Acrylamide exposure induces growth retardation, neurotoxicity, stress, and immune/antioxidant disruption in Nile tilapia (Oreochromis niloticus): The alleviative effects of Chlorella vulgaris diets.

This study looked at the toxic impacts of water-born acrylamide (ACR) on Nile tilapia (Oreochromis niloticus) in terms of behaviors, growth, immune/antioxidant parameters and their regulating genes, biochemical indices, tissue architecture, and resistance to Aeromonas hydrophila. As well as the probable ameliorative effect of Chlorella vulgaris (CV) microalgae as a feed additive against ACR exposure was studied. The 96-h lethal concentration 50 of ACR was investigated and found to be 34.67 mg/L for O. niloticus. For the chronic exposure study, a total of 180 healthy O. niloticus (24.33 ± 0.03 g) were allocated into four groups in tri-replicates (15 fish/replicate), C (control) and ACR groups were fed a basal diet and exposed to 0 and 1/10 of 96-h LC50 of ACR (3.46 mg/L), respectively. ACR+ CV5 and ACR+ CV10 groups were fed basal diets with 5 % and 10 % CV supplements, respectively and exposed to 1/10 of 96-h LC50 of ACR for 60 days. After the exposure trial (60 days) the experimental groups were challenged with A. hydrophila. The findings demonstrated that ACR exposure induced growth retardation (P˂0.01) (lower final body weight, body weight gain, specific growth rate, feed intake, protein efficiency ratio, final body length, and condition factor as well as higher feed conversion ratio). A substantial decrease in the immune/antioxidant parameters (P˂0.05) (lysozyme, serum bactericidal activity %, superoxide dismutase, and reduced glutathione) and neurotransmitter (acetylcholine esterase) (P˂0.01) was noticed with ACR exposure. A substantial increase (P˂0.01) in the serum levels of hepato-renal indicators, lipid peroxidation biomarker, and cortisol was noticed as a result of ACR exposure. ACR exposure resulted in up-regulation (P˂0.05) of the pro-inflammatory cytokines and down-regulation (P˂0.05) of the antioxidant-related gene expression. Furthermore, the hepatic, renal, brain, and splenic tissues were badly affected by ACR exposure. ACR-exposed fish were more sensitive to A. hydrophila infection and recorded the lowest survival rate (P˂0.01). Feeding the ACR-exposed fish with CV diets significantly improved the growth and immune/antioxidant status, as well as modulating the hepatorenal functions, stress, and neurotransmitter level compared to the exposed-non fed fish. In addition, modulation of the pro-inflammatory and antioxidant-related gene expression was noticed by CV supplementation. Dietary CV improved the tissue architecture and increased the resistance to A. hydrophila challenge in the ACR-exposed fish. Noteworthy, the inclusion of 10 % CV produced better results than 5 %. Overall, CV diets could be added as a feed supplement in the O. niloticus diet to boost the fish's health, productivity, and resistance to A. hydrophila challenge during ACR exposure.

Impact of CD 28, CD86, CTLA-4 and PD-1 genes polymorphisms on acute renal allograft rejection and graft survival among Egyptian recipients.

To study the impact of four gene polymorphisms on acute renal allograft rejection (AR) and graft survival among Egyptian population. These 4 gene polymorphisms include: (1) CD 28 (rs3116496), (2) CD86 (rs1129055), (3) CTLA-4 (rs3087243), (4) PD-1 (rs2227982). This is a non-concurrent cohort study including 50 kidney transplant recipients diagnosed histopathologically as (AR) [study group] and another 50 matched allograft recipients without AR [control group]. Blood samples were taken from both groups and subjected to genotyping for the selected four genetic polymorphisms by TaqMan genotyping assay. The difference in genotypic distribution of CD 28: rs3116496 and CD86: rs1129055 wasn't statistically significant between the study and control groups (P = 0.22 and 0.33 respectively) and also both polymorphisms had no effect on graft survival (P = 0.36 and 0.74 respectively) while the addition of C allele to IVS3 +17T/C polymorphism in CD28 gene showed a protective effect against AR (P = 0.03). CTLA-4: rs3087243 AG genotype showed a protective effect against AR as it was more frequent in no rejection group compared to those with AR (P = 0.001) with a statistically significant impact on graft survival (P < 0.001), while PD-1: rs2227982 AG genotype was equally distributed between both groups (variant of unknown significance). There was no detected association between CD86 polymorphism: rs1129055 and CD 28 polymorphism: rs3116496 with the development of AR. However, C allele of CD 28 IVS3 +17T/C polymorphism and CTLA-4 polymorphism: rs3087243AG genotype both demonstrated a protective effect against AR.

