High- Dose Agomelatine Combined to Haloperidol Decanoate Improves Cognition, Downregulating MT2, Against Upregulating D5, Maintaining Krüppel- Like Factor 9, Though Alters Cardiac Electrophysiology.

Haloperidol decanoate (HD) was implicated in cognitive impairment. Agomelatine (AGO) was claimed to improve cognition. We aimed at investigating the effects of HD + low- or high- dose AGO on cognition, verifying the melatonergic/dopaminergic-to-the cholinergic hypothesis of cognition and exploring relevant cardiovascular issues in adult male Wistar albino rats. HD + high- dose AGO prolonged the step through latency by +61.47% ( ρ < 0.0001), increased the time spent in bright light by +439.49% ( ρ < 0.0001), reduced the time spent in dim light by -66.25% ( ρ < 0.0001), and increased the percent of alternations by +71.25% ( ρ < 0.0001), despite the reductions in brain acetylcholine level by -10.67%, ( ρ < 0.0001) Neurodegeneration was minimal, while the mean power frequency of source wave was reduced by -23.39% ( ρ < 0.05). Concurrently, the relative expression of brain melatonin type-2 receptors was reduced by -18.75% (ρ < 0.05), against increased expressions of dopamine type- 5 receptors by +22.22% ( ρ < 0.0001) and angiopoietin-like 4 by +119.18% (ρ < 0.0001). Meanwhile, ECG demonstrated inverted P wave and reduced P wave duration by -36.15% ( ρ < 0.0001) and PR interval by -19.91% ( ρ < 0.0001), prolonged RR interval by +27.97% ( ρ < 0.05), increased R wave amplitude by +523.15% ( ρ < 0.0001), a depressed ST segment and inverted T wave. In rats administered AGO, HD, or HD+ low- dose AGO, Alzheimer's disease-like neuropathologic features were more evident, accompanied by extensive ECG and neurochemical alterations. HD + high- dose AGO enhances cognition but alters cardiac electrophysiology. Significance Statement Given the issue of cognitive impairment associated with haloperidol decanoate (HD) and the claimed cognitive enhancing activity of agomelatine (AGO), combined high- dose AGO to HD improved cognition of adult male rats, and exhibited minimal neurodegenerative changes. HD+ high- dose AGO was relatively safe regarding triggering epileptogenesis, while altered cardiac electrophysiology. In presence of low ACh, the melatonergic/dopaminergic hypothesis, added to ANGPTL4 and KLF9, could have some clue, thus, offering novel targets for pharmacologic manipulation of cognition.

EPI-X4, a CXCR4 antagonist inhibits tumor growth in pancreatic cancer and lymphoma models.

Endogenous peptide inhibitor for CXCR4 (EPI-X4) is a CXCR4 antagonist with potential for cancer therapy. It is a processed fragment of serum albumin from the hemofiltrate of dialysis patients. This study reports the efficacy of fifteen EPI-X4 derivatives in pancreatic cancer and lymphoma models. In vitro, the peptides were investigated for antiproliferation (cytotoxicity) by MTT assay. The mRNA expression for CXCR4 and CXCL12 was determined by RT-PCR, chip array and RNA sequencing. Chip array analysis yielded 634 genes associated with CXCR4/CXCL12 signaling. About 21% of these genes correlated with metastasis in the context of cell motility, proliferation, and survival. Expression levels of these genes were altered in pancreatic cancer (36%), lymphoma models (53%) and in patients' data (58%). EPI-X4 derivatives failed to inhibit cell proliferation due to low expression of CXCR4 in vitro, but inhibited tumor growth in the bioassays with significant efficacy. In the pancreatic cancer model, EPI-X4a, f and k inhibited mean tumor growth by > 50% and even caused complete remissions. In the lymphoma model, EPI-X4b, n and p inhibited mean tumor growth by > 70% and caused stable disease. Given the non-toxic and non-immunogenic properties of EPI-X4, these findings underscore its status as a promising therapy of pancreatic cancer and lymphoma and warrant further studies. SIMPLE SUMMARY: This study examined the value of chemokine receptor CXCR4 as an antineoplastic target for the endogenous peptide inhibitor of CXCR4 (EPI-X4), a 12-meric peptide derived from serum albumin. EPI-X4 inhibits CXCR4 interaction with its natural ligand, CXCL12 (SDF1). Therefore, malignancies (including pancreatic cancer and lymphoma) that depend on the CXCR4/CXCL12 pathway for progression can be targeted with EPI-X4. Of 634 genes that were linked to the CXCR4/CXCL12 pathway, 21% were associated with metastasis. In cultured human Suit2-007 pancreatic cancer cells, CXCR4 showed low to undetectable expression, which was why EPI-X4 did not inhibit pancreatic cancer cell proliferation. These findings were different in vivo, where CXCR4 was highly expressed and EPI-X4 inhibited tumor growth in rodents harboring pancreatic cancer or lymphoma. In the pancreatic cancer model, EPI-X4 derivatives a, f and k caused complete remissions, while in lymphomas EPI-X4 derivatives b, n and p caused stable disease.

Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol.

BACKGROUND: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease. OBJECTIVE: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol. METHODS: The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity. RESULTS: ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression. CONCLUSIONS: The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

White matter hyperintensities influence distal cortical ß-amyloid accumulation in default mode network pathways.

BACKGROUND AND PURPOSE: Cerebral small vessel disease (SVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Yet, the role of SVD in potentially contributing to AD pathology is unclear. The main objective of this study was to test the hypothesis that WMHs influence amyloid ß (Aß) levels within connected default mode network (DMN) tracts and cortical regions in cognitively unimpaired older adults. METHODS: Regional standard uptake value ratios (SUVr) from Aß-PET and white matter hyperintensity (WMH) volumes from three-dimensional magnetic resonance imaging FLAIR images were analyzed across a sample of 72 clinically unimpaired (mini-mental state examination ≥26), older adults (mean age 74.96 and standard deviation 8.13) from the Alzheimer's Disease Neuroimaging Initiative (ADNI3). The association of WMH volumes in major fiber tracts projecting from cortical DMN regions and Aß-PET SUVr in the connected cortical DMN regions was analyzed using linear regression models adjusted for age, sex, ApoE, and total brain volumes. RESULTS: The regression analyses demonstrate that increased WMH volumes in the superior longitudinal fasciculus were associated with increased regional SUVr in the inferior parietal lobule (p = .011). CONCLUSION: The findings suggest that the relation between Aß in parietal cortex is associated with SVD in downstream white matter (WM) pathways in preclinical AD. The biological relationships and interplay between Aß and WM microstructure alterations that precede overt WMH development across the continuum of AD progression warrant further study.

Expression profile of LncRNA ANRIL, miR-186, miR-181a, and MTMR-3 in patients with preeclampsia.

Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity and mortality worldwide. Several studies demonstrated the role of lncRNAs and miRNAs in the pathogenesis of preeclampsia; the aim was to detect the expression profiles of serum LncRNA ANRIL, miR-186, miR-181a, and MTMR-3 in patients with preeclampsia. The study included 160 subjects divided into 80 subjects considered as a control group, 80 patients with preeclampsia. We found that there was a significant difference between the preeclampsia and control groups with up-regulation of miR-186 median (IQR) = 4, 29 (1.35-7.73) (P < 0.0001), miR-181a median (IQR) = 2.45 (0.83-6.52) (P = 0.028), and downregulation of lncRNA ANRIL median (IQR) = 0.35(0.28-0.528) (P < 0.0001), MTMR median (IQR) = 0.32(0.155-1.11), (P < 0.0001). ROC curve of lncRNA ANRIL, miR-186, miR-181a, and MTMR-3 in preeclampsia patients showing the roles of these markers in the diagnosis of preeclampsia. In conclusion, serum LncRNA ANRIL, miR-186, miR-181a, and MTMR-3 could be promising biomarkers in the diagnosis of preeclampsia.

