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Oxidative Medicine and Cellular... 2023Olive leaves extracts are known to exert potential pharmacological activities especially, antidiabetic and antiobesity. This study explores the anti-insulin resistant...
Olive leaves extracts are known to exert potential pharmacological activities especially, antidiabetic and antiobesity. This study explores the anti-insulin resistant effect of olive leaves extracts and oleuropein in 3 T3-L1 cells and in high-fat diet fed rats. Our results showed that ethanol extract (EE) suppressed significantly ( < 0.01) triacylglycerol accumulation. In preadipocytes cells, EE 1/100 decreased cell viability and induced apoptosis. Real-time PCR analysis showed that EE reduced the mRNA levels of adipogenesis (CEBP-, PPAR, SREBP-1c, and FAS) and proinflammatory (TNF- and IL-6) genes. Moreover, the cotreatment of EE 1/1000 or oleuropein with insulin increased considerably the expression of p-IRS, p85-pI3K, and p-AKT. model, the oral administration of oleuropein at 50 mg/kg in rats fed with high fat diet for 8 weeks reduced inflammation in liver and adipose tissues (WAT), improved glucose intolerance, and decreased hyperinsulinemia. Furthermore, the immunohistochemistry revealed that the expression level of p-Akt, IRS1, and Glut-4 were significantly enhanced in liver and WAT tissues after oleuropein supplementation comparing with that in HFD group. Additionally, the expression of IRS1 was markedly ameliorated in pancreas. Our obtained results can be adopted as an approach to used olive leaves as complement to prevent insulin-resistance disease.
Topics: Animals; Mice; Rats; 3T3-L1 Cells; Adipogenesis; Diet, High-Fat; Insulin; Insulin Resistance; Mice, Inbred C57BL; Olea; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Plant Extracts
PubMed: 36647430
DOI: 10.1155/2023/6828230 -
Arthritis Research & Therapy Dec 2022Uncontrolled/refractory gout patients are recalcitrant/intolerant to oral urate-lowering therapies (ULTs), experiencing frequent gout flares, functionally limiting...
Improved joint and patient-reported health assessments with pegloticase plus methotrexate co-therapy in patients with uncontrolled gout: 12-month exploratory outcomes of the MIRROR open-label trial.
BACKGROUND
Uncontrolled/refractory gout patients are recalcitrant/intolerant to oral urate-lowering therapies (ULTs), experiencing frequent gout flares, functionally limiting tophi, and low quality of life. Pegloticase lowers urate, but anti-pegloticase antibodies limit urate-lowering efficacy and increase infusion reaction (IR) risk. Immunomodulator + pegloticase co-administration may improve treatment response rates, with 79% of MIRROR open-label trial (MIRROR-OL, pegloticase + oral methotrexate) participants meeting 6-month response criteria. Exploratory outcomes from MIRROR-OL are described here.
METHODS
Adults with uncontrolled gout (serum urate [SU] ≥ 6 mg/dL and ULT-intolerance/recalcitrance or functionally limiting tophi) were included. Oral methotrexate (15 mg/week) was administered 4 weeks before and during pegloticase treatment (biweekly 8 mg infusion, ≤ 52 weeks). Exploratory outcomes included change from baseline (CFB) in number of affected joints, Health Assessment Questionnaires (HAQs), and Gout Global Assessments.
RESULTS
Fourteen patients received ≥ 1 pegloticase infusion, with 13 included in 52-week analyses (1 enrolled before treatment-extension amendment, exited at 24 weeks). Three patients prematurely exited due to SU rise; 10 completed 52-week evaluations (8 completed 52 weeks of co-therapy, 2 completed 24 weeks [met treatment goals]). At 52 weeks, SU averaged 1.1 ± 2.5 mg/dL, with improvements in HAQ pain and health (CFB: - 33.6 and - 0.7, respectively), Patient and Physician Global Assessments (CFB: - 4.6 and - 5.7, respectively), and joint involvement (CFB: - 5.6, - 8.4, - 6.0 tender, swollen, tophi-affected joints, respectively). Two patients underwent dual-energy computed tomography, showing concomitant monosodium urate volume reductions. All patients had ≥ 1 AE, with 92.9% experiencing acute flare. One mild IR ("cough") occurred and no new safety signals were identified.