Impact of corticosteroid administration on the response of exposed dental pulp to capping with bioactive cements-experimental study on mongrel dogs.

BACKGROUND: Corticosteroids are commonly used as a treatment for a variety of pathological conditions, however, systemic corticosteroid administration has adverse effects including impaired immune response and wound healing. Such complications may affect pulp healing after direct pulp capping. The current study evaluated the influence of corticosteroids on the healing ability of exposed dogs' dental pulps after direct pulp capping (DPC) with bioactive materials. METHODS: Ten healthy male dogs were assigned randomly into two groups, 5 dogs each: group I represent the control group which did not receive any medication, and group II was given corticosteroid for 45 days before DPC and till the dogs were euthanized (n = 75 teeth for each group). Following mechanical exposure, the pulps were randomly capped with either Ca(OH)2, MTA, or Biodentine. The pulpal tissues' reaction to the capping materials was evaluated 65 days postoperatively according to the following parameters: calcific bridge formation, pulpal inflammation, pulp necrosis, and bacterial infiltration. RESULTS: The corticosteroid-treated group revealed no significant difference compared to the control group concerning the pulp healing response (P > 0.05). Both Biodentine and MTA-treated specimens revealed significant differences with Ca(OH)2-treated specimens (P < 0.05) which displayed a superior positive effect of both MTA and Biodentine to Ca(OH)2 regarding all the parameters. CONCLUSIONS: Direct pulp capping technique whenever indicated in subjects treated with corticosteroid immunosuppressive drugs like prednisone performed well in aseptic conditions especially when capped with bioactive materials.

Karyomegalic interstitial nephritis as a rare cause of kidney graft dysfunction: case report and review of literature.

Karyomegalic interstitial nephritis (KIN) is a rare cause of chronic interstitial nephritis characterized by enlarged renal tubular epithelial nuclei. The first case of KIN reported in a kidney graft was in 2019. Here, we report the first case of KIN in 2 brothers receiving kidneys from 2 different unrelated living donors. A male kidney transplant recipient with focal segmental glomerulosclerosis as the original kidney disease presented with graft impairment and proteinuria, and graft biopsy revealed KIN. This patient had a brother who was also a kidney transplant recipient and had one episode of graft impairment and was diagnosed with KIN as well.

HSAS-MD Analyzer: A Hybrid Security Analysis System Using Model-Checking Technique and Deep Learning for Malware Detection in IoT Apps.

Established Internet of Things (IoT) platforms suffer from their inability to determine whether an IoT app is secure or not. A security analysis system (SAS) is a protective shield against any attack that breaks down data privacy and security. Its main task focuses on detecting malware and verifying app behavior. There are many SASs implemented in various IoT applications. Most of them build on utilizing static or dynamic analysis separately. However, the hybrid analysis is the best for obtaining accurate results. The SAS provides an effective outcome according to many criteria related to the analysis process, such as analysis type, characteristics, sensitivity, and analysis techniques. This paper proposes a new hybrid (static and dynamic) SAS based on the model-checking technique and deep learning, called an HSAS-MD analyzer, which focuses on the holistic analysis perspective of IoT apps. It aims to analyze the data of IoT apps by (1) converting the source code of the target applications to the format of a model checker that can deal with it; (2) detecting any abnormal behavior in the IoT application; (3) extracting the main static features from it to be tested and classified using a deep-learning CNN algorithm; (4) verifying app behavior by using the model-checking technique. HSAS-MD gives the best results in detecting malware from malicious smart Things applications compared to other SASs. The experimental results of HSAS-MD show that it provides 95%, 94%, 91%, and 93% for accuracy, precision, recall, and F-measure, respectively. It also gives the best results compared with other analyzers from various criteria.