Comparable detection of nasopharyngeal swabs and induced sputum specimens for viral nucleic acid detection of suspected novel coronavirus (SARS-Cov-2) patients in Fayoum governorate, Egypt.

Background: The most commonly utilized samples for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) are nasopharyngeal swabs (NPS) and oropharyngeal swabs. However, there are some drawbacks. For SARS-CoV-2 detection, induced sputum might be analyzed and may be equivalent to pharyngeal swabs. This study was done to assess the potential superiority of induced sputum over NPS for SARS-CoV-2 detection. Sixty symptomatic COVID-19 patients who attended Fayoum University Hospitals in Fayoum Governorate, Egypt, were included in this cross-sectional descriptive study. Paired NPS and induced sputum samples were collected from each subject on the third and tenth days after symptoms began for RT-qPCR SARS-COV2 diagnosis. Results: At day 3, 52 (86.7%) of NPS and 48 (80.00%) of induced sputum specimens had positive RT-qPCR results with a significant statistical difference (P = 0.001). At day 10, 41 induced sputum samples (68.3%) were negative, while 19 (31.7%) were positive. Only three (5.0%) of the 19 positive induced sputum samples tested positive for NPS. NPS samples had a higher viral load than induced sputum samples at day 3 [25 (41.7%) vs. 23 (38.3%)]. At day 10, induced sputum samples had a higher viral load than NPS [9 (15.0%) vs. 6 (10.0%)]. A statistically significant positive correlation between the viral load value of the NPS and the induced sputum sample at day 3 (r = 0.497, p = 0.00) denoting similarity in the results of the two types of samples. By ROC analysis, the highest area under the curve for the overall CT value of the induced sputum was (0.604), with a statistically significant difference (p value = 0.0418). Conclusion: In the early stages of the disease, induced sputum and NPS tests had comparable results, but NPS yielded more false negative results later in the disease course than an induced sputum sample, which yielded higher sample positivity and viral load than NPS. Furthermore, induced sputum collection is a straightforward, non-invasive, and risk-free method. As a result, induced sputum could be useful for COVID-19 confirmation in patients with radiologically or epidemiologically suspected COVID-19 who have a negative NPS or in difficult-to-diagnose COVID-19 patients.

Amyloid-PET and White Matter Hyperintensities Have Independent Effects on Baseline Cognitive Function and Synergistic Effects on Longitudinal Executive Function.

Co-occurrence of beta amyloid (Aß) and white matter hyperintensities (WMHs) increase the risk of dementia and both are considered biomarkers of preclinical dementia. Moderation and mediation modeling were used to define the interplay between global and regional Aß and WMHs measures in relation to executive function (EF) and memory composite scores outcomes at baseline and after approximately 2 years across a sample of 714 clinically normal participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI 2). The moderation regression analysis showed additive effects of Aß and WMHs over baseline memory and EF scores (p = 0.401 and 0.061, respectively) and synergistic effects over follow-up EF (p < 0.05). Through mediation analysis, the data presented demonstrate that WMHs effects, mediated by global and regional amyloid burden, are responsible for baseline cognitive performance deficits in memory and EF. These findings suggest that Aß and WMHs contribute to baseline cognition independently while WMHs volumes exert effects on baseline cognitive performance directly and through influences on Aß accumulation.

Diagnostic and prognostic values of miR181b-5p and miR21-5p for neonatal sepsis risk and their link to SNAP II score and disease mortality.

