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Angiotensin I converting enzyme (ACE1) maintains blood pressure homeostasis by converting angiotensin I into angiotensin II in the renin-angiotensin system (RAS). ACE1 is expressed in the brain, where an intrinsic RAS regulates complex cognitive functions including learning and memory. ACE1 has been implicated in neurodegenerative disorders including Alzheimer's disease and Parkinson's disease, but the mechanisms remain incompletely understood. Here, we performed single-nucleus RNA sequencing to characterize the expression of RAS genes in the hippocampus and discovered that Ace is mostly expressed in CA1 region excitatory neurons. To gain a deeper understanding of the function of neuronal ACE1, we generated ACE1 conditional knockout (cKO) mice lacking ACE1 expression specifically in hippocampal and cortical excitatory neurons. ACE1 cKO mice exhibited hippocampus-dependent memory impairment in the Morris water maze, y-maze, and fear conditioning tests. Total ACE1 level was significantly reduced in the cortex and hippocampus of ACE1 cKO mice showing that excitatory neurons are the predominant cell type expressing ACE1 in the forebrain. Despite similar reductions in total ACE1 level in both the hippocampus and cortex, the RAS pathway was dysregulated in the hippocampus only. Importantly, ACE1 cKO mice exhibited age-related capillary loss selectively in the hippocampus. Here, we show selective vulnerability of the hippocampal microvasculature and RAS pathway to neuronal ACE1 knockout. Our results provide important insights into the function of ACE1 in the brain and demonstrate a connection between neuronal ACE1 and cerebrovascular function in the hippocampus., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Clinical neurosciences, and psychiatry specifically, have been challenged by the lack of a comprehensive and practical framework that explains the core mechanistic processes of variable psychiatric presentations. Current conceptualization and classification of psychiatric presentations are primarily centered on a non-biologically based clinical descriptive approach. Despite various attempts, advances in neuroscience research have not led to an improved conceptualization or mechanistic classification of psychiatric disorders. This perspective article proposes a new-work-in-progress-framework for conceptualizing psychiatric presentations based on neural network components (NNC). This framework could guide the development of mechanistic disease classification, improve understanding of underpinning pathology, and provide specific intervention targets. This model also has the potential to dissolve artificial barriers between the fields of psychiatry and neurology., (Copyright © 2024 President and Fellows of Harvard College.)

Introduction: Angiotensin-converting enzyme (ACE) has been implicated in the metabolism of amyloid beta; however, the causal effect of ACE inhibition on risk of Alzheimer's disease (AD) dementia and other common dementias is largely unknown., Methods: We examined the causal association of genetically proxied ACE inhibition with four types of dementias using a two-sample Mendelian randomization (MR) approach., Results: Genetically proxied ACE inhibition was associated with increased risk of AD dementia (odds ratio per one standard deviation reduction in serum ACE [95% confidence interval]; 1.07 [1.04-1.10], P = 5 × 10 -07 ) and frontotemporal dementia (1.16 [1.04-1.29], P = 0.01) but not with Lewy body dementia or vascular dementia (P > 0.05). These findings were independently replicated and remained consistent in sensitivity analyses., Discussion: This comprehensive MR study provided genetic evidence for an association between ACE inhibition and the risk for AD and frontotemporal dementias. These results should encourage further studies of the neurocognitive effects of ACE inhibition., Highlights: This study evaluated genetically proxied angiotensin-converting enzyme (ACE) inhibition association with dementias. The results suggest an association between ACE inhibition and Alzheimer's disease. The results suggest an association between ACE inhibition and frontotemporal dementia. Those associations can be interpreted as potentially causal., (© 2023 the Alzheimer's Association.)

