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Drug Design, Development and Therapy 2024Buch.-Ham. ex D. Don (), a traditional herb used in Miao medicine, is renowned for its heart-clearing properties. Davidiin, the primary bioactive component...
BACKGROUND
Buch.-Ham. ex D. Don (), a traditional herb used in Miao medicine, is renowned for its heart-clearing properties. Davidiin, the primary bioactive component (approximately 1%), has been used to treat various conditions, including diabetes. Given its wide range of effects and the diverse biomolecular pathways involved in diabetes, there is a crucial need to study how davidiin interacts with these pathways to better understand its anti-diabetic properties.
MATERIALS AND METHODS
Diabetic rats were induced using a high-fat diet and streptozotocin (STZ) administered intraperitoneally at 35 mg/kg. Out of these, 24 rats with blood glucose levels ≥ 11.1 mmol/L and fasting blood glucose levels ≥ 7.0 mmol/L were selected for three experimental groups. These groups were then treated with either metformin (gavage, 140 mg/kg) or davidiin (gavage, 90 mg/kg) for four weeks. After the treatment period, we measured body weight, blood glucose levels, and conducted untargeted metabolic profiling using UPLC-QTOF-MS.
RESULTS
Davidiin has been shown to effectively treat diabetes by reducing blood glucose levels from 30.2 ± 2.6 mmol/L to 25.1 ± 2.4 mmol/L (P < 0.05). This effect appears stronger than that of metformin, which lowered glucose levels to 26.5 ± 2.6 mmol/L. The primary outcomes of serum metabolomics are significant changes in lipid and lipid-like molecular profiles. Firstly, davidiin may affect phosphatide metabolism by increasing levels of phosphatidylinositol and sphingosine-1-phosphate. Secondly, davidiin could influence cholesterol metabolism by reducing levels of glycocholic acid and glycochenodeoxycholic acid. Lastly, davidiin might impact steroid hormone metabolism by increasing hepoxilin B3 levels and decreasing prostaglandins.
CONCLUSION
Our study demonstrates that davidiin modulates various lipid-related metabolic pathways to exert its anti-diabetic effects. These findings offer the first detailed metabolic profile of davidiin's action mechanism, contributing valuable insights to the field of Traditional Chinese Medicine in the context of diabetes treatment.
Topics: Animals; Diabetes Mellitus, Experimental; Rats; Hypoglycemic Agents; Male; Streptozocin; Rats, Sprague-Dawley; Metabolome; Blood Glucose; Diet, High-Fat; Drugs, Chinese Herbal
PubMed: 38855535
DOI: 10.2147/DDDT.S459931 -
BMC Urology Jun 2024This study investigated the relaxation effect of PGE2 on the ureter and its role in promoting calculi expulsion following calculi development.
BACKGROUND
This study investigated the relaxation effect of PGE2 on the ureter and its role in promoting calculi expulsion following calculi development.
METHODS
By using immunofluorescence and Western blot, we were able to locate EP receptors in the ureter. In vitro experiments assessed the impact of PGE2, receptor antagonists, and agonists on ureteral relaxation rate. We constructed a model of ureteral calculi with flowable resin and collected ureteral tissue from postoperative side of the ureter after obstruction surgery. Western blot analysis was used to determine the protein expression levels of EP receptors and the PGE2 terminal synthase mPGES-1. Additionally, PGE2 was added to smooth muscle cells to observe downstream cAMP and PKA changes.
RESULTS
The expression of EP2 and EP4 proteins in ureteral smooth muscle was verified by Western blot analysis. According to immunofluorescence, EP2 was primarily found on the cell membrane, while EP4 was found in the nucleus. In vitro, PGE2 induced concentration-dependent ureteral relaxation. Maximum diastolic rate was 70.94 ± 4.57% at a concentration of 30µM. EP2 antagonists hindered this effect, while EP4 antagonists did not. Obstructed ureters exhibited elevated mPGES-1 and EP2 protein expression (P < 0.01). Smooth muscle cells treated with PGE2 displayed increased cAMP and phosphorylated PKA.
CONCLUSIONS
PGE2 binding to EP2 induces ureteral relaxation through the cAMP-PKA pathway. This will provide a new theoretical basis for the development of new therapeutic approaches for the use of PGE2 in the treatment of ureteral stones.