Stent-Save a Life international survey on the practice of primary percutaneous coronary intervention during the COVID-19 pandemic.

Aim: To assess the impact of the COVID-19 pandemic on admissions of patients with acute coronary syndromes (ACS) and primary percutaneous coronary intervention (PPCI) in countries participating in the Stent-Save a Life (SSL) global initiative. Methods and Results: We conducted a multicenter observational survey to collect data on patient admissions for ACS, ST-elevation myocardial infarction (STEMI) and PPCI in participating SSL member countries through a period during the COVID-19 outbreak (March and April 2020) compared with the equivalent period in 2019. Of the 32 member countries of the SSL global initiative, 17 agreed to participate in the survey (three in Africa, five in Asia, six in Europe and three in Latin America). Overall reductions of 27.5% and 20.0% were observed in admissions for ACS and STEMI, respectively. The decrease in PPCI was 26.7%. This trend was observed in all except two countries. In these two, the pandemic peaked later than in the other countries. Conclusions: This survey shows that the COVID-19 outbreak was associated with a significant reduction in hospital admissions for ACS and STEMI as well as a reduction in PPCI, which can be explained by both patient- and system-related factors.

Objetivos: Avaliar o impacto da pandemia COVID-19 nas admissões de doentes com síndromes coronárias agudas (SCA) e angioplastia coronária primária (PPCI) em países que participam da iniciativa global Stent-Save a Life (SSL). Métodos e resultados: Realizámos estudo observacional multicêntrico para coletar dados sobre admissões de doentes por ACS, STEMI e PPCI nos países participantes no SSL durante um período do surto COVID-19 (março e abril de 2020) em comparação com o período homólogo de 2019. Dos 32 países membros da iniciativa global SSL, 17 aceitaram participar no estudo (3 de África, 5 da Ásia, 6 da Europa e 3 da América Latina (LATAM)). Observámos uma redução global de 27,5% e 20,0% nos internamentos com SCA e STEMI, respetivamente. A diminuição do PPCI foi de 26,7%. Essa tendência foi observada em todos os países, exceto dois. Nestes dois países, a pandemia atingiu o pico mais tarde do que nos restantes. Conclusões: Este estudo mostra que o surto de COVID-19 foi associado a uma redução significativa de admissões hospitalares por SCA e STEMI, bem como uma redução de PPCI, o que pode ser explicado por fatores relacionados com o doente e com o sistema.

Influence of selective immunosuppressive drug regimens on the healing of exposed dogs' dental pulp capped with a recent calcium silicate-based cement.

OBJECTIVES: In the clinical medicine, immunosuppressive drugs are used for an assortment of disorders, while their effect on the pulp healing is a controversial issue. This study evaluated the effect of different immunosuppressive drugs on the healing capacity of mechanically exposed dogs' dental pulps after direct pulp capping (DPC) with calcium silicate-based cement. MATERIALS AND METHODS: Twelve healthy male dogs were randomly allocated into four equal groups, 3 dogs each: group I allocated as a control group where no drugs were received; group П given prednisone (Pred); group III given a combination of Pred and cyclosporine A (CsA); and group IV given triple dose including Pred, CsA, and mycophenolate mofetil (MMF) for 45 days before the operative procedures and until the dogs were euthanized. In each dog, 16 class V cavities were prepared on the labial surfaces of anterior teeth. Following mechanical exposure, the pulps were capped with Biodentine, calcium silicate-based cement. The pulpal tissues response to Biodentine was assessed 65 days postoperatively. RESULTS: The pulp healing response was inferior in the Pred-CsA- and Pred-CsA-MMF-treated groups compared with the control and Pred-treated groups (P < 0.05). Non-significant difference was found between control and Pred-treated groups (P > 0.05). CONCLUSIONS: Within the limitation of this study, DPC with calcium silicate-based cement performed under strict aseptic condition for traumatically exposed dental pulp can be considered as a successful treatment option for those who receiving Pred immunosuppressive therapy. Meanwhile, DPC with those receiving a combination of Pred, CsA, and/or MMF immunosuppressive drug regimens demonstrated unfavorable results. CLINICAL RELEVANCE: Direct capping of mechanically exposed pulps with calcium silicate-based cement performed with special care for preventing infection considered a suitable strategic measure for preserving pulp vitality in patients receiving corticosteroid immunosuppressive drug.