Objective: To examine whether genetically proxied lean mass is associated with risk of Alzheimer's disease., Design: Mendelian randomisation study., Setting: The UK Biobank study and genome wide association study meta-analyses of Alzheimer's disease and cognitive performance., Participants: Summary level genetic data from: 450 243 UK Biobank participants with impedance measures of lean mass and fat mass; an independent sample of 21 982 patients with Alzheimer's disease and 41 944 controls without Alzheimer's disease; a replication sample of 7329 patients with Alzheimer's disease and 252 879 controls; and 269 867 individuals taking part in a genome wide association study of cognitive performance., Main Outcome Measure: Effect of genetically proxied lean mass on the risk of Alzheimer's disease, and the related phenotype of cognitive performance., Results: An increase in genetically proxied appendicular lean mass of one standard deviation was associated with a 12% reduced risk of Alzheimer's disease (odds ratio 0.88, 95% confidence interval 0.82 to 0.95, P=0.001). This finding was replicated in an independent cohort of patients with Alzheimer's disease (0.91, 0.83 to 0.99, P=0.02) and was consistent in sensitivity analyses that are more robust to the inclusion of pleiotropic variants. Higher genetically proxied appendicular lean mass was also associated with increased cognitive performance (standard deviation increase in cognitive performance for each standard deviation increase in appendicular lean mass 0.09, 95% confidence interval 0.06 to 0.11, P=0.001), and adjusting for potential mediation through genetically proxied cognitive performance did not reduce the association between appendicular lean mass and risk of Alzheimer's disease. Similar results were found for the outcomes of Alzheimer's disease and cognitive performance when the risk factors of genetically proxied trunk lean mass and whole body lean mass were used, respectively, adjusted for genetically proxied fat mass., Conclusions: These findings suggest that lean mass might be a possible modifiable protective factor for Alzheimer's disease. The mechanisms underlying this finding, as well as the clinical and public health implications, warrant further investigation., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the British Heart Foundation Centre of Research Excellence for the submitted work; DG is employed part time by Novo Nordisk; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background and Objectives: Primary progressive aphasia (PPA) is a neurodegenerative syndrome of progressive language decline. PPA has 3 main subtypes: logopenic, semantic, and agrammatic. Observational studies suggested an association between language-related neurodevelopmental phenotypes and an increased risk of PPA. We sought to assess such relationships through Mendelian randomization (MR) approach, which can suggest potentially causal associations., Methods: Genome-wide significant single-nucleotide polymorphisms (SNPs) associated with dyslexia (42 SNPs), developmental speech disorders (29 SNPs), and left-handedness (41 SNPs) were used as genetic proxies for the exposures. Eighteen of 41 SNPs of left-handedness were associated with structural asymmetry of the cerebral cortex. Genome-wide association study summary statistics were obtained from publicly available databases for semantic (308 cases/616 controls) and agrammatic PPA (269 cases/538 controls). The logopenic PPA (324 cases/3,444 controls) was approximated by proxy through the rubric of clinically diagnosed Alzheimer disease with salient language impairment. Inverse-weighted variance MR was performed as the main analysis for testing the relationship between the exposures and outcomes. Sensitivity analyses were completed to test the robustness of the results., Results: Dyslexia, developmental speech disorders, and left-handedness were not associated with any PPA subtype ( p > 0.05). The genetic proxy of cortical asymmetry in left-handedness was significantly associated with agrammatic PPA (β = 4.3, p = 0.007), but not with other PPA subtypes. This association was driven by microtubule-related genes, primarily by a variant that is in complete linkage disequilibrium with MAPT gene. Sensitivity analyses were overall consistent with the primary analyses., Discussion: Our results do not support a causal association between dyslexia, developmental speech disorders, and handedness with any of the PPA subtypes. Our data suggest a complex association between cortical asymmetry genes and agrammatic PPA. Whether the additional association with left-handedness is necessary remains to be determined but is unlikely, given the absence of association between left-handedness and PPA. Genetic proxy of brain asymmetry (regardless of handedness) was not tested as an exposure due to lack of suitable genetic proxy. Furthermore, the genes related to cortical asymmetry associated with agrammatic PPA are implicated in microtubule-related proteins ( TUBA1B , TUBB , and MAPT ), which is keeping with the association of tau-related neurodegeneration in this PPA variant., (© 2023 American Academy of Neurology.)

Study Objectives: Narcolepsy often begins during adolescence and young adulthood, which are crucial periods for social development. The symptoms of narcolepsy likely impact social interactions, but little research has assessed the effects of narcolepsy on social relationships. The current study investigated the impact of narcolepsy on friendships and romantic and sexual relationships., Methods: Young adults (18-39 years) with narcolepsy were recruited through national narcolepsy patient organizations. Participants (n = 254) completed an online survey assessing their friendships and romantic and sexual relationships, including communication about their social relationships with medical providers., Results: All participants (mean age = 28.8 years; 87% female, 92% White/Caucasian) reported that narcolepsy made their social life more challenging. They reported receiving more support from significant others, compared to family or friends ( P < .05). Most (80%) indicated that narcolepsy currently impacted their sex life. Only a few participants reported that their providers asked about their social and sex lives, though they wanted providers to ask., Conclusions: Narcolepsy impacts social functioning in young adults. Many individuals with narcolepsy prioritize single, meaningful, romantic relationships as developing and sustaining new relationships may be challenging. In addition, narcolepsy symptoms impact sexual functioning. Though many participants wanted to discuss their social and sex lives with providers, only a few providers ask. Treatment of narcolepsy in young adulthood should include supporting individuals regarding the impact on social, romantic, and sexual health., Citation: Davidson RD, Biddle K, Nassan M, Scammell TE, Zhou ES. The impact of narcolepsy on social relationships in young adults. J Clin Sleep Med . 2022;18(12):2751-2761., (© 2022 American Academy of Sleep Medicine.)

Insomnia and restless leg syndrome (RLS) are associated with increased risk for suicidal behavior (SB), which is often comorbid with mood or thought disorders; however, it is unclear whether these relationships are causal. We performed a two-sample Mendelian randomization study using summary-level genetic associations with insomnia symptoms and RLS against the outcomes of risk of major depressive disorder (MDD), bipolar disorder (BP), schizophrenia (SCZ), and SB. The inverse-variance weighted method was used in the main analysis. We performed replication and sensitivity analyses to examine the robustness of the results. We identified outcome cohorts for MDD (n = 170,756 cases/329,443 controls), BP (n = 20,352/31,358), SCZ (n = 69,369/236,642), SB-Cohort-2019 (n = 6569/14,996 all with MDD, BP or SCZ; and SB within individual disease categories), and SB-Cohort-2020 (n = 29,782/519,961). Genetically proxied liability to insomnia symptoms significantly associated with increased risk of MDD (odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.2-1.26, P = 1.37 × 10 -61 ), BP (OR = 1.15, 95% CI = 1.07-1.23, P = 5.11 × 10 -5 ), SB-Cohort-2019 (OR = 1.17, 95% CI = 1.07-1.27, P = 2.30 × 10 -4 ), SB-Cohort-2019 in depressed patients (OR = 1.34, 95% CI = 1.16-1.54, P = 5.97 × 10 -5 ), and SB-Cohort-2020 (OR = 1.24, 95% CI = 1.18-1.3, P = 1.47 × 10 -18 ). Genetically proxied liability to RLS did not significantly influence the risk of any of the outcomes (all corrected P > 0.05). Results were replicated for insomnia with MDD and SB in Mass General Brigham Biobank and were consistent in multiple lines of sensitivity analyses. In conclusion, human genetic evidence supports for the first time a potentially independent and causal effect of insomnia on SB and encourages further clinical investigation of treatment of insomnia for prevention or treatment of SB., (© 2022. The Author(s).)