Background: Neonatal sepsis is a lethal syndrome that necessitates prompt treatment to avoid disease complications. As a result, biomarkers that may either differentiate sepsis early or predict the outcome of sepsis are essential. Aim: The goal of this research was to find out the clinical weight of using miR181b-5p and miR21-5p expression levels as diagnostic and prognostic new genetic markers for neonatal sepsis. Method: A total of 60 neonates with sepsis and 60 healthy neonates were involved in this study. Laboratory tests include complete blood count (CBC), random blood sugar (RBS), arterial blood gases (ABG), and serum C-reactive protein (CRP). Neonates with sepsis were assessed by the Score for Neonatal Acute Physiology II (SNAP II). The serum fold changes of the target miRNAs were determined using qRT-PCR and the 2-ΔΔCt equation. Results: The relative serum level of miR181b-5p was [ median (IQR) = 0.2509 (0.0009-4.11)] and for miR21-5p was [median (IQR) = 0.07 (0.007-7.16)] which were significantly downregulated in patients with neonatal sepsis compared to controls (p < 0.001 each). There was a strong significant positive correlation between miR181b-5p and miR21-5p with r = 0.718 and p < 0.001. MiR181b-5p and miR21-5p were significantly negatively correlated with total leucocytic count (TLC), lymphocytic count, and CRP. While they were both positively correlated to the SNAP II score. Obvious association between higher expressions of target genes and higher SNAP II score groups. After a following-up period, twenty-two (36.7%) neonates died, while 38 (63.3%) of the babies became better and were released from the hospital. We reported that miR-181-5p, miR21-5p, SNAP II score and CRP were significantly higher in non-survivors than survivors. Only miR181b-5p, miR21-5p, and SNAP II were predictive factors of septic mortality. Conclusion: MiR181b-5p and miR21-5p are diagnostic and prognostic biomarkers of neonatal sepsis.

Serum lncRNAs, NBAT-1, and FOXCUT signature in hepatocellular carcinoma developed on top of chronic hepatitis C.

BACKGROUND: Hepatocellular Carcinoma (HCC) is a universal health problem responsible for 8.2% of all cancer deaths. Numerous risk factors were documented to be contributed to HCC development with viral hepatitis C ranking as the major predisposing factor in Egypt. The presence of a detectable amount of long noncoding RNAs (lncRNAs) in the circulation is linked to the development and spread of tumors. LncRNAs NBAT-1 and FOXCUT expression levels were used as genetic markers for the detection of gastrointestinal tract cancers. We hypothesized that serum expression levels of NBAT-1 and FOXCUT are new biomarkers for HCC that are related to laboratory and pathological markers. PATIENTS AND METHODS: This study included 165 hepatitis C virus (HCV)-related HCC Egyptian patients, 180 HCV-infected noncancer patients, and 180 healthy controls, the serum expression levels of NBAT-1 and FOXCUT were measured by using quantitative real-time polymerase chain reaction. RESULTS: This study's results include that medians (inter-quartile range [IQRs]) of NBAT-1 in HCC and HCV patients were (1.9 [0.87-4.94], 10.01 [7.34-13.29] respectively) which exhibited significantly higher expression than controls, while the medians (IQRs) of FOXCUT in HCC and HCV patients were (0.15 [0.04-0.52], 6.42 [2.49-10.10], respectively) that exhibited significantly lower expression than controls regarding HCC patients but significantly higher expression than controls regarding HCV patients. In comparing serum fold changes of NBAT-1 and FOXCUT between HCC patients and HCV patients; we obtained significantly higher levels of target genes in HCV patients (p < 0.001) than in HCC patients. Also, a positive correlation was detected between NBAT-1 and FOXCUT in HCC group (r = 0.262, p = 0.001) and in HCV group (r = 0.937, p < 0.001). Higher serum NBAT-1 and FOXCUT were significantly associated with better clinical and laboratory data of the disease. Multivariate regression analysis showed that FOXCUT was an independent predictor for HCC among HCV patients (p < 0.001). CONCLUSION: Our study cited that NBAT-1 and FOXCUT could be considered new diagnostic serum biomarkers for HCC on top of HCV.

Synthesis and molecular docking of new N4-piperazinyl ciprofloxacin hybrids as antimicrobial DNA gyrase inhibitors.