Pulmonary sling in a patient with common arterial trunk.

We report a rare association of common arterial trunk with left pulmonary artery sling and highlight the importance of cross-sectional imaging in complex congenital cardiac lesions. The patient was antenatally diagnosed with common arterial trunk and underwent surgical repair in the neonatal period. At the age of 20 months, the patient presented with respiratory symptoms and increased right ventricular pressure. Multislice computed tomography demonstrated a pulmonary sling with compression of the distal trachea. Surgical correction of the pulmonary sling and change of the right ventricular to pulmonary artery conduit to a bigger size was performed.

Serial right ventricular assessment in patients with hypoplastic left heart syndrome: a multiparametric cardiovascular magnetic resonance study.

OBJECTIVES: The aim of this study was to assess single right ventricular (RV) function in a large cohort of hypoplastic left heart syndrome (HLHS) patients after the completion of total cavopulmonary connection by analysing serial cardiovascular magnetic resonance (CMR) studies. METHODS: CMR studies from 95 HLHS patients were analysed. RV end-diastolic and end-systolic volumes (RVEDV, RVESV), ejection fraction (RVEF) and long-axis strain (LAS) were measured from cine images. RESULTS: All 95 patients had at least 2 CMR scans and 35 patients had 3 CMR scans. The median age (first quartile-third quartile) at the 3 examinations was 4.2 (3.3-6.1), 9.4 (6.1-11.4) and 14.6 (11.8-16.8) years. RV indexed volumes (RVEDVi and RVESVi) increased from first to the second and from the first and second examination to the third examination in patients with >10 years of age (P < 0.05). There was a slight decrease in RVEF and LAS throughout the examinations, but this was not statistically significant. Correlations were found between RVEF and LAS (r = -0.23; P < 0.01). Both RVEF and LAS correlated with RVEDVi and RVESVi (r = -0.17 to 0.43; P < 0.05). CONCLUSIONS: Serial assessment of CMR studies in HLHS patients after total cavopulmonary connection completion demonstrate an increase in indexed RV volumes in older HLHS patients but only mild reduction in RVEF and LAS. The correlation of indexed RV volumes with RVEF and LAS together with the significant increase in RV volumes over time suggests that indexed RV volumes might be superior to RV functional markers to monitor the RV in HLHS patients.

Coronary artery ectasia in a child after arterial switch operation for transposition of the great arteries and suspected multisystem inflammatory syndrome in children associated with COVID-19: a case report.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) with features resembling Kawasaki disease has been reported in association with coronavirus disease 2019 (COVID-19). CASE SUMMARY: We report the rare case of a 22 months old boy with a history of operated simple transposition of the great arteries (TGA), who developed features of MIS-C likely to be associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection and involving the coronary arteries. Cardiovascular magnetic resonance imaging and cardiac catheterization showed long-distance ectasia of both coronary arteries after their origins and an origin stenosis of the right coronary artery with a perfusion defect. The patient was treated with oral anticoagulation together with antiplatelet therapy and remains under careful monitoring. DISCUSSION: This rare case demonstrates that also patients with TGA after the arterial switch operation (ASO) can develop coronary artery dilatation in association with MIS-C. The most interesting finding in this patient was that the origins of the reimplanted coronary arteries were not dilated. We speculate that scar tissue formation in the area of coronary artery transfer after ASO has prevented proximal coronary artery dilation.