This study investigated the productive traits and some blood biochemical parameters of high-yielding Ayrshire dairy cows fed at different levels of Agro-Matic@LLC NGO, Russia (Agro-Matic (AM)) protein concentrate. A total of 45 high-yielding Ayrshire cows were selected and divided into three groups, each 15. The control group (0AM) fed the basal ration, while group two (1AM) and group three (2AM) fed a basal ration by replacing sunflower cake with different levels of AM (1 and 1.5 kg/head/day), respectively. Milk and blood samples were collected. The current results revealed that the ratio of rumen undegradable protein to rumen degradable protein during the period of lactation was significantly higher in the 1AM and 2AM compared with 0AM and represented (55.04, 62.14, and 41.73%), respectively. The 1AM had a beneficial effect on the digestibility of crude protein. Daily and whole fat-corrected milk (FCM 4 %) was significantly increased by 3 kg/day and 987 kg/entire lactation in 2AM when compared with 0AM, respectively. Blood total protein was significantly higher in the 1AM group (86.9 vs. 77.8 g/l) than the 0AM, while AM decreased urea concentration. Consequently, the inclusions of AM protein concentrate have a positive impact on increasing milk production and optimizing the rations in terms of the amount of non-digestible protein and the economic efficiency of milk production., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Buryakov, Aleshin, Buryakova, Zaikina, Nasr, Nassan and Fathala.)

Endogenous biological clocks, orchestrated by the suprachiasmatic nucleus, time the circadian rhythms that synchronize physiological and behavioural functions in humans. The circadian system influences most physiological processes, including sleep, alertness and cognitive performance. Disruption of circadian homeostasis has deleterious effects on human health. Neurodegenerative disorders involve a wide range of symptoms, many of which exhibit diurnal variations in frequency and intensity. These disorders also disrupt circadian homeostasis, which in turn has negative effects on symptoms and quality of life. Emerging evidence points to a bidirectional relationship between circadian homeostasis and neurodegeneration, suggesting that circadian function might have an important role in the progression of neurodegenerative disorders. Therefore, the circadian system has become an attractive target for research and clinical care innovations. Studying circadian disruption in neurodegenerative disorders could expand our understanding of the pathophysiology of neurodegeneration and facilitate the development of novel, circadian-based interventions for these disabling disorders. In this Review, we discuss the alterations to the circadian system that occur in movement (Parkinson disease and Huntington disease) and cognitive (Alzheimer disease and frontotemporal dementia) neurodegenerative disorders and provide directions for future investigations in this field., (© 2021. Springer Nature Limited.)

Several reasons may underlie the dramatic increase in type2 diabetes mellitus. One of these reasons is the genetic basis and variations. Vitamin D receptor polymorphisms are associated with different diseases such as rheumatoid arthritis and diabetes. The aim of this study is to investigate the possible association of two identified mutations ApaI (rs7975232) and TaqI (rs731236). Eighty-nine healthy individuals and Fifty-six Type 2 Diabetic (T2D) patients were investigated using RFLP technique for genotyping and haplotyping as well. The distribution of Apal genotypes was not statistically significant among the control (P=0.65) as well as for diabetic patients (P=0.58). For Taql allele frequencies of T allele was 0.61 where of G allele was 0.39. The frequency distribution of Taql genotypes was not statistically significant among the control (P=0.26) as well as diabetic patients (P=0.17). Relative risk of the allele T of Apa1 gene is 1.28 and the odds ratio of the same allele is 1.53, while both estimates were < 1.0 of the allele G. Similarly, with the Taq1 gene the relative risk and the odds ratio values for the allele T are 1.09 and 1.27 respectively and both estimates of the allele C were 0.86 for the relative risk and 0.79 for the odds ratio. The pairwise linkage disequilibrium between the two SNPs Taq1/apa1 was statistically significant in control group (D = 0.218, D' = 0.925 and P value < 0.001) and similar data in diabetic groups (D = 0.2, D' = 0.875 and P value < 0.001). These data suggest that the T allele of both genes Apa1 and Taq1 is associated with the increased risk of type 2 diabetes. We think that we need a larger number of volunteers to reach a more accurate conclusion.