CONCLUSION
Pegloticase + methotrexate co-therapy resulted in sustained SU-lowering with meaningful improvements in clinical measures, urate burden, and patient-reported outcomes.
TRIAL REGISTRATION
ClinicalTrials.gov (NCT03635957).
Topics: Adult; Humans; Uric Acid; Methotrexate; Gout Suppressants; Quality of Life; Gout; Polyethylene Glycols; Urate Oxidase; Treatment Outcome
PubMed: 36575505
DOI: 10.1186/s13075-022-02979-4 -
Nutrients Dec 2022(1) Background: Studies on the long-term patterns of using vasopressors in patients with shock and their correlations with the risk of feeding intolerance (FI) are... (Observational Study)
Observational Study
(1) Background: Studies on the long-term patterns of using vasopressors in patients with shock and their correlations with the risk of feeding intolerance (FI) are limited. This study aimed to characterize the norepinephrine equivalent dose (NEQ) trajectories and explore its correlations with FI in patients with shock. (2) Methods: This study prospectively enrolled patients with shock, who received vasopressors from August 2020 to June 2022. The Growth Mixed Model (GMM) was used to traverse longitudinal NEQ data at six-hour intervals and identify the latent trajectories of NEQ use in these patients. Cox proportional hazards regression models were used to examine the correlations of NEQ trajectories with FI. (3) Results: This study included a total of 210 patients with shock recruited from August 2020 to June 2022. Four trajectories of NEQ dose were identified and characterized by low-dose stable NEQ (L-NEQ, n = 98), moderate-dose stable NEQ (M-NEQ, n = 74), high-dose stable NEQ (H-NEQ, n = 21), and rapidly rising NEQ (R-NEQ, n = 17), with NEQ doses of 0.2, 0.4, 0.4, and 0.5 µg/kg/min at enteral nutrition (EN) initiation, respectively. The incidences of FI were 37.76%, 67.57%, 80.95%, and 76.47% in the L-NEQ, M-NEQ, H-NEQ, and R-NEQ groups, respectively (p < 0.001). As compared to the L-NEQ group, the risk of FI occurrence increased in the M-NEQ, H-NEQ, and R-NEQ groups (all p < 0.05). (4) Conclusions: The risk of FI was significantly associated with NEQ trajectories. It might be appropriate to initiate EN when the NEQ dose is stabilized below 0.2 µg/kg/min in patients with shock.
Topics: Humans; Infant, Newborn; Enteral Nutrition; Norepinephrine; Prospective Studies; Time Factors
PubMed: 36558552
DOI: 10.3390/nu14245393 -
Neurobiology of Disease Feb 2023Epidemiological studies identified alcohol use disorder (AUD) as a risk factor for Alzheimer's disease (AD), yet there is conflicting evidence on how alcohol use...