Role of exopolysaccharides (EPSs) as anti-Mir-155 in cancer cells.

Micro-RNAs (MiRNAs) are a class of small non-coding RNAs that regulate cellular gene expression. MiR-155 overexpression has been implicated in many types of cancer. Besides, miR-155 appears to help tumor invasion and migration and works as a moderator of epithelial-to-mesenchymal transition (EMT). Exopolysaccharides (EPSs) are a large group of natural heterogeneous polymers of sugars with a biologically antitumor effect. Herein, we test a hypothesis that EPS might promote its anti-tumorigenic effect via regulating miR-155 expression and its target pathways. Expression of miR-155 and a panel of targeted genes were investigated by real-time PCR. In our study, we have succeeded in the extraction, purification of exopolysaccharide with great cytotoxicity to different cancer cell lines, HepG II, Caco-2, and MCF-7. We reported that EPSs have a suppression effect on the oncogenic miR-155. In conclusion, this work clarifies a new possible mechanism for the anti-tumorigenic effect of EPSs in cancer cells and provides insights into the biological pathways through which EPSs act. Moreover, it paves the way for new prospective cancer therapeutics as anti-miRNA.

Effect of Everolimus versus Bone Marrow-Derived Stem Cells on Glomerular Injury in a Rat Model of Glomerulonephritis: A Preventive, Predictive and Personalized Implication.

Glomerular endothelial injury and effectiveness of glomerular endothelial repair play a crucial role in the progression of glomerulonephritis. Although the potent immune suppressive everolimus is increasingly used in renal transplant patients, adverse effects of its chronic use have been reported clinically in human glomerulonephritis and experimental renal disease. Recent studies suggest that progenitor stem cells could enhance glomerular endothelial repair with minimal adverse effects. Increasing evidence supports the notion that stem cell therapy and regenerative medicine can be effectively used in pathological conditions within the predictive, preventive and personalized medicine (PPPM) paradigm. In this study, using an experimental model of glomerulonephritis, we tested whether bone marrow-derived stem cells (BMDSCs) could provide better effect over everolimus in attenuating glomerular injury and improving the repair process in a rat model of glomerulonephritis. Anti-Thy1 glomerulonephritis was induced in male Sprague Dawley rats by injection of an antibody against Thy1, which is mainly expressed on glomerular mesangial cells. Additional groups of rats were treated with the immunosuppressant everolimus daily after the injection of anti-Thy1 or injected with single bolus dose of BMDSCs after one week of injection of anti-Thy1 (n = 6-8). Nine days after injection of anti-Thy1, glomerular albumin permeability and albuminuria were significantly increased when compared to control group (p < 0.05). Compared to BMDSCs, everolimus was significantly effective in attenuating glomerular injury, nephrinuria and podocalyxin excretion levels as well as in reducing inflammatory responses and apoptosis. Our findings suggest that bolus injection of BMDSCs fails to improve glomerular injury whereas everolimus slows the progression of glomerular injury in Anti-Thy-1 induced glomerulonephritis. Thus, everolimus could be used at the early stage of glomerulonephritis, suggesting potential implications of PPPM in the treatment of progressive renal injury.

Prosthetic graft replacement of a large subclavian aneurysm in a child with Loeys-Dietz syndrome: a case report.

BACKGROUND: Loeys-Dietz syndrome (LDS) is a genetic connective tissue disorder, which is characterized by rapid development of aortic and peripheral arterial aneurysms. Loeys-Dietz syndrome has some overlapping phenotypic features with other inherited aortopathies such as Marfan syndrome. However, LDS has a more aggressive vascular course with patient morbidity and mortality occurring at an early age. CASE SUMMARY: We present the rare case of an 11-year-old girl with LDS who underwent valve sparing aortic root replacement at the age of 2.9 years with good results. She had routine follow-up cardiovascular magnetic resonance imaging and was found to have a large aneurysm of the right subclavian artery. After multidisciplinary team discussion, successful surgical resection with prosthetic graft replacement of the right subclavian artery was performed. DISCUSSION: This case illustrates that large aneurysms of aortic branches can already develop in childhood and underlines the need for frequent follow-ups including cross-sectional imaging and multidisciplinary team management.