The study was aimed to evaluate the therapeutic effects of Zizyphus oxyphyla leaves methanolic (ZOX-LME), on serum liver, kidney and hematology along with other serum parameters in Carbon tetrachloride (CCl4) intoxicated rabbits. Experimental animals were divided into five groups, six rabbits in each. These were: group NC (normal control), group, TC (toxic control) and group ST i.e. silymarine administered group at dose rate (50) mg/kg body weight (BW). Group ET1 and group ET2 treated with (ZOX-LME) at dose 200 mg/kg BW and 400 mg/kg BW. CCl4 administration caused significant (P> 0.05) impairment in serum liver enzymes, blood factors and other serum indices. Treatment with (ZOX-LME) significantly (P<0.05) reduced and normalized the levels of serum alanine transaminase (ALT) aspartate transaminase (AST) and alkaline phosphatase (ALP) and hematological indices. Also significant (P< 0.05) reduction was observed in creatinine, urea, uric acid, blood urea nitrogen (BUN), and albumin and glucose concentrations. The altered levels of lipid profile and serum electrolytes (Ca, Mg, Cl, Na, K, and P) were significantly (P<0.05) change toward normal levels with (ZOX-LME) feeding. In addition (ZOX-LME) ingestion caused significant improvement in GSH, GST and CAT levels, while reducing the TBARS levels, exhibited antioxidant capacity. Also (ZOX-LME) showed increase inhibition against percent scavenging of 2, 2-diphenile-1-picrylehydrazyle (DPPH) free radical. Significant (P<0.05) normalizing effects were observed with high dose 400 mg/kg BW of (ZOX-LME and were equivalent to silymarine administered groups. The histological study of liver supported the hepatoprotective and renal curative activity of (ZOX-LME).

Background: Bipolar disorder (BD) and borderline personality disorder (BPD) share overlapping phenomenology and are frequently misdiagnosed. This study investigated the diagnostic accuracy of the Mood Disorder Questionnaire (MDQ) and McLean Screening Instrument for Borderline Personality Disorder (MSI) in a clinical inpatient setting and whether individual screening items could differentiate BD from BPD., Methods: 757 sequential inpatients admitted to a Mood Disorder Unit completed both the MDQ and MSI. Screen positive for the MDQ was defined as ≥7/13 symptoms endorsed with concurrence and at least moderate impact. Screen positive for the MSI was defined as a score of ≥7. The clinical discharge summary diagnosis completed by a board-certified psychiatrist was used as the reference standard to identify concordance rates of a positive screen with clinical diagnosis. Individual items predicting one disorder and simultaneously predicting absence of other disorder by odds ratio (OR>and <1) were identified., Results: Both screening instruments were more specific than sensitive (MDQ 83.7%/ 67.8%, MSI 73.2% / 63.3%). MDQ individual items (elevated mood, grandiosity, increased energy, pressured speech, decreased need for sleep, hyperactivity) were significant predictors of BD diagnosis and non-predictors of BPD diagnosis. Whereas MSI subitem, self-harm behaviors/suicidal attempts predicted BPD in the absence of BD; distrust and irritability were additional predictors of BPD., Conclusion: While this study is limited by the lack of structured diagnostic interview, these data provide differential symptoms to discriminate BD and BPD. Further work with larger datasets and more rigorous bioinformatics machine learning methodology is encouraged to continue to identify distinguishing features of these two disorders to guide diagnostic precision and subsequent treatment recommendations., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Several antiepileptic drugs (AEDs) have US Food and Drug Administration (FDA) approval for use as mood stabilizers in bipolar disorder (BD), but not all BD patients respond to these AED mood stabilizers (AED-MSs). To identify genetic polymorphisms that contribute to the variability in AED-MS response, we performed a discovery genome-wide association study (GWAS) of 199 BD patients from the Mayo Clinic Bipolar Disorder Biobank. Most of these patients had been treated with the AED-MS valproate/divalproex and/or lamotrigine. AED-MS response was assessed using the Alda scale, which quantifies clinical improvement while accounting for potential confounding factors. We identified two genome-wide significant single-nucleotide polymorphism (SNP) signals that mapped to the THSD7A (rs78835388, P = 7.1E-09) and SLC35F3 (rs114872993, P = 3.2E-08) genes. We also identified two genes with statistically significant gene-level associations: ABCC1 (P = 6.7E-07; top SNP rs875740, P = 2.0E-6), and DISP1 (P = 8.9E-07; top SNP rs34701716, P = 8.9E-07). THSD7A SNPs were previously found to be associated with risk for several psychiatric disorders, including BD. Both THSD7A and SLC35F3 are expressed in excitatory/glutamatergic and inhibitory/γ-aminobutyric acidergic (GABAergic) neurons, which are targets of AED-MSs. ABCC1 is involved in the transport of valproate and lamotrigine metabolites, and the SNPs in ABCC1 and DISP1 with the strongest evidence of association in our GWAS are strong splicing quantitative trait loci in the human gut, suggesting a possible influence on drug absorption. In conclusion, our pharmacogenomic study identified novel genetic loci that appear to contribute to AED-MS treatment response, and may facilitate precision medicine in BD., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: The brain-derived neurotrophic factor (BDNF) rs6265 (Val66Met) Met allele is associated with early onset (≤ 19 years old) bipolar disorder (BD). Val66Met (G196A) creates a CpG site when the Val/G allele is present. We sought to study the methylation of the BDNF promoter and its interaction with Val66Met genotype in BD., Methods: Sex/age-matched previously genotyped DNA samples from BD-Type 1 cases [N = 166: early onset (≤ 19 years old) n = 79, late onset (> 20 years old) n = 87] and controls (N = 162) were studied. Pyrosequencing of four CpGs in Promoter-I, four CpGs in promoter-IV, and two CpGs in Promoter-IX (CpG2 includes G= Val allele) was performed. Logistic regression adjusting for batch effect was used to compare cases vs. controls. Analyses also included stratification by disease onset and adjustment for Val66Met genotype. Secondary exploratory analyses for the association of life stressors, comorbid substance abuse, and psychotropic use with methylation patterns were performed., Results: Comparing all BD cases vs. controls and adjusting for Val66Met genotype, BD cases had significantly higher methylation in promoter -IX/CPG-2 (p = 0.0074). This was driven by early onset cases vs. controls (p = 0.00039) and not late onset cases vs. controls (p = 0.2)., Limitation: Relatively small sample size., Conclusion: Early onset BD is associated with increased methylation of CpG site created by Val=G allele of the Val66Met variance. Further studies could include larger sample size and postmortem brain samples in an attempt to replicate these findings., Competing Interests: Declaration of Competing Interest Mark A. Frye: Previous Grant Support: Assurex Health, Mayo Foundation, Medibio. Consultancies: Actify Neurotherapies, Allergan, Intra-Cellular Therapies, Inc., Janssen, Myriad, Neuralstem Inc.,Takeda, Teva Pharmaceuticals. CME/Travel/Honoraria: American Physician Institute, CME Outfitters, Global Academy for Medical Education. None of the other authors have any reportable potential conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