Epidemiological studies identified alcohol use disorder (AUD) as a risk factor for Alzheimer's disease (AD), yet there is conflicting evidence on how alcohol use promotes AD pathology. In this study, a 10-week moderate two-bottle choice drinking paradigm was used to identify how chronic ethanol exposure alters amyloid-β (Aβ)-related pathology, metabolism, and behavior. Ethanol-exposed APPswe/PSEN1dE9 (APP/PS1) mice showed increased brain atrophy and an increased number of amyloid plaques. Further analysis revealed that ethanol exposure led to a shift in the distribution of plaque size in the cortex and hippocampus. Ethanol-exposed mice developed a greater number of smaller plaques, potentially setting the stage for increased plaque proliferation in later life. Ethanol drinking APP/PS1 mice also exhibited deficits in nest building, a metric of self-care, as well as increased locomotor activity and central zone exploration in an open field test. Ethanol exposure also led to a diurnal shift in feeding behavior which was associated with changes in glucose homeostasis and glucose intolerance. Complementary in vivo microdialysis experiments were used to measure how acute ethanol directly modulates Aβ in the hippocampal interstitial fluid (ISF). Acute ethanol transiently increased hippocampal ISF glucose levels, suggesting that ethanol directly affects cerebral metabolism. Acute ethanol also selectively increased ISF Aβ40, but not ISF Aβ42, levels during withdrawal. Lastly, chronic ethanol drinking increased N-methyl-d-aspartate receptor (NMDAR) and decreased γ-aminobutyric acid type-A receptor (GABAR) mRNA levels, indicating a potential hyperexcitable shift in the brain's excitatory/inhibitory (E/I) balance. Collectively, these experiments suggest that ethanol may increase Aβ deposition by disrupting metabolism and the brain's E/I balance. Furthermore, this study provides evidence that a moderate drinking paradigm culminates in an interaction between alcohol use and AD-related phenotypes with a potentiation of AD-related pathology, behavioral dysfunction, and metabolic impairment.
Topics: Animals; Mice; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Disease Models, Animal; Ethanol; Glucose; Hippocampus; Mice, Transgenic; Plaque, Amyloid; Presenilin-1
PubMed: 36535550
DOI: 10.1016/j.nbd.2022.105967 -
Cureus Oct 2022Metronidazole is an antibiotic commonly prescribed for anaerobic and protozoan infections. Despite its good safety profile, this drug frequently causes a series of...
Metronidazole is an antibiotic commonly prescribed for anaerobic and protozoan infections. Despite its good safety profile, this drug frequently causes a series of well-known side effects (nausea and intestinal transit disorders, dysgeusia, headaches, and alcohol intolerance). However, there are few data in the literature, mainly case reports and case series, about the onset of peripheral neuropathy with a generally self-limiting course after drug withdrawal. Thus, we herein describe two cases of peripheral neuropathy due to treatment with metronidazole. A 69-year-old woman treated with a total of 55 g of metronidazole for diverticular disease and a 52-year-old male patient on a long course of antibiotic therapy for hepatic abscesses (a cumulative dose of 168 g) developed peripheral neuropathy. The suspicion of metronidazole side effects was raised after the exclusion of other causes. After the suspension of the drug, different degrees of improvement were observed. Metronidazole is an effective antibiotic for treating infections caused by anaerobic or protozoan pathogens, and it has a good pharmacological and economic safety profile. However, in the existing literature, prolonged therapy regimens (>4 weeks of treatment and/or 42 g cumulative dose) may increase the risk of developing neurological complications, in particular peripheral polyneuropathy.
PubMed: 36465791
DOI: 10.7759/cureus.30889 -
Journal of Health Psychology Jul 2023The COVID-19 pandemic continues to impact global psychological wellbeing. To investigate the sustained impact of COVID-19 on wellbeing, the current study longitudinally...
The COVID-19 pandemic continues to impact global psychological wellbeing. To investigate the sustained impact of COVID-19 on wellbeing, the current study longitudinally assessed fear of COVID-19, anxiety, depression, intolerance of uncertainty, worry, sleep quality, loneliness and alcohol use during the pandemic in the United Kingdom. Timepoint 1 (T1; = 445) took place in February 2021 following the highest number of pandemic-related deaths in the UK. Timepoint 2 (T2, = 198) took place in June 2021 when pandemic-related deaths had declined considerably, and many had been vaccinated. At T1, COVID-19 fear predicted elevated levels of anxiety, depression, intolerance of uncertainty, worry, sleep quality and loneliness. At T2, we observed that levels of COVID-19 fear, depression, loneliness and sleep quality decreased. However, COVID-19 fear continued to predict elevated intolerance of uncertainty, worry and impaired sleep quality. These findings demonstrate the longitudinal impact of COVID-19 fear on psychological wellbeing.
Topics: Humans; Pandemics; COVID-19; Fear; Anxiety; United Kingdom; Depression
PubMed: 36397647
DOI: 10.1177/13591053221134848 -
European Heart Journal Supplements :... Nov 2022Resistant hypertension consists in the failure to achieve effective control of blood pressure despite the use of at least three drugs, including a diuretic, at the...