Topics: Receptors, Prostaglandin E, EP2 Subtype; Cyclic AMP; Dinoprostone; Cyclic AMP-Dependent Protein Kinases; Ureteral Calculi; Animals; Ureter; Signal Transduction; Male; Muscle Relaxation
PubMed: 38851678
DOI: 10.1186/s12894-024-01504-w -
Auris, Nasus, Larynx Jun 2024Idiopathic sudden sensorineural hearing loss (ISSNHL) is characterized by abruptly appearing hearing loss, sometimes accompanied by vertigo. Vascular pathologies (e.g.,... (Review)
Review
Idiopathic sudden sensorineural hearing loss (ISSNHL) is characterized by abruptly appearing hearing loss, sometimes accompanied by vertigo. Vascular pathologies (e.g., cochlear ischemia, or cochlear infarction) are one of the most likely causes of ISSNHL. This review aims to present current understanding of inner ear anatomy, clinical features of ISSNHL, and its treatment strategies. The labyrinthine artery is the only end artery supplying blood to the inner ear, and it has three branches: the anterior vestibular artery, the main cochlear artery, and the vestibulo-cochlear artery (VCA). Occlusion of the VCA can be caused by a variety of factors. The VCA courses through a narrow bone canal. ISSNHL is usually diagnosed after excluding retrocochlear pathologies of sudden sensorineural hearing loss (SSNHL), such as vestibular schwannoma. Therefore, a head MRI or assessing auditory brainstem responses are recommended for patients with SSNHL. Severe SSNHL patients with high CHADS scores, an index of stroke risk, have a significantly lower rate of vestibular schwannoma than severe SSNHL patients with low CHADS scores, suggesting that severe ISSNHL in individuals at high risk of stroke is caused by vascular impairments. Intralabyrinthine hemorrhage causes SSNHL or vertigo, as in ISSNHL. The diagnosis of intralabyrinthine hemorrhage requires careful interpretation of MRI, and a small percentage of patients diagnosed with ISSNHL may in fact have intralabyrinthine hemorrhage. Many studies have reported an association between ISSNHL and atherosclerosis or cardiovascular risk factors (e.g., diabetes mellitus, hypertension, dyslipidemia and cardiovascular disease), and subsequent risk of stroke in patients with ISSNHL may be elevated compared to controls. Increased hearing level on the healthy ear side, high Framingham risk score, high neutrophil-to-lymphocyte ratio, high platelet-to-lymphocyte ratio, and severe white matter lesions may be poor prognostic factors for patients with ISSNHL. The association between thrombosis-related genes and susceptibility to ISSNHL has been reported in many studies (e.g., coagulation factor 2, coagulation factor 5, plasminogen activator inhibitor-1, platelet-associated genes, a homocysteine metabolism-related enzyme gene, endothelin-1, nitric oxide 3, phosphodiesterase 4D, complement factor H, and protein kinase C-eta). Treatment of ISSNHL with the aim of mitigating the vascular impairment in the inner ear includes systemically administered steroids, intratympanic steroid injections, hyperbaric oxygen therapy, prostaglandin E1, defibrinogenation therapy, and hydrogen inhalation therapy, but there is currently no evidence-based treatment for ISSNHL. Breakthroughs in the unequivocal diagnosis and treatment of ISSNHL due to vascular impairment are crucial to improve quality of life.
PubMed: 38850720
DOI: 10.1016/j.anl.2024.05.009 -
Archives of Dermatological Research Jun 2024Loss and absence of melanocytes due to a number of factors is responsible for vitiligo; known to be the commonest disorder of pigmentation. The aim of the current work... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Loss and absence of melanocytes due to a number of factors is responsible for vitiligo; known to be the commonest disorder of pigmentation. The aim of the current work was to compare the efficacy and safety of excimer light with topical tacrolimus ointment 0.1% versus excimer light with topical bimatoprost gel 0.01% in treatment of facial vitiligo. The study was carried out on 48 patients presented with facial vitiligo. The patients were divided randomly using sealed envelope method into two groups (24 patients each). Group 1 were treated with excimer light plus topical tacrolimus ointment 0.1% and group 2 treated with excimer light plus topical bimatoprost gel 0.01%. Clinical improvement based on the quartile grading scale at the end of treatment did not show any statistically significant difference between groups. The majority of subjects in both groups experienced good to excellent improvement. Only 20.9% of patients in group 1 and 33.3% of subjects in group 2 achieved less than 50% repigmentation (p = 0.889). Our study demonstrated that 0.01% topical bimatoprost gel in combination with excimer light is considered safe and effective as treatment of nonsegmental facial vitiligo with comparable results to 0.1% tacrolimus.