This study explored the probable in vivo cardiac and renal toxicities together with in silico approaches for predicting the apoptogenic potential of Euphorbia peplus methanolic extract (EPME) in rats. Cardiac and renal injury biomarkers were estimated with histopathological and immunohistochemical evaluations of both kidney and heart. The probable underlying mechanism of E. peplus compounds to potentiate p53 activity is examined using Molecular Operating Environment (MOE) docking software and validated experimentally by immunohistochemical localization of p53 protein in the kidney and heart tissues. The gas chromatography/mass spectrometry analysis of E. peplus revealed the presence of nine different compounds dominated by di-(2-ethylhexyl) phthalate (DEHP). Significant elevations of troponin, creatine phosphokinase, creatine kinase-myocardium bound, lactate dehydrogenase, aspartate transaminase, alkaline phosphatase, urea, creatinine, and uric acid were evident in the EPME treated rats. The EPME treated rats showed strong renal and cardiac p53 expression and moderate cardiac TNF-α expression. Further, our in silico results predicted the higher affinity and good inhibition of DEHP, glyceryl linolenate, and lucenin 2 to the MDM2-p53 interface compared to the standard reference 15 a compound. Conclusively, EPME long-term exposure could adversely affect the cardiac and renal tissues probably due to their inflammatory and apoptotic activity. Moreover, the in silico study hypothesizes that EPME inhibits MDM2-mediated degradation of p53 suggesting possible anticancer potentials which confirmed experimental by strong p53 expression in renal and cardiac tissues.

Juniperus procera, a coniferous tree in the cypress family, is one of the famous medicinal plants traditionally used in the southern area of the Arabian peninsula. This study examined the anti-hyperglycemic action of Juniperus procera extract (JPE) on diabetic rats. Sixty male rats were divided into 6 equal groups: control, control treated with JPE (200 mg/kg), diabetic, diabetic treated with insulin (1 U/kg), diabetic treated with JPE (200 mg/kg), and diabetic treated with both insulin and JPE. Blood and tissue samples were collected for serum chemistry, gene expression, and immunohistochemistry analyses, the results of which revealed hyperglycemia and inflammation following diabetes induction. Administration of JPE alone or with insulin reduced the hyperglycemia reported in diabetic rats by 25 %. The immunohistochemical examination of pancreatic tissues demonstrated a moderate restoration of insulin and NF-κB expression in pancreatic and hepatic tissues. Significant recovery was observed for glutathione-S-transferase (GST), superoxide dismutase (SOD), and glutathione peroxidase (GPx) mRNA expression in the livers of rats treated with JPE. Administration of JPE led to similar amelioration of the mRNA expression of pyruvate kinase (PK) and phosphoenol pyruvate carboxy kinase (PEPCK) in the livers of diabetic rats. In addition, diabetic rats treated with insulin, JPE, or a combination of these agents demonstrated an improvement in the mRNA expression of IRS-1 and IRS-2 in hepatic and pancreatic tissues, reaching levels approaching normal. Our findings led us to conclude that JPE has a powerful anti-inflammatory effect accompanied by a moderate hypoglycemic effect that occurs via different mechanisms., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Mitochondrial DNA mutations have been reported to be associated with bipolar disorder (BD). In this study, we performed genome-wide analyses to assess mitochondrial single-nucleotide polymorphism (mtSNP) effects on BD risk and early-onset BD (EOBD) among BD patients, focusing on interaction effects between nuclear SNPs (nSNPs) and mtSNPs. Common nSNP and mtSNP data from European American BD cases ( n = 1,001) and controls ( n = 1,034) from the Genetic Association Information Network BD study were analyzed to assess the joint effect of nSNP and nSNP-mtSNP interaction on the risk of BD and EOBD. The effect of nSNP-mtSNP interactions was also assessed. For BD risk, the strongest evidence of an association was obtained for nSNP rs1880924 in MGAM and mtSNP rs3088309 in CytB ( p joint = 8.2 × 10 -8 , p int = 1.4 × 10 -4 ). Our results also suggest that the minor allele of the nSNP rs583990 in CTNNA2 increases the risk of EOBD among carriers of the mtSNP rs3088309 minor allele, while the nSNP has no effect among those carrying the mtSNP major allele (OR = 4.53 vs. 1.05, p joint = 2.1 × 10 -7 , p int = 1.16 × 10 -6 ). While our results are not statistically significant after multiple testing correction and a large-sample replication is required, our exploratory study demonstrates the potential importance of considering the mitochondrial genome for identifying genetic factors associated with BD.

