Evaluation of the diuretic potentials of naringenin in hypercholesterolemic rats

Purpose: To investigate the diuretic potentials of naringenin (NGN) in obesity induced in rats by high fat diet (HFD).Methods: To prepare HFD, normal pellet diet was crushed and thoroughly mixed with cholesterol powder (1 % w/w). The mixture was mixed with some water and made into pellets which were then oven-baked to dry. Four groups of male Wistar albino rats (n = 6) were used for the study. Normal control (group I) received normal pellet diet. Group 2 (HFD-only) was fed HFD for 28 days, while Groups 3 and 4 were co-administered HFD and NGN at doses of 50 and 100 mg/kg, respectively. All treatments were given orally, and lasted for 28 days. Twenty-four hours after the last dose of NGN, blood was collected from all rats and total cholesterol levels determined to confirm obesity. Thereafter, the rats were placed in metabolic cages and urine samples were collected at two time-points (5 and 24 h) for measurement of urine volume, urinary pH, conductivity and electrolyte levels (Na, K and Cl).Results: Treatment with HFD resulted in significantly (p < 0.05) increased serum cholesterol level (178.83 ± 5.43 mg/dL) when compared to normal control rats (88.17 ± 4.04 mg/dL). It also led to decrease in urinary volume (~50 %) at both time points (5 and 24 h) and in excretion of urinary electrolytes (sodium, potassium and chloride ions). However, the changes in these parameters were significantly reversed by NGN administration (p < 0.05).Conclusion: These results demonstrate the diuretic activity of NGN in HFD-induced obese rats. Thus, NGN can be further explored for use in combination with hypolipidemic agents to tackle obesity.Keywords: High-fat diet, Hypercholesterolemia, Naringenin, Obesit

Behavior of thin-walled tubes with combined cross-sectional geometries under oblique loading

Hollow tubes are the most important part of any structure because of their load-bearing capacity, lightweight and inexpensive manufacturing cost. One of the methods for improving the performance under quasi-static loading is to vary the cross-sectional shapes. In the real case, structures are seldom subjected to pure axial or pure bending rather they are subjected to a combination of two load cases i.e. oblique loading. In this paper, the circular cross-section was combined with four different polygonal cross-sections namely tetragon, hexagon, octagon and decagon and a total of 13 geometries were obtained. The buckling behavior of each tube was investigated numerically at various angles of inclination. Each tube was modeled in SOLIDWORKS and then was analyzed in ANSYS. Linear buckling code was used for finding the critical load at various angles ranging from 0° to 14°. The overall result was then compared and it was found that the proposed geometry can be a good alternative over conventional circular tubes in terms of load-bearing capacity at angular load

Prevalence of CADASIL and Fabry Disease in a Cohort of MRI Defined Younger Onset Lacunar Stroke.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by mutations in the NOTCH3 gene, is the most common monogenic disorder causing lacunar stroke and cerebral small vessel disease (SVD). Fabry disease (FD) due to mutations in the GLA gene has been suggested as an underdiagnosed cause of stroke, and one feature is SVD. Previous studies reported varying prevalence of CADASIL and FD in stroke, likely due to varying subtypes studied; no studies have looked at a large cohort of younger onset SVD. We determined the prevalence in a well-defined, MRI-verified cohort of apparently sporadic patients with lacunar infarct. METHODS: Caucasian patients with lacunar infarction, aged ≤70 years (mean age 56.7 (SD8.6)), were recruited from 72 specialist stroke centres throughout the UK as part of the Young Lacunar Stroke DNA Resource. Patients with a previously confirmed monogenic cause of stroke were excluded. All MRI's and clinical histories were reviewed centrally. Screening was performed for NOTCH3 and GLA mutations. RESULTS: Of 994 subjects five had pathogenic NOTCH3 mutations (R169C, R207C, R587C, C1222G and C323S) all resulting in loss or gain of a cysteine in the NOTCH3 protein. All five patients had confluent leukoaraiosis (Fazekas grade ≥2). CADASIL prevalence overall was 0.5% (95% CI 0.2%-1.1%) and among cases with confluent leukoaraiosis 1.5% (95% CI 0.6%-3.3%). No classic pathogenic FD mutations were found; one patient had a missense mutation (R118C), associated with late-onset FD. CONCLUSION: CADASIL cases are rare and only detected in SVD patients with confluent leukoaraiosis. No definite FD cases were detected.The UK Young Lacunar Stroke DNA Study was funded by a grants from the Wellcome Trust (WT072952, www.wellcome.ac.uk) and the Stroke Association (TSA 2010/01& TSA 2013/02, www.stroke.org.uk). Fabry disease screening was supported by an unrestricted scientific grant from Shire Human Genetic Therapies (www.shire.com). The sponsors of the study had no role in the study design, data collection, data analysis, interpretation, writing of the manuscript, or the decision to submit the manuscript for publication. L R-J’s salary is funded by a Stroke Association/ British Heart Foundation grant. (TSA/BHF 2010/01). HM is supported by an National Institute for Health Research Senior Investigator award (www.nihr.ac.uk). HM and SB are supported by the Cambridge University Trust National Institute for Health Research Comprehensive Research Centre (www.cambridge-brc.org.uk).This is the final version of the article. It first appeared from PLoS via http://dx.doi.org/10.1371/journal.pone.013635

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Isosorbide Mononitrate and Cilostazol Treatment in Patients With Symptomatic Cerebral Small Vessel Disease: The Lacunar Intervention Trial-2 (LACI-2) Randomized Clinical Trial