Topics: Humans; Vitiligo; Tacrolimus; Bimatoprost; Female; Male; Adult; Treatment Outcome; Young Adult; Adolescent; Middle Aged; Lasers, Excimer; Administration, Topical; Skin Pigmentation; Face; Administration, Cutaneous; Child; Combined Modality Therapy; Immunosuppressive Agents
PubMed: 38850408
DOI: 10.1007/s00403-024-03054-5 -
BMJ Open Gastroenterology Jun 2024The management of non-alcoholic steatohepatitis (NASH) is an unmet clinical need. Misoprostol, a structural analogue of naturally occurring prostaglandin E1, has been... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
The management of non-alcoholic steatohepatitis (NASH) is an unmet clinical need. Misoprostol, a structural analogue of naturally occurring prostaglandin E1, has been reported to decrease proinflammatory cytokine production and may have a potential role in treating NASH. We aimed to evaluate the efficacy and safety of misoprostol in treating patients with NASH.
METHODS
In this phase 2, double-blind, randomised, placebo-controlled trial, patients with NASH were randomly assigned in a 1:1 ratio to receive 200 µg of misoprostol or placebo thrice daily for 2 months. The primary endpoint was an improvement in liver function tests (LFTs), interleukin-6 (IL-6) and endotoxin levels. The secondary endpoint was improvement in insulin resistance, dyslipidaemia, hepatic fibrosis and hepatic steatosis.
RESULTS
A total of 50 patients underwent randomisation, of whom 44 (88%) were males. The age range was 25-64 years (mean±SE of mean (SEM) 38.1±1.4). 19 (38%) patients had concomitant type 2 diabetes mellitus. 32 (64%) patients were either overweight or obese. At the end of 2 months' treatment, a reduction in total leucocyte count (TLC) (p=0.005), alanine aminotransferase (ALT) (p<0.001), aspartate aminotransferase (AST) (p=0.002) and controlled attenuation parameter (CAP) (p=0.003) was observed in the misoprostol group, whereas placebo ensued a decline in ALT (p<0.001), AST (p=0.018), gamma-glutamyl transferase (GGT) (p=0.003), CAP (p=0.010) and triglycerides (p=0.048). There was no diminution in insulin resistance, hepatic fibrosis (elastography) and dyslipidaemia in both groups. However, misoprostol resulted in a significant reduction in CAP as compared with the placebo group (p=0.039). Moreover, in the misoprostol group, pretreatment and post-treatment IL-6 and endotoxin levels remained stable, while in the placebo group, an increase in the IL-6 levels was noted (p=0.049). Six (12%) patients had at least one adverse event in the misoprostol group, as did five (10%) in the placebo group. The most common adverse event in the misoprostol group was diarrhoea. No life-threatening events or treatment-related deaths occurred in each group.
CONCLUSION
Improvement in the biochemical profile was seen in both misoprostol and placebo groups without any statistically significant difference. However, there was more improvement in steatosis, as depicted by CAP, in the misoprostol group and worsening of IL-6 levels in the placebo group.
TRIAL REGISTRATION NUMBER
NCT05804305.
Topics: Humans; Male; Female; Non-alcoholic Fatty Liver Disease; Middle Aged; Double-Blind Method; Adult; Misoprostol; Interleukin-6; Treatment Outcome; Insulin Resistance; Liver Cirrhosis; Liver Function Tests; Liver
PubMed: 38844374
DOI: 10.1136/bmjgast-2023-001342 -
Frontiers in Pharmacology 2024Ginseng leaves are known to contain high concentrations of bioactive compounds, such as ginsenosides, and have potential as a treatment for various conditions, including...