In a prior discovery study, increased levels of serum Growth Differentiation Factor 15 (GDF15), Hepsin (HPN), and Matrix Metalloproteinase-7 (MMP7) were observed in bipolar depressed patients vs controls. This exploratory post-hoc analysis applied a proteomic-informed genomic research strategy to study the potential functional role of these proteins in bipolar disorder (BP). Utilizing the Genotype-Tissue Expression (GTEx) database to identify cis-acting blood expression quantitative trait loci (cis-eQTLs), five eQTL variants from the HPN gene were analyzed for association with BP cases using genotype data of cases from the discovery study (n = 58) versus healthy controls (n = 777). After adjusting for relevant covariates, we analyzed the relationship between these 5 cis-eQTLs and HPN serum level in the BP cases. All 5 cis-eQTL minor alleles were significantly more frequent in BP cases vs controls [(rs62122114, OR = 1.6, p = 0.02), (rs67003112, OR = 1.6, p = 0.02), (rs4997929, OR = 1.7, p = 0.01), (rs12610663, OR = 1.7, p = 0.01), (rs62122148, OR = 1.7, P = 0.01)]. The minor allele (A) in rs62122114 was significantly associated with increased serum HPN level in BP cases (Beta = 0.12, P = 0.049). However, this same minor allele was associated with reduced gene expression in GTEx controls. These exploratory analyses suggest that genetic variation in/near the gene encoding for hepsin protein may influence risk of bipolar disorder. This genetic variation, at least for the rs62122114-A allele, may have functional impact (i.e. differential expression) as evidenced by serum HPN protein expression. Although limited by small sample size, this study highlights the merits of proteomic informed functional genomic studies as a tool to investigate with greater precision the genetic risk of bipolar disorder and secondary relationships to protein expression recognizing, and encouraging in subsequent studies, high likelihood of epigenetic modification of genetic disease risk., (Copyright © 2017. Published by Elsevier Ltd.)

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

Background: Although multiple genes have been implicated in bipolar disorder (BD), they explain only a small proportion of its heritability. Identifying additional BD risk variants may be impaired by phenotypic heterogeneity, which is usually not taken into account in genome-wide association studies (GWAS). BD with early age at onset is a more homogeneous familial form of the disorder associated with greater symptom severity., Methods: We conducted a GWAS of early-onset BD (onset of mania/hypomania ≤19 years old) in a discovery sample of 419 cases and 1034 controls and a replication sample of 181 cases and 777 controls. These two samples were meta-analyzed, followed by replication of one signal in a third independent sample of 141 cases and 746 controls., Results: No single nucleotide polymorphism (SNP) associations were genome-wide significant in the discovery sample. Of the top 15 SNPs in the discovery analysis, rs114034759 in the muskelin (MKLN1) gene was nominally significant in the replication analysis, and was among the top associations in the meta-analysis (p=2.63E-06, OR=1.9). In the third sample, this SNP was again associated with early-onset BD (p=0.036, OR=1.6). Gene expression analysis showed that the rs114034759 risk allele is associated with decreased hippocampal MKLN1 expression., Limitations: The sample sizes of the early-onset BD subgroups were relatively small., Conclusions: Our results suggest MKLN1 is associated with early-onset BD. MKLN1 regulates cellular trafficking of GABA-A receptors, which is involved in synaptic transmission and plasticity, and is implicated in the mechanism of action of a group of antiepileptic mood stabilizers. These results therefore indicate that GABAergic neurotransmission may be implicated in early-onset BD. We propose that an increase in GABA-A receptors in the hippocampus in BD patients due to lower MKLN1 expression might increase the excitability during the GABA-excited early phase of young neurons, leading to an increased risk of developing a manic/hypomanic episode. Further studies are needed to test this model., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Converging genetic, postmortem gene-expression, cellular, and neuroimaging data implicate mitochondrial dysfunction in bipolar disorder. This study was conducted to investigate whether mitochondrial DNA (mtDNA) haplogroups and single nucleotide variants (SNVs) are associated with sub-phenotypes of bipolar disorder. MtDNA from 224 patients with Bipolar I disorder (BPI) was sequenced, and association of sequence variations with 3 sub-phenotypes (psychosis, rapid cycling, and adolescent illness onset) was evaluated. Gene-level tests were performed to evaluate overall burden of minor alleles for each phenotype. The haplogroup U was associated with a higher risk of psychosis. Secondary analyses of SNVs provided nominal evidence for association of psychosis with variants in the tRNA, ND4 and ND5 genes. The association of psychosis with ND4 (gene that encodes NADH dehydrogenase 4) was further supported by gene-level analysis. Preliminary analysis of mtDNA sequence data suggests a higher risk of psychosis with the U haplogroup and variation in the ND4 gene implicated in electron transport chain energy regulation. Further investigation of the functional consequences of this mtDNA variation is encouraged., (Copyright © 2016. Published by Elsevier Ltd.)