Importance Cerebral small vessel disease (cSVD) is a common cause of stroke (lacunar stroke), is the most common cause of vascular cognitive impairment, and impairs mobility and mood but has no specific treatment.Objective To test the feasibility, drug tolerability, safety, and effects of 1-year isosorbide mononitrate (ISMN) and cilostazol treatment on vascular, functional, and cognitive outcomes in patients with lacunar stroke.Design, Setting, and Participants The Lacunar Intervention Trial-2 (LACI-2) was an investigator-initiated, open-label, blinded end-point, randomized clinical trial with a 2 × 2 factorial design. The trial aimed to recruit 400 participants from 26 UK hospital stroke centers between February 5, 2018, and May 31, 2021, with 12-month follow-up. Included participants had clinical lacunar ischemic stroke, were independent, were aged older than 30 years, had compatible brain imaging findings, had capacity to consent, and had no contraindications to (or indications for) the study drugs. Data analysis was performed on August 12, 2022.Interventions All patients received guideline stroke prevention treatment and were randomized to ISMN (40-60 mg/d), cilostazol (200 mg/d), ISMN-cilostazol (40-60 and 200 mg/d, respectively), or no study drug.Main Outcomes The primary outcome was recruitment feasibility, including retention at 12 months. Secondary outcomes were safety (death), efficacy (composite of vascular events, dependence, cognition, and death), drug adherence, tolerability, recurrent stroke, dependence, cognitive impairment, quality of life (QOL), and hemorrhage.Results Of the 400 participants planned for this trial, 363 (90.8%) were recruited. Their median age was 64 (IQR, 56.0-72.0) years; 251 (69.1%) were men. The median time between stroke and randomization was 79 (IQR, 27.0-244.0) days. A total of 358 patients (98.6%) were retained in the study at 12 months, with 257 of 272 (94.5%) taking 50% or more of the allocated drug. Compared with those participants not receiving that particular drug, neither ISMN (adjusted hazard ratio [aHR], 0.80 [95% CI, 0.59 to 1.09]; P = .16) nor cilostazol (aHR, 0.77 [95% CI, 0.57 to 1.05]; P = .10) alone reduced the composite outcome in 297 patients. Isosorbide mononitrate reduced recurrent stroke in 353 patients (adjusted odds ratio [aOR], 0.23 [95% CI, 0.07 to 0.74]; P = .01) and cognitive impairment in 308 patients (aOR, 0.55 [95% CI, 0.36 to 0.86]; P = .008). Cilostazol reduced dependence in 320 patients (aHR, 0.31 [95% CI, 0.14 to 0.72]; P = .006). Combination ISMN-cilostazol reduced the composite (aHR, 0.58 [95% CI, 0.36 to 0.92]; P = .02), dependence (aOR, 0.14 [95% CI, 0.03 to 0.59]; P = .008), and any cognitive impairment (aOR, 0.44 [95% CI, 0.23 to 0.85]; P = .02) and improved QOL (adjusted mean difference, 0.10 [95% CI, 0.03 to 0.17]; P = .005) in 153 patients. There were no safety concerns.Conclusions and Relevance These results show that the LACI-2 trial was feasible and ISMN and cilostazol were well tolerated and safe. These agents may reduce recurrent stroke, dependence, and cognitive impairment after lacunar stroke, and they could prevent other adverse outcomes in cSVD. Therefore, both agents should be tested in large phase 3 trials.Trial Registration ClinicalTrials.gov Identifier: NCT0345159

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Utilization of Nanotechnology to Improve Bone Health in Osteoporosis Exploiting Nigella sativa and Its Active Constituent Thymoquinone

Osteoporosis, a chronic bone disorder, is one of the leading causes of fracture and morbidity risk. Numerous medicinally important herbs have been evaluated for their efficacy in improving bone mass density in exhaustive preclinical and limited clinical studies. Nigella sativa L. has been used as local folk medicine, and traditional healers have used it to manage various ailments. Its reported beneficial effects include controlling bone and joint diseases. The present manuscript aimed to provide a sound discussion on the pharmacological evidence of N. sativa and its active constituent, thymoquinone, for its utility in the effective management of osteoporosis. N. sativa is reported to possess anti-IL-1 and anti-TNF-&alpha;-mediated anti-inflammatory effects, leading to positive effects on bone turnover markers, such as alkaline phosphatase and tartrate-resistant acid phosphatase. It is reported to stimulate bone regeneration by prompting osteoblast proliferation, ossification, and decreasing osteoclast cells. Thymoquinone from N. sativa has exhibited an antioxidant effect on bone tissue by reducing the FeNTA-induced oxidative stress. The present manuscript highlights phytochemistry, pharmacological effect, and the important mechanistic perspective of N. sativa and its active constituents for the management of osteoporosis. Further, it also provides sound discussion on the utilization of a nanotechnology-mediated drug delivery approach as a promising strategy to improve the therapeutic performance of N. sativa and its active constituent, thymoquinone, in the effective management of osteoporosis

FLAIR Brain MRIs scans from two of the patients with notch 3 mutations.

<p>The upper panel 1 shows images from patient 1 (R169C), and the lower panel two shows images from patient 2 panel 2 (C1222G). These show leukoaraiosis in both cases (images C and D) but minimal anterior pole involvement in patient 1 (image upper panel A) and no involvement in patient 2 (image lower panel A). Patient 1 also shows confluent external capsule involvement (image B), but this is absent from patient 4 (lower panel B).</p