A series of N-4 piperazinyl ciprofloxacin derivatives as urea-tethered ciprofloxacin-chalcone hybrids 2a-j and thioacetyl-linked ciprofloxacin-pyrimidine hybrids 5a-i were synthesized. The target compounds were investigated for their antibacterial activity against S. aureus, P. aeruginosa, E. coli, and C. albicans strains, respectively. Ciprofloxacin derivatives 2a-j and 5a-i revealed broad antibacterial activity against either Gram positive or Gram negative strains, with MIC range of 0.06-42.23 µg/mL compared to ciprofloxacin with an MIC range of 0.15-3.25 µg/mL. Among the tested compounds, hybrids 2b, 2c, 5a, 5b, 5h, and 5i exhibited remarkable antibacterial activity with MIC range of 0.06-1.53 µg/mL against the tested bacterial strains. On the other hand, compounds 2c, 2e, 5c, and 5e showed comparable antifungal activity to ketoconazole against candida albicans with MIC range of 2.03-3.89 µg/mL and 2.6 µg/mL, respectively. Further investigations showed that some ciprofloxacin hybrids have inhibitory activity against DNA gyrase as potential molecular target compared to ciprofloxacin with IC50 range of 0.231 ± 0.01-7.592 ± 0.40 µM and 0.323 ± 0.02 µM, respectively. Docking studies of compounds 2b, 2c, 5b, 5c, 5e, 5h, and 5i on the active site of DNA gyrase (PDB: 2XCT) confirmed their ability to form stable complex with the target enzyme like that of ciprofloxacin.

Meningeal Tuberculoma Masquerading as a Brain Tumor: A Case Report.

Central nervous system (CNS) tuberculosis (TB) is a common extrapulmonary manifestation of TB. However, tuberculoma is a rare finding and meningeal tuberculoma is even rarer. This is a case report of a 47-year-old recent immigrant from Africa who presented with stroke-like symptoms. The human immunodeficiency virus (HIV) screening was reactive. Imaging revealed significant vasogenic edema surrounding a brain mass. Biopsy proved TB, and symptoms improved with steroids and anti-TB medication. This case serves to remind clinicians of a rare form of TB that can mimic brain tumors and strokes in presentation.

MiR-146a and miR-155 polymorphisms in Egyptian patients with Behcet's disease.

Introduction: The current study was designed to analyze whether polymorphisms of miR-146a and miR-155 are related to Behçet's disease (BD) in the Egyptian population. Material and methods: A total of 96 unrelated BD patients and 100 healthy subjects were genotyped for miR-146a (rs2910164) and miR-155 (rs767649) using real-time polymerase chain reaction. Results: The results showed significant elevation in the frequency of rs2910164 GG and CC genotypes in BD patients compared with controls (adjusted OR = 22.156, 95% CI: 4.728-103.818; p < 0.001 and adjusted OR = 40.358, 95% CI: 8.928-182.440; p < 0.001, respectively). Also, the rs2910164 G allele conferred a higher risk of developing BD (adjusted OR = 3.665, 95% CI: 2.013-6.671; p < 0.001). MiR-146a (rs2910164) polymorphism was a risk factor for susceptibility to BD in dominant, recessive and additive models of inheritance (all p < 0.001), while the miR-155 (rs767649) polymorphism was a risk factor in the recessive model only (p = 0.021). GG and CG genotypes of rs2910164 were associated with higher Behcet's disease current activity index (BDCAI) and ocular involvement compared with CC genotype (p = 0.005 and p = 0.004, respectively). Genotype AT of rs767649 was related to higher BDCAI (p = 0.026) compared with TT and AA genotypes. Conclusions: miR-146a (rs2910164) and miR-155 (rs767649) are likely to play an important role in the Egyptian population in development of BD and also influence disease severity.

Thymic Hyperplasia-Associated Autoimmune Encephalitis Mimicking Neuroleptic Malignant Syndrome: A Case Report.