The present study was conducted to test the effect of Origanum Majoranum Extract (OME) of leaves on alterations induced in a model of type 2 diabetic rats. Adult male Wistar rats were fed high fat diet for 3 weeks and injected a single dose of streptozotocin (35 mg/kg) intraperitoneally to induce type 2 diabetic rats. Diabetic rats were given aqueous extract of OME in a dose of 20 mg/kg orally for 3 weeks. Changes in lipid profiles, glucose, insulin, expression of some genes related to glucose metabolism and histopathological changes in liver and kidney were examined. Administration of OME improved and normalized dyslipidemia recorded in type 2 diabetic rats together with reduction in glucose and insulin levels. OME induced up-regulation in gene expression of glucose [adiponectin and glucose transporter-2 (GLUT-2)] and lipid metabolism [lipoprotein lipase (LPL)]. Moreover, OME normalized histopathological changes occurred in liver and kidney of diabetic rats. OME decreased lipids accumulation in liver and kidney and increased regeneration of hepatic parenchyma and restored normal renal architecture with disappearance of fat droplets. In conclusion, OME improved dyslipidemia associated with type 2 diabetes through regulation of genes related to glucose and lipid metabolism.

Antidepressants are commonly prescribed medications in the United States, and there is increasing interest in individualizing treatment selection for more than 20 US Food and Drug Administration-approved treatments for major depressive disorder. Providing greater precision to pharmacotherapeutic recommendations for individual patients beyond the large-scale clinical trials evidence base can potentially reduce adverse effect toxicity profiles and increase response rates and overall effectiveness. It is increasingly recognized that genetic variation may contribute to this differential risk to benefit ratio and thus provides a unique opportunity to develop pharmacogenetic guidelines for psychiatry. Key studies and concepts that review the rationale for cytochrome P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19) genetic testing can be delineated by serum levels, adverse events, and clinical outcome measures (eg, antidepressant response). In this article, we report the evidence that contributed to the implementation of pharmacokinetic pharmacogenetic guidelines for antidepressants primarily metabolized by CYP2D6 and CYP2C19., (Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objectives: Brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) functional polymorphism has been implicated in early-onset bipolar disorder. However, results of studies are inconsistent. We aimed to further explore this association., Methods: DNA samples from the Treatment of Early Age Mania (TEAM) and Mayo Clinic Bipolar Disorder Biobank were investigated for association of rs6265 with early-onset bipolar disorder. Bipolar cases were classified as early onset if the first manic or depressive episode occurred at age ≤19 years (versus adult-onset cases at age >19 years). After quality control, 69 TEAM early-onset bipolar disorder cases, 725 Mayo Clinic bipolar disorder cases (including 189 early-onset cases), and 764 controls were included in the analysis of association, assessed with logistic regression assuming log-additive allele effects., Results: Comparison of TEAM cases with controls suggested association of early-onset bipolar disorder with the rs6265 minor allele [odds ratio (OR) = 1.55, p = 0.04]. Although comparison of early-onset adult bipolar disorder cases from the Mayo Clinic versus controls was not statistically significant, the OR estimate indicated the same direction of effect (OR = 1.21, p = 0.19). When the early-onset TEAM and Mayo Clinic early-onset adult groups were combined and compared with the control group, the association of the minor allele rs6265 was statistically significant (OR = 1.30, p = 0.04)., Conclusions: These preliminary analyses of a relatively small sample with early-onset bipolar disorder are suggestive that functional variation in BDNF is implicated in bipolar disorder risk and may have a more significant role in early-onset expression of the disorder., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The aim of the present study was to engage a national advocacy group and local stakeholders for guidance in developing a bipolar disorder biobank through a web-based survey and a community advisory board., Methods: The Depression and Bipolar Support Alliance and the Mayo Clinic Bipolar Biobank conducted a national web-based survey inquiring about interest in participating in a biobank (i.e., giving DNA and clinical information). A community advisory board was convened to guide establishment of the biobank and identify key deliverables from the research project and for the community., Results: Among 385 survey respondents, funding source (87%), professional opinion (76%), mental health consumer opinion (79%), and return of research results (91%) were believed to be important for considering study participation. Significantly more patients were willing to participate in a biobank managed by a university or clinic (78.2%) than one managed by government (63.4%) or industry (58.2%; both p < 0.001). The nine-member community advisory board expressed interest in research to help predict the likelihood of bipolar disorder developing in a child of an affected parent and which medications to avoid. The advisory board endorsed the use of a comprehension questionnaire to evaluate participants' understanding of the study (e.g., longevity of DNA specimens, right to remove samples, accessing medical records) as a means to strengthen the informed consent process., Conclusions: These national survey and community advisory data support the merit of establishing a biobank to enable studies of disease risk, provided that health records and research results are adequately protected. The goals of earlier diagnosis and individualized treatment of bipolar disorder were endorsed., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Recent studies showed prominent antimicrobial activity of some plant extracts on some pathogenic microorganisms so we evaluated antimicrobial activity of aqueous extracts of clove and cinnamon using the agar well diffusion method. An in vivo study was carried out on 40 adult healthy male albino rats divided into four groups: Group 1: negative control group (received intragastric saline solution daily); Group 2: injected with mixed bacterial suspension of S. aureus and E.coli as a model of pyelonephritis then received intragastric saline solution daily; Group 3: injected with the same dose of mixed bacterial suspension then received intragastric clove extract 500 mg/kg/day; and Group (4): injected with mixed bacterial suspension then received intragastric cinnamon 500 mg/kg/day. Five rats from each group were sacrificed after 1 and 4 weeks. Serum and blood samples were collected for lysozymes activity and nitric oxide production, lymphocyte transformation test, as well as counting of both total and differential leukocytes and erythrocytes. Kidney samples were tested histopathologically. Both in vivo and in vitro results confirmed the efficacy of clove extract as natural antimicrobials and suggested the possibility of its use in treatment of such bacterial infections., (© The Author(s) 2015.)