Insulin Resistance and Hepatitis C Virus-Associated Subclinical Inflammation Are Hidden Causes of Pruritus in Egyptian Hemodialysis Patients: A Multicenter Prospective Observational Study.

BACKGROUND: Pruritus is one of the most common and disturbing symptoms in hemodialysis (HD) patients. The pathogenesis of pruritus in HD patients is multifactorial; however, a little progress in understanding this pathogenesis has been achieved. OBJECTIVES: To evaluate the frequency and risk factors of pruritus among HD patients in Dakahlia, Egypt. METHODS: A total of 193 patients from 4 HD centers were included in this study. Pruritus intensity was assessed by visual analog scale. All patients were assessed by clinical and laboratory parameters, such as age, sex, duration of dialysis, dialysis adequacy, urea, calcium, phosphorus, parathyroid hormone, fasting insulin, fasting sugar, HOMA-IR, serum ferritin, high-sensitive C-reactive protein (hs-CRP) and hemoglobin. They were also investigated for hepatitis C virus (HCV) infection by HCV enzyme-linked immunosorbent assay, HCV-PCR for plasma and buffy coat for further detection of occult HCV infection. RESULTS: Male gender, dialysis duration, inadequate dialysis, anemia, high ferritin, hyperphosphatemia, hypocalcemia, hs-CRP, and insulin resistance were characteristic features in pruritic patients (p = 0.01, 0.006, 0.0001, 0.047, 0.01, 0.0001, 0.024, 0.000, and 0.0001, respectively). Significant positive correlations were found between pruritus score and each of age (p = 0.002, r = 0.222), duration of dialysis (p = 0.03, r = 0.151), serum ferritin (p = 0.001, r = 0.213), serum phosphorus (p = 0.0001, r = 0.59), fasting insulin (p = 0.001, r= 0.273), and HOMA-IR (p = 0.0001, r = 0.349), while there was a negative correlation with Kt/V (p= 0.0001, r = -0.459). Linear multivariate regression analysis showed that age, duration of dialysis, serum phosphorus, Kt/v, and hs-CRP were good predictors for pruritic score in HD patients. All HCV-infected patients (who were positive for both plasma and buffy coat HCV-PCR) had pruritus with -significantly higher pruritus score than non-infected patients (p = 0.009), they also showed significantly higher fasting insulin, HOMA-IR, and hs-CRP levels (p = 0.0001). CONCLUSIONS: Uremic pruritus (UP) is a serious problem in HD patients. hs-CRP, male gender, dialysis duration, insulin resistance, dialysis inadequacy, and hyperphosphatemia are positively correlated with the intensity of UP. HCV infection is associated with severe UP, insulin resistance, and inflammation.

Fluoxetine induces direct inhibitory effects on mesenchymal stem cell­derived osteoprogenitor cells independent of serotonin concentration.