Resistant hypertension consists in the failure to achieve effective control of blood pressure despite the use of at least three drugs, including a diuretic, at the maximum tolerated dosage. Despite the progress made in terms of improving awareness and effectiveness of the available therapeutic strategies, the percentage of patients with resistant hypertension represents up to 18% of the entire hypertensive population. The management of resistant hypertension includes the combination of different strategies from lifestyle changes to complex interventional procedures. Lifestyle interventions include reducing salt intake, weight loss, quitting smoking and alcohol consumption, and performing aerobic physical activity. With regard to drug therapy, international guidelines recommend the introduction of a mineralocorticoid receptor antagonist or, if not tolerated, of a loop diuretic, or of the beta-blocker bisoprolol, or of the alpha-blocker doxazosin. In the last few years, promising results have been obtained from studies that have evaluated the efficacy and safety of the denervation of the renal arteries by ablation. This procedure may constitute an increasingly widespread option for those patients suffering from resistant hypertension despite the use of different drug classes, or who are intolerant or poorly adherent to medical therapy.
PubMed: 36380803
DOI: 10.1093/eurheartjsupp/suac094 -
Pharmaceuticals (Basel, Switzerland) Sep 2022Tuberculosis (TB) is currently one of the leading causes of death due to infective agents, and the growing rate of multidrug-resistant tuberculosis (MDR TB) cases poses...
Tuberculosis (TB) is currently one of the leading causes of death due to infective agents, and the growing rate of multidrug-resistant tuberculosis (MDR TB) cases poses an emergent public health threat. Fluoroquinolones are commonly used in the treatment of both MDR TB and drug-sensitive tuberculosis patients who are intolerant to first-line antitubercular agents. Unfortunately, these drugs have mild side effects, relevant to the prolonged treatment regimens and diminished bioavailability due to binding of metal ions. Moreover, the resistance to fluoroquinolones is also on the rise, a characteristic of extensively drug-resistant TB (XDR TB). Here, we developed esters as prodrugs of the fluoroquinolones levofloxacin and ciprofloxacin, with long-chain fatty alcohols. Both the alcohols and the quinolone have previously shown antimycobacterial activity and the aim was to develop esters with improved lipophilicity and capable of delivering the free acid inside mycobacterial cells. The carboxylic acid group of fluoroquinolones is essential to the mode of action but is also responsible for many of its side effects and metal-chelating properties. The synthesis, stability in biological media, and antibacterial activity were evaluated, the latter not only against but also against other clinically relevant bacterial species, since the parent compounds display a broad spectrum of activity. The biological results show a reduction in the antitubercular activity of the synthesized derivatives, probably due to deficient activation of the ester prodrug. Despite this, it was found that the derivatives exhibit bioactivity against other fluoroquinolone-resistant bacteria, indicating a different mode of action and suggesting that it may be worthwhile to research further modifications to the carboxylic acid group. This might lead to new compounds that are efficient against resistant strains. This idea that the compounds may act by a different mechanism of action was further supported by a brief computer investigation that demonstrated the potential lack of selectivity of the esters to the fluoroquinolone target.
PubMed: 36297325
DOI: 10.3390/ph15101213 -
The Journal of Nutritional Biochemistry Jan 2023Fat and fructose are the two major components over-represented in the Western diet. The aim of this study was to determine the combined effects of different types of...