Background: An overdose of paracetamol is a frequent reason for liver and renal toxicity and possible death and curcumin has hepatoprotective properties against liver damage. The exact mechanism of such protection is not clear. Therefore, this study was conducted to examine the molecular levels of the protective effect of curcumin on paracetamol overdose induced hepatic toxicity in rats., Methods: Male Wistar rats were allocated into 4 groups. Control group, administered corn oil; curcumin group, administered curcumin (400 mg/kg BW daily intra-gastric) dissolved in corn oil; paracetamol group, administered corn oil with a single dose of paracetamol (500 mg/kg BW intra-gastric) and protective group, administered curcumin with a single dose of paracetamol. Curcumin was administered for 7 successive days, while paracetamol was administered at day six of treatment. Blood and liver tissues were collected for biochemical, histopathological, immunohistochemical and molecular examination., Results: Serum analysis revealed an alteration in parameters of kidney and liver. A decrease in the antioxidant activity of liver was recorded in paracetamol group while curcumin administration restored it. Histopathological findings showed an extensive coagulative necrosis in hepatocytes together with massive neutrophilic and lymphocytic infiltration. Immunostaining of liver matrix metalloproteinase-8 (MMP-8) in paracetamol administered rats showed an increase in MMP-8 expression in the area of coagulative necrosis surrounding the central vein of hepatic lobules. Curcumin administration decreased MMP-8 expression in liver of paracetamol administered rats. Gene expression measurements revealed that paracetamol decreased the expression of antioxidant genes and increased the expression of interleukin-1β (IL-1β), IL-8, tumor necrosis factor-α (TNF-α) and acute phase proteins. Curcumin administration ameliorated paracetamol-induced alterations in genes expression of antioxidant and inflammatory cytokines., Conclusion: The results clarified the strong protective effect of curcumin on paracetamol induced hepatic toxicity in rats at the immunohistochemical and molecular levels.

Recent studies showed prominent antimicrobial activity of various plant extracts on certain pathogenic microorganisms, therefore we prepared crude aqueous extracts of black pepper, ginger and thyme and carried out an in vitro study by measuring antimicrobial activity of these extracts using the agar well diffusion method. An in vivo study was carried out on 50 adult healthy male albino rats which were divided into 5 groups, 10 rats each. Group 1: negative control group which received saline solution intragastrically daily; Group 2: Positive control group, injected with mixed bacterial suspension of S.aureus and E.coli as a model of pyelonephritis, then received saline solution intragastrically daily; Group 3: injected with the same dose of mixed bacterial suspension, then received 100 mg/kg/day black pepper extract intragastrically; Group 4: injected with mixed bacterial suspension then received 500 mg/kg/day ginger extract intragastrically. Group 5: injected with mixed bacterial suspension then received 500 mg/kg/day thyme extract intragastrically. All groups were sacrificed after either 1 or 4 weeks. Serum and blood samples were collected for lysozyme activity estimation using agarose lysoplate, measurement of nitric oxide production, and lymphocyte transformation test as well as for counting both total and differential leukocytes and erythrocytes. Kidney samples were tested histopathologically. Both in vivo and in vitro results confirm the efficacy of these extracts as natural antimicrobials and suggest the possibility of using them in treatment procedures.

Retinal dystrophy (RD) is a heterogeneous group of hereditary diseases caused by loss of photoreceptor function and contributes significantly to the etiology of blindness globally but especially in the industrialized world. The extreme locus and allelic heterogeneity of these disorders poses a major diagnostic challenge and often impedes the ability to provide a molecular diagnosis that can inform counseling and gene-specific treatment strategies. In a large cohort of nearly 150 RD families, we used genomic approaches in the form of autozygome-guided mutation analysis and exome sequencing to identify the likely causative genetic lesion in the majority of cases. Additionally, our study revealed six novel candidate disease genes (C21orf2, EMC1, KIAA1549, GPR125, ACBD5, and DTHD1), two of which (ACBD5 and DTHD1) were observed in the context of syndromic forms of RD that are described for the first time.