Anti-NMDA (N-methyl-D-aspartate) receptor encephalitis is a common autoimmune encephalitis. It is commonly associated with underlying malignancy. We present a 24-year-old patient with sudden onset of behavioral changes and acute psychosis who was treated with antipsychotics followed by the development of generalized rigidity, facial twitching, and sympathetic overactivity. MRI and EEG were inconclusive. The neuroleptic malignant syndrome was presumed and bromocriptine was started. Multiple antiepileptics were started to control this twitching without success. NMDA receptor reactivity in the CSF established the diagnosis. Searching for underlying malignancy was unyielding except for an anterior mediastinal mass seen on the CT chest. The patient had only mild improvement in response to corticosteroids, plasmapheresis, and intravenous immunoglobulin (IVIG). Significant improvement was achieved after the thymectomy. This case serves to remind clinicians of key aspects of the disease including general rigidity and paroxysmal sympathetic hyperactivity, and the potential to confuse these with other diagnoses including neuroleptic malignant syndrome. This case is also unique in that the association with thymic hyperplasia is very rare and only a few cases were reported in English literature.

In Vitro Differential Sensitivity of Head and Neck Squamous Cell Carcinoma to Cisplatin, Silver Nanoparticles, and Photodynamic Therapy.

Background: The clinical effect of photodynamic therapy (PDT) may be correlated with the degree of dysplasia of cancer tissues. The aim of this study was to compare the effects of cisplatin, silver nanoparticles (AgNps), and photodynamic therapy (PDT) using methylene blue (MB) photosensitizer on Head and Neck squamous cell carcinoma - cell line (HNSCC), Hep-2, through genes expression. Methods: Hep-2 cells were divided into four groups: group I as control and without any treatment, group II and III were treated by cisplatin and AgNps, respectively, and group IV were incubated with MB for four minutes followed by PDT using laser irradiation at 650 nm for 8 minutes. The resulting toxicity was assessed in cell lines using MTT cytotoxicity assay. Further, apoptosis and the response to treatment was examined via RT-qPCR. Results: MB-PDT inhibited the proliferation of Hep-2 cells. Following PDT, compared with AgNps cells and via MTT assay, a highly significant decrease was observed in cell proliferation in Cancer cells treated with AgNps and MB- PDT groups compared to cancer group cells and cancer cells treated with Cisplatin (p value< 0.001). Mechanistically, both the mRNA and protein expression levels of Bcl-2, Caspase-3, Cyclin-D, HIF-1, IL-8, MAPK-38, and ROS were found to be down regulated in Hep-2 cell line after MB-PDT. Discussion: MB-PDT effectively killed Hep-2 cells in vitro, however, under the same conditions, the susceptibilities of the cell line to cisplatin, AgNps, and MB-PDT were different. Further studies are necessary to confirm whether this difference is present in clinical oral cancer lesions.

Amyloid-PET Levels in the Precuneus and Posterior Cingulate Cortices Are Associated with Executive Function Scores in Preclinical Alzheimer's Disease Prior to Overt Global Amyloid Positivity.

BACKGROUND: Global amyloid-ß (Aß) deposition in the brain can be quantified by Aß-PET scans to support or refute a diagnosis of preclinical Alzheimer's disease (pAD). Yet, Aß-PET scans enable quantitative evaluation of regional Aß elevations in pAD, potentially allowing even earlier detection of pAD, long before global positivity is achieved. It remains unclear as to whether such regional changes are clinically meaningful. OBJECTIVE: Test the hypothesis that early focal regional amyloid deposition in the brain is associated with cognitive performance in specific cognitive domain scores in pAD. METHODS: Global and regional standardized uptake value ratios (SUVr) from 18F-florbetapir PET/CT scanning were determined using the Siemens Syngo.via® Neurology software package across a sample of 99 clinically normal participants with Montreal Cognitive Assessment (MoCA) scores≥23. Relationships between regional SUVr and cognitive test scores were analyzed using linear regression models adjusted for age, sex, and education. Participants were divided into two groups based on SUVr in the posterior cingulate and precuneus gyri (SUVR≥1.17). Between group differences in cognitive test scores were analyzed using ANCOVA models. RESULTS: Executive function performance was associated with increased regional SUVr in the precuneus and posterior cingulate regions only (p < 0.05). There were no significant associations between memory and Aß-PET SUVr in any regions of the brain. CONCLUSION: These data demonstrate that increased Aß deposition in the precuneus and posterior cingulate (the earliest brain regions affected with Aß pathology) is associated with changes in executive function that may precede memory decline in pAD.

