by concomitant knockdown of p53, thus suggesting p53 dependency. In vivo experiments in the zebrafish model demonstrated that the tubulus cells of the larvae undergo cell death after the knockdown of mdm2. Doxycycline-induced deletion of MDM2 in tubular cell-specific MDM2-knockout mice Pax8rtTa-cre; MDM2f/f caused acute kidney injury with increased plasma creatinine and blood urea nitrogen and sharp decline of glomerular filtration rate. Histological analysis showed massive swelling of renal tubular cells and later their loss and extensive tubular dilation, markedly in proximal tubules. Ultrastructural changes of tubular epithelial cells included swelling of the cytoplasm and mitochondria with the loss of cristae and their transformation in the vacuoles. The pathological phenotype of the tubular cell-specific MDM2-knockout mouse model was completely rescued by co-deletion of p53. Tubular epithelium compensates only partially for the cell loss caused by MDM2 depletion by proliferation of surviving tubular cells, with incomplete MDM2 deletion, but rather mesenchymal healing occurs. We conclude that MDM2 is a non-redundant survival factor for proximal tubular cells by protecting them from spontaneous p53 overexpression-related cell death.