Ginseng leaves are known to contain high concentrations of bioactive compounds, such as ginsenosides, and have potential as a treatment for various conditions, including fungal infections, cancer, obesity, oxidative stress, and age-related diseases. This study assessed the impact of ginseng leaf extract (GLE) on mast cell-mediated allergic inflammation and atopic dermatitis (AD) in DNCB-treated mice. GLE reduced skin thickness and lymph node nodules and suppressed the expression and secretion of histamine and pro-inflammatory cytokines. It also significantly lowered the production of inflammatory response mediators including ROS, leukotriene C4 (LTC4), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). GLE inhibited the phosphorylation of MAPKs (ERK, P38, JNK) and the activation of NF-κB, which are both linked to inflammatory cytokine expression. We demonstrated that GLE's inhibitory effect on mast cell-mediated allergic inflammation is due to the blockade of the NF-κB and inflammasome pathways. Our findings suggest that GLE can be an effective therapeutic agent for mast-cell mediated and allergic inflammatory conditions.
PubMed: 38841363
DOI: 10.3389/fphar.2024.1403285 -
Archivos Espanoles de Urologia May 2024Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common chronic disease, and its aetiology and pathogenesis remain unclear. This study aimed to identify...
BACKGROUND
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common chronic disease, and its aetiology and pathogenesis remain unclear. This study aimed to identify potential urine and serum biomarkers in patients with IC/BPS to further understand the pathogenesis and diagnosis of the disease.
METHODS
Patients with IC/BPS diagnosed and treated in the First Hospital of Hebei Medical University from 1 July 2021 to 30 July 2023 were selected. The urine and serum biomarkers of 50 patients with IC/BPS were investigated and compared with the urine and serum samples of 50 healthy controls. IBM SPSS Statistics 26.0 was used for statistical analysis of the recorded data by using chi-square test, -test and logistic regression analysis.
RESULTS
Overall, 50 patients with IC/BPS (mean age, 54.20 ± 8.15 years) were included in the study. Those with history of urinary diseases, anxiety or depression were susceptible to IC/BPS. Levels of interleukin (IL)-6, tumor necrosis factor-α (TNF-α), nerve growth factor, and prostaglandin E2 (PGE2) in urine, as well as IL-8, TNF-α, and PGE2 in serum, were found to significantly increase in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). These differences were statistically significant ( < 0.05). Multifactor analysis showed that anxiety, depression, IL-6, IL-8, TNF-α and PEG2 are risk factors for patients with IC/BPS.
CONCLUSIONS
Multiple biomarkers were identified in the urine and serum of patients with IC/BPS, suggesting a potential close relationship to the pathogenesis of IC/BPS.
Topics: Humans; Cystitis, Interstitial; Biomarkers; Middle Aged; Female; Male; Adult; Tumor Necrosis Factor-alpha; Interleukin-6
PubMed: 38840277
DOI: 10.56434/j.arch.esp.urol.20247704.48 -
Reproductive Health Jun 2024Medical abortion with mifepristone and misoprostol can be provided up to 63 days' gestation in India. This accounts for 67.5 percent of all abortions in the country. We...
BACKGROUND
Medical abortion with mifepristone and misoprostol can be provided up to 63 days' gestation in India. This accounts for 67.5 percent of all abortions in the country. We conducted an assessment to determine the availability of medical abortion medicines, specifically the combi-pack, in India.
METHODS
We applied the World Health Organization landscape assessment protocol at the national level. The assessment protocol included a five-step adaptation of an existing availability framework, including online data collection, desk review, country-level key informant interviews, and an analysis to identify barriers and opportunities to improve medical abortion availability. The assessment was conducted between August and March 2021.
RESULTS
Medicines for medical abortion are included in the national essential drug list and available with prescription in India. The assessment identified 42 combi-pack products developed by 35 manufacturers. The quality of medical abortion medicines is regulated by national authorities; but as health is devolved to states, there are significant inter-state variations. This is seen across financing, procurement, manufacturing, and monitoring mechanisms for quality assurance of medical abortion medicines prior to distribution. There is a need to strengthen supply chain systems, ensure consistent availability of trained providers and build community awareness on use of medical abortion medicines for early abortions, at the time of the assessment.
CONCLUSION
Opportunities to improve availability and quality of medical abortion medicines exist. For example, uniform implementation of regulatory standards, greater emphasis on quality-assurance during manufacturing, and standardizing of procurement and supply chain systems across states. Regular in-service training of providers on medical abortion is required. Finally, innovations in evidence dissemination and community engagement about the recently amended abortion law are needed.