Administration of hemin ameliorates ovarian ischemia reperfusion injury via modulation of heme oxygenase-1 and p-JNK/p-NF-κBp65/iNOS signaling pathway.

AIMS: Ovarian torsion is the fifth common gynecological emergency that can affect females of all ages particularly during reproductive age and its management by detorsion leads to ovarian ischemia reperfusion (IR) injury. Therefore, prophylactic measures are required to protect the ovarian function after detorsion. So that, our study aimed to assess the effect and underlying mechanisms of heme oxygenase-1 (HO-1) inducer; hemin against ovarian damage induced by IR injury in rats. MAIN METHODS: Female rats were divided into: sham group, hemin group, ovarian IR (OIR) groups with and without hemin treatment. Serum levels of reduced glutathione (GSH) and interleukin 1 ß (IL-1ß) were measured in addition to ovarian levels of malondialdehyde (MDA), nitric oxide (NO) and superoxide dismutase (SOD). Ovarian phospho-Janus kinase (p-JNK) levels and gene expressions of HO-1 and inducible nitric oxide synthase (iNOS) were determined. Moreover, histopathological changes and expressions of phospho-nuclear factor kappa B p65 (p-NF-κB p65) and cleaved caspase-3 were done. KEY FINDINGS: Treatment of OIR rats with hemin led to significant attenuation of ovarian damage through histological examination which was associated with significant increase in ovarian expression of HO-1, ovarian SOD and serum GSH levels with significant decrease in ovarian p-JNK levels, expressions of p-NF-κB p65, iNOS and cleaved caspase-3 in addition to serum IL-1ß levels. SIGNIFICANCE: The protective effect of hemin can be attributed to the increased expression of HO-1 which showed antioxidant, anti-inflammatory and anti-apoptotic effects. Therefore, hemin can be administered to prevent ovarian IR injury which occurs after detorsion.

Serum miR-34a-5p and miR-199a-3p as new biomarkers of neonatal sepsis.

BACKGROUND: Neonatal sepsis is a serious condition. Recent clinical studies have indicated that microRNAs (miRNAs) are key players in the pathogenesis of sepsis, which could be used as biomarkers for this condition. PATIENTS AND METHODS: A total of 90 neonates with sepsis and 90 healthy neonates were enrolled in this study. qRT-PCR was performed to measure the expression levels of serum miR-34a-5p and miR-199a-3p. RESULTS: miR-34a-5p and miR-199a-3p serum levels were significantly reduced in neonates with sepsis compared with those in healthy neonates (P = 0.006 and P = 0.001, respectively). Significant correlations of miR-34a-5p and miR-199a-3p with each of TLC, RDW, RBS, and C-reactive protein (CRP) as well as SNAPII were observed, indicating their associations with the severity of neonatal sepsis. CONCLUSION: miR-34a-5p and miR-199a-3p may be useful as novel biomarkers in neonatal sepsis and may provide a new direction for its treatment.

Protective effect of hydrogen sulfide against stress-induced lung injury: involvement of Nrf2, NFκB/iNOS, and HIF-1α signaling pathways.