Selective serotonin reuptake inhibitors are the most commonly prescribed antidepressants worldwide, which have been reported to exert potential detrimental effects on bone mineral density and increase the risk of developing fractures. The present study aimed to investigate the pathways underlying the negative effects of fluoxetine on bone using mesenchymal stem cells (MSCs) derived from rat adipose tissue as a source of osteoprogenitor cells. MSCs were harvested from adipose tissue using a collagenase enzyme digestion method and were allowed to differentiate into osteoprogenitor cells. Various concentrations of fluoxetine were added to the cells, which were harvested and analyzed by flow cytometry to detect apoptotic markers Annexin V and caspase­3, in order to assess the levels of apoptosis. The levels of endogenous serotonin released in the extracellular matrix were measured using a serotonin ELISA kit. The underlying molecular pathways associated with the effects of fluoxetine on bone were investigated with reverse transcription­quantitative polymerase chain reaction. The results of the present study revealed a significant dose­dependent increase in apoptosis in response to increasing doses of fluoxetine, which was independent of serotonin levels in the culture supernatant. These findings indicated that fluoxetine exerted a direct inhibitory effect on bone cells via an apoptosis­dependent pathway. Furthermore, the expression levels of serotonergic genes, including serotonin 1B receptor, serotonin 2A receptor (HTR2A), serotonin 2B receptor and serotonin transporter, were down regulated; of these genes, HTR2A exhibited the highest expression levels. Further in vitro and in vivo studies are required to verify this association and to determine the molecular pathways involved in fluoxetine­induced bone loss. Fluoxetine­induced apoptosis of osteoprogenitor cells may be the mechanism underlying the increased incidence of bone loss observed in patients treated with fluoxetine.

siRNA Blocking of Mammalian Target of Rapamycin (mTOR) Attenuates Pathology in Annonacin-Induced Tauopathy in Mice.

Tauopathy is a pathological hallmark of many neurodegenerative diseases. It is characterized by abnormal aggregates of pathological phosphotau and somatodendritic redistribution. One suggested strategy for treating tauopathy is to stimulate autophagy, hence, getting rid of these pathological protein aggregates. One key controller of autophagy is mTOR. Since stimulation of mTOR leads to inhibition of autophagy, inhibitors of mTOR will cause stimulation of autophagy process. In this report, tauopathy was induced in mice using annonacin. Blocking of mTOR was achieved through stereotaxic injection of siRNA against mTOR. The behavioral and immunohistochemical evaluation revealed the development of tauopathy model as proven by deterioration of behavioral performance in open field test and significant tau aggregates in annonacin-treated mice. Blocking of mTOR revealed significant clearance of tau aggregates in the injected side; however, tau expression was not affected by mTOR blockage.

Bone marrow mesenchymal stem cell repair of cyclophosphamide-induced ovarian insufficiency in a mouse model.

OBJECTIVE: Attempting in vivo healing of cyclophosphamide-induced ovarian insufficiency in a mouse model using bone marrow mesenchymal stem cells (BMMSCs). METHODS: Female BALB/c white mice were used to prepare a model for premature ovarian failure by single intraperitoneal injection of cyclophosphamide (80 mg/kg). Ten mice were injected with BMMSCs and then sacrificed after 21 days for morphometric evaluation of the ovaries. Hormonal profile was evaluated while mice were being sacrificed. Another 10 mice were left for natural breeding with male mice, and 5 of these were injected with BMMSCs. Oocyte-like structures were obtained from 3 mice and were subjected to in vitro fertilization/intracytoplasmic sperm injection. RESULTS: Morphometric analysis of the ovaries demonstrated the presence of newly formed primordial follicles. Contribution of MSCs to the formation of these follicles was proven by a labeling technique. There was a drop in estradiol and rise in follicle-stimulating hormone levels, followed by resumption of the hormonal levels to near normal 21 days after MSCs therapy. The 5 mice that were injected with MSCs became pregnant after natural breeding. Fertilization and further division was reported in 5 oocytes subjected to intracytoplasmic sperm injection, but division did not continue. CONCLUSION: From this proof-of-concept trial, we can say that healing of damaged ovaries after chemotherapy in mice is possible using in vivo therapy with BMMSCs. This should open the gate for a series of animal studies that test the possibility of in vitro maturation of germinal epithelium of the ovary into mature oocytes.