Fat and fructose are the two major components over-represented in the Western diet. The aim of this study was to determine the combined effects of different types of dietary fat and fructose on the development of nonalcoholic fatty liver disease (NAFLD) in a murine model. Eight-week-old male C57BL/6J mice were fed with high-fat diet enriched with saturated fat (HSF), or omega-6 polyunsaturated fat (n6HUSF), or omega-3 polyunsaturated fat (n3HUSF) with 42% of calories derived from the fat. Fructose supplementation was given via 10% fructose (w/v) in the drinking water ad libitum for 20 weeks. While both HSF and n6HUSF fed mice developed obesity, HSF fed mice exhibited severe hepatic steatosis associated with hepatomegaly and liver injury. Fructose feeding promotes the development of liver fibrosis in HSF fed mice. n6HUSF fed mice were characterized with moderate hepatic steatosis, accompanied with hypertriglyceridemia and hyperlipidemia. Notably, fructose supplementation led to remarkable glucose intolerance in n6HUSF fed mice compared to controls. Hepatic lipidomic analysis revealed that the total saturated fatty acids and total monounsaturated fatty acids were significantly increased by fructose in the free fatty acid pool in HSF fed mice. Moreover, fructose supplementation increased hepatic and plasma cholesterol levels in the HSF fed mice. Our data suggest that excess energy from HSF intake results in fat storage in the liver, likely due to impaired triglyceride secretion; whereas excess energy from n6HUSF diet is stored in the periphery. Both effects are exacerbated by fructose supplementation. n3HUSF is beneficial, even consumed with fructose.
Topics: Mice; Male; Animals; Fructose; Dietary Fats; Mice, Inbred C57BL; Diet, High-Fat; Non-alcoholic Fatty Liver Disease; Liver; Phenotype
PubMed: 36272691
DOI: 10.1016/j.jnutbio.2022.109189 -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Oct 2022To analyze the disease spectrums underlying orthostatic intolerance (OI) and sitting intolerance (SI) in Chinese children, and to understand the clinical empirical...
OBJECTIVE
To analyze the disease spectrums underlying orthostatic intolerance (OI) and sitting intolerance (SI) in Chinese children, and to understand the clinical empirical treatment options.
METHODS
The medical records including history, physical examination, laboratory examination, and imagological examination of children were retrospectively studied in Peking University First Hospital from 2012 to 2021. All the children who met the diagnostic criteria of OI and SI were enrolled in the study. The disease spectrums underlying OI and SI and treatment options during the last 10 years were analyzed.
RESULTS
A total of 2 110 cases of OI and SI patients were collected in the last 10 years, including 943 males (44.69%) and 1 167 females (55.31%) aged 4-18 years, with an average of (11.34±2.84) years. The overall case number was in an increasing trend over the year. In the OI spectrum, postural tachycardia syndrome (POTS) accounted for 826 cases (39.15%), followed by vasovagal syncope (VVS) (634 cases, 30.05%). The highest proportion of SI spectrum was sitting tachycardia (STS) (8 cases, 0.38%), followed by sitting hypertension (SHT) (2 cases, 0.09%). The most common comorbidity of OI and SI was POTS coexisting with STS (36 cases, 1.71%). The highest proportion of treatment options was autonomic nerve function exercise (757 cases, 35.88%), followed by oral rehydration salts (ORS) (687 cases, 32.56%), metoprolol (307 cases, 14.55%), midodrine (142 cases, 6.73%), ORS plus metoprolol (138 cases, 6.54%), and ORS plus midodrine (79 cases, 3.74%). The patients with POTS coexisting with VVS were more likely to receive pharmacological intervention than the patients with POTS and the patients with VVS (41.95% 30.51% . 28.08%, = 20.319, < 0.01), but there was no significant difference in the proportion of treatment options between the patients with POTS and the patients with VVS.
CONCLUSION
POTS and VVS in children are the main underlying diseases of OI, while SI is a new disease discovered recently. The number of children with OI and SI showed an increasing trend. The main treatment methods are autonomic nerve function exercise and ORS. Children with VVS coexisting with POTS were more likely to take pharmacological treatments than those with VVS or POTS only.
Topics: Child; Female; Humans; Male; Electrolytes; Metoprolol; Midodrine; Orthostatic Intolerance; Postural Orthostatic Tachycardia Syndrome; Retrospective Studies; Salts; Sitting Position; Syncope, Vasovagal; Tilt-Table Test
PubMed: 36241239
DOI: 10.19723/j.issn.1671-167X.2022.05.024