Stress is a common phenomenon that is attracting increasing attention. Hydrogen sulfide (H2S) is a gasotransmitter that plays an important role in many physiological and pathological events. Our study aimed to estimate the effect and the underlying mechanisms of the H2S donor, sodium hydrosulfide (NaHS), against immobilization stress (IS)-induced lung injury. Forty adult male rats were classified into control group, NaHS group, and IS groups with and without NaHS treatment. Serum was obtained to determine corticosterone (CORT), total antioxidant capacity (TAC), tumor necrosis factor-α (TNF-α), and interleukin-10 (IL-10) levels. Lung H2S, nitric oxide (NO), inducible nitric oxide synthase (iNOS), and malondialdehyde (MDA) levels were measured. Lung expressions of H2S synthesizing enzymes and Western blot analysis of nuclear factor erythroid 2-related factor 2 (Nrf2) and hypoxia-inducible factor 1 alpha (HIF 1α) were estimated. Histopathological changes and immunohistochemical assessment of nuclear factor kappa B (NF-κB) and caspase-3 were also done. Pretreatment with NaHS led to marked histological protection from lung damage seen in IS rats. Furthermore, pretreatment with NaHS before IS protected lung H2S levels and expressions of H2S-synthesizing enzymes. Similarly, the levels of CORT, TNF-α, IL-10, MDA, TAC, NO, iNOS, HIF-1 α, and nuclear Nrf2 and expressions of NF-kB and caspase 3 were all maintained at near control levels in contrast to that in the IS rats. In conclusion, NaHS is protective against stress-induced lung injury due to its antioxidant, anti-inflammatory, anti-fibrotic, and antiapoptotic effects. Thus, NaHS can be used to minimize stress complications on lung.

Muscle adaptation to sleeve gastrectomy: Potential role of nutritional supplementation and physical exercise.

Skeletal muscle is metabolically and functionally flexible and contractile under normal conditions. Obesity is a risk factor that causes metabolic disorders and reduces muscle contractility. Sleeve gastrectomy (SG) has been used for surgical correction of obesity. This work aimed to investigate how obesity and its surgical correction affects skeletal muscle and the possible role of nutritional supplementation and physical exercise. Adult male albino rats were randomly divided into five groups, 8 rats per group: group Ia (control non-obese), group Ib (control obese), group II (post-operative, SG), group III (post SG + nutritional supplementation) and group IV (post SG + nutritional supplementation + physical exercise). SG resulted in cellular and metabolic degenerative disorders in the muscle including wasting, weakness and fibrosis with elevated inflammatory, oxidative and injury markers. Nutritional supplementation induced the post SG muscle regeneration indicated by high expression of insulin growth factor-1 (IGF-1) and myogenin and low expression of transforming growth factor beta 1 (TGF-ß1). Interestingly, it improved the metabolic state of the muscle by reducing the oxidative stress, inflammatory and muscle injury markers and delaying the onset of fatigue. What is more, physical exercise along with nutritional supplementation resulted in further improvement of the muscle metabolic state and function. In conclusion, nutritional supplementations together with physical exercise after SG are essential for preserving muscle mass and contractility and improving its metabolic and functional status.

GAS5 rs2067079 and miR-137 rs1625579 functional SNPs and risk of chronic hepatitis B virus infection among Egyptian patients.

Hepatitis B virus (HBV) infection is a significant health issue worldwide.. We attempted to fulfill the molecular mechanisms of epigenetic and genetic factors associated with chronic HBV (CHBV). Expression levels of the lncRNA growth arrest-specific 5 (GAS5) and miR-137 and their corresponding SNPs, rs2067079 (C/T) and rs1625579 (G/T) were analyzed in 117 CHBV patients and 120 controls to investigate the probable association between these biomarkers and CHBV pathogenesis in the Egyptian population. Serum expression levels of GAS5 and miR-137 were significantly down-regulated in cases vs controls. Regarding GAS5 (rs2067079), the mutant TT genotype showed an increased risk of CHBV (p < 0.001), while the dominant CC was a protective factor (p = 0.004). Regarding miR-137 rs1625579, the mutant genotype TT was reported as a risk factor for CHBV (p < 0.001) and the normal GG genotype was a protective factor, p < 0.001. The serum GAS5 was significantly higher in the mutant TT genotype of GAS5 SNP as compared to the other genotypes (p = 0.007). Concerning miR-137 rs1625579, the mutant TT genotype was significantly associated with a lower serum expression level of miR-137 (p = 0.018). We revealed the dysregulated expression levels of GAS5 and miR-137 linked to their functioning SNPs were associated with CHBV risk and might act as potential therapeutic targets.