Effect of intranasal stem cell administration on the nigrostriatal system in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. It affects the locomotor system, leading to a final severe disability through degeneration of dopaminergic neurons. Despite several therapeutic approaches used, no treatment has been proven to be effective; however, cell therapy may be a promising therapeutic method. In addition, the use of the intranasal (IN) route has been advocated for delivering various therapies to the brain. In the present study, the IN route was used for administration of mesenchymal stem cells (MSCs) in a mouse model of PD, with the aim to evaluate IN delivery as an alternative route for cell based therapy administration in PD. The PD model was developed in C57BL/6 mice using intraperitoneal rotenone administration for 60 consecutive days. MSCs were isolated from the mononuclear cell fraction of pooled bone marrow from C57BL/6 mice and incubated with micrometer-sized iron oxide (MPIO) particles. For IN administration, we used a 20 µl of 5×105 cell suspension. Neurobehavioral assessment of the mice was performed, and after sacrifice, brain sections were stained with Prussian blue to detect the MPIO-labeled MSCs. In addition, immunohistochemical evaluation was conducted to detect tyrosine hydroxylase (TH) antibodies in the corpus striatum and dopaminergic neurons in the substantia nigra pars compacta (SNpc). The neurobehavioral assessment revealed progressive deterioration in the locomotor functions of the rotenone group, which was improved following MSC administration. Histopathological evaluation of brain sections in the rotenone+MSC group revealed successful delivery of MSCs, evidenced by positive Prussian blue staining. Furthermore, rotenone treatment led to significant decrease in dopaminergic neuron number in SNpc, as well as similar decrease in the corpus striatum fiber density. By contrast, in animals receiving IN administration of MSCs, the degeneration caused by rotenone treatment was significantly counteracted. In conclusion, the present study validated that IN delivery of MSCs may be a potential safe, easy and cheap alternative route for stem cell treatment in neurodegenerative disorders.

Comparative study of allogenic and xenogeneic mesenchymal stem cells on cisplatin-induced acute kidney injury in Sprague-Dawley rats.

BACKGROUND: The paracrine and regenerative activities of mesenchymal stem cells (MSCs) may vary with different stem cell sources. The aim of the present study is to compare the effects of MSCs from different sources on acute kidney injury (AKI) induced by cisplatin and their influence on renal regeneration. METHODS: A single intraperitoneal injection of cisplatin (5 mg/kg) was used to induce AKI in 120 Sprague-Dawley rats. Rats were treated with either rat bone marrow stem cells (rBMSCs), human adipose tissue-derived stem cells (hADSCs), or human amniotic fluid-derived stem cells (hAFSCs). 5 × 10(6) MSCs of different sources were administered through rat tail vein in a single dose, 24 hours after cisplatin injection. Within each group, rats were sacrificed at the 4th, 7th, 11th, and 30th day after cisplatin injection. Serum creatinine, BUN, and renal tissue oxidative stress parameters were measured. Renal tissue was scored histopathologically for evidence of injury, regeneration, and chronicity. Immunohistochemistry was also done using Ki67 for renal proliferative activity evaluation. RESULTS: MSCs of the three sources were able to ameliorate cisplatin-induced renal function deterioration and tissue damage. The rat BMSCs-treated group had the lowest serum creatinine by day 30 (0.52 ± 0.06) compared to hADSCs and hAFSCs. All MSC-treated groups had nearly equal antioxidant activity as indicated by the decreased renal tissue malondialdehyde (MDA) and increased reduced glutathione (GSH) level and superoxide dismutase (SOD) activity at different time intervals. Additionally, all MSCs improved injury and regenerative scores. Rat BMSCs had the highest count and earliest proliferative activity in the renal cortex by day 7 as identified by Ki67; while, hAFSCs seem to have the greatest improvement in the regenerative and proliferative activities with a higher count of renal cortex Ki67-positive cells at day 11 and with the least necrotic lesions. CONCLUSIONS: Rat BMSCs, hADSCs, and hAFSCs, in early single IV dose, had a renoprotective effect against cisplatin-induced AKI, and were able to reduce oxidative stress markers. Rat BMSCs had the earliest proliferative activity by day 7; however, hAFSCs seemed to have the greatest improvement in the regenerative activities. Human ADSCs were the least effective in the terms of proliferative and regenerative activities.