Topics: Humans; India; Abortion, Induced; Female; Pregnancy; Health Services Accessibility; Abortifacient Agents; Misoprostol; Mifepristone; Drugs, Essential
PubMed: 38840263
DOI: 10.1186/s12978-024-01774-5 -
BMJ Open Jun 2024Public training in cardiopulmonary resuscitation and treatment in emergency and intensive care unit have made tremendous progress. However, cardiac arrest remains a... (Observational Study)
Observational Study
INTRODUCTION
Public training in cardiopulmonary resuscitation and treatment in emergency and intensive care unit have made tremendous progress. However, cardiac arrest remains a major health burden worldwide, with brain damage being a significant contributor to disability and mortality. Lipocalin-type prostaglandin D synthase (L-PGDS), which is mainly localised in the central nervous system, has been previously shown to inhibit postischemia neuronal apoptosis. Therefore, we aim to observe whether serum L-PGDS can serve as a potential biomarker and explore its role in determining the severity and prognosis of patients who have achieved restoration of spontaneous circulation (ROSC).
METHODS AND ANALYSIS
This is a prospective observational study. The participants (n = 60) who achieve ROSC will be distributed into two groups (non-survivor and survivor) based on 28-day survival. Healthy volunteers (n = 30) will be enrolled as controls. Each individual's relevant information will be extracted from Electronic Medical Record System in Xinhua Hospital, including demographic characteristics, clinical data, laboratory findings and so on. On days 1, 3 and 7 after ROSC, blood samples will be drawn and batch tested on the level of serum neuron-specific enolase, soluble protein 100β, L-PGDS, procalcitonin, tumour necrosis factor-alpha and interleukin-6. The cerebral performance category score was assessed on the 28th day after ROSC.
ETHICS AND DISSEMINATION
This study was performed with the approval of the Clinical Ethical Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Approval No. XHEC-C-2023-130-1). The results will be published in a peer-reviewed journal.
TRIAL REGISTRATION NUMBER
Chinese Clinical Trial Registry (ChiCTR2300078564).
Topics: Humans; Prospective Studies; Intramolecular Oxidoreductases; Lipocalins; Heart Arrest; Biomarkers; Prognosis; Male; Cardiopulmonary Resuscitation; Female; Predictive Value of Tests; Adult; Middle Aged; Observational Studies as Topic
PubMed: 38839386
DOI: 10.1136/bmjopen-2023-083136 -
Bioorganic Chemistry Aug 2024Targeting protein kinases that regulate signalling pathways in inflammation is an effective pharmacological approach to alleviate uncontrolled inflammatory diseases. In...
Targeting protein kinases that regulate signalling pathways in inflammation is an effective pharmacological approach to alleviate uncontrolled inflammatory diseases. In this context, the natural product indirubin and its 6-bromo-substituted analogue 6-bromoindirubin-3 -glycerol-oxime ether (6BIGOE; 1) were identified as potent inhibitors of glycogen synthase kinase-3β (GSK-3β). These inhibitors suppress the release of pro-inflammatory cytokines and prostaglandins (PG) from human monocytes. However, indirubin derivatives target several protein kinases such as cyclin-dependent kinases (CDKs) which has been a major concern for their application in inflammation therapy. Here, we report on a library of 13 5-bromo-substituted indirubin derivatives that have been designed to improve potency and target selectivity. Side-by-side comparison of reference compound 1 (6BIGOE) with 5-bromo derivatives revealed its isomer 2 (5BIGOE), as the most potent derivative able to supress pro-inflammatory cytokine and PG release in lipopolysaccharide-stimulated human monocytes. Analysis of protein kinase inhibition in intact monocytes, supported by our in silico findings, proposed higher selectivity of 1 for GSK-3β inhibition with lesser potency against CDKs 8 and 9. In contrast, 2 supressed the activity of these CDKs with higher effectiveness than GSK-3β, representing additional targets of indirubins within the inflammatory response. Encapsulation of 1 and 2 into polymer-based nanoparticles (NP) improved their pharmacological potential. In conclusion, the 5- and 6-brominated indirubins 1 and 2 as dual GSK-3β and CDK8/9 inhibitors represent a novel concept for intervention with inflammatory disorders.
Topics: Humans; Monocytes; Indoles; Protein Kinase Inhibitors; Signal Transduction; Structure-Activity Relationship; Molecular Structure; Inflammation Mediators; Dose-Response Relationship, Drug; Lipopolysaccharides; Cytokines; Molecular Docking Simulation
PubMed: 38838619
DOI: 10.1016/j.bioorg.2024.107470