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Indian Journal of Ophthalmology Oct 2023To compare the efficacy of oral propranolol, oral rifampicin, and intravitreal anti-VEGF therapies on resolution-time and visual outcome in patients with central serous... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To compare the efficacy of oral propranolol, oral rifampicin, and intravitreal anti-VEGF therapies on resolution-time and visual outcome in patients with central serous chorioretinopathy (CSCR).
METHODS
A total of 30 patients with CSCR were randomized into three groups of 10 patients. Group A was given oral propranolol, Group B was given oral rifampicin 4 weeks each, and Group C was given 0.05 ml intravitreal injection of anti-VEGF. Comparisons of mean BCVA, contrast sensitivity, and central macular thickness (CMT) performed between baseline and follow-up at 4 weeks, 6 weeks, and 3 months.
RESULTS
Statistically significant improvement in BCVA and contrast sensitivity was noted among all three groups. Complete resolution of SRF as indicated by CMT was seen at the end of 4 weeks in Group C, whereas there was a steady decline in CMT until 3 months in Groups A and B.
CONCLUSION
Intravitreal anti-VEGF therapy shows a significantly faster SRF resolution. However, oral propranolol and oral rifampicin could prove as a useful, cost-effective treatment of CSCR.
Topics: Humans; Central Serous Chorioretinopathy; Propranolol; Rifampin; Treatment Outcome; Tomography, Optical Coherence; Intravitreal Injections
PubMed: 37787239
DOI: 10.4103/IJO.IJO_169_23 -
International Journal of Molecular... Dec 2023Heart failure and chronic kidney disease (CKD) share several mediators of cardiac pathological remodelling. Akin to heart failure, this remodelling sets in motion a...
Heart failure and chronic kidney disease (CKD) share several mediators of cardiac pathological remodelling. Akin to heart failure, this remodelling sets in motion a vicious cycle of progressive pathological hypertrophy and myocardial dysfunction in CKD. Several decades of heart failure research have shown that beta blockade is a powerful tool in preventing cardiac remodelling and breaking this vicious cycle. This phenomenon remains hitherto untested in CKD. Therefore, we set out to test the hypothesis that beta blockade prevents cardiac pathological remodelling in experimental uremia. rats had subtotal nephrectomy or sham surgery and were followed up for 10 weeks. The animals were randomly allocated to the beta blocker metoprolol (10 mg/kg/day) or vehicle. In vivo and in vitro cardiac assessments were performed. Cardiac tissue was extracted, and protein expression was quantified using immunoblotting. Histological analyses were performed to quantify myocardial fibrosis. Beta blockade attenuated cardiac pathological remodelling in nephrectomised animals. The echocardiographic left ventricular mass and the heart weight to tibial length ratio were significantly lower in nephrectomised animals treated with metoprolol. Furthermore, beta blockade attenuated myocardial fibrosis associated with subtotal nephrectomy. In addition, the Ca- calmodulin-dependent kinase II (CAMKII) pathway was shown to be activated in uremia and attenuated by beta blockade, offering a potential mechanism of action. In conclusion, beta blockade attenuated hypertrophic signalling pathways and ameliorated cardiac pathological remodelling in experimental uremia. The study provides a strong scientific rationale for repurposing beta blockers, a tried and tested treatment in heart failure, for the benefit of patients with CKD.
Topics: Humans; Rats; Animals; Rats, Wistar; Metoprolol; Heart Failure; Renal Insufficiency, Chronic; Hypertrophy; Fibrosis
PubMed: 38203544
DOI: 10.3390/ijms25010373 -
BMC Endocrine Disorders Nov 2023Patients with bilateral primary aldosteronism (PA) generally are treated with antihypertensive drugs, but optimal treatment for patients with complications due to...
BACKGROUND
Patients with bilateral primary aldosteronism (PA) generally are treated with antihypertensive drugs, but optimal treatment for patients with complications due to refractory hypertension has not been established. In this report, we present a case with bilateral PA who presented with persistent hypertension, despite treatment with 6 drugs, and left-dominant heart failure, which was improved after unilateral adrenalectomy.
CASE PRESENTATION
A 61-year-old man was admitted to our hospital because of severe left-dominant heart failure. His heart rhythm was atrial fibrillation and the left ventricle was diffusely hypertrophic and hypokinetic. Coronary arteries were normal on coronary arteriogram. Primary aldosteronism was suspected based on severe hypokalemia (2.5 mEq/L) and plasma aldosterone concentration (PAC; 1,410 pg/mL). Although computed tomography (CT) showed a single left cortical nodule, adrenal vein sampling (AVS) indicated bilateral PA. Early in the case, heart failure and hyperkalemia in this patient were improved by treatment with a combination of 6 antihypertensive drugs (spironolactone 25 mg/day, eplerenone 100 mg/day, azosemide 60 mg/day, tolvaptan 7.5 mg/day, enalapril 5 mg/day, and bisoprolol fumarate 10 mg/day); however, heart failure relapsed after four months of treatment. We hypothesized that hypertension caused by excess aldosterone was inducing the patient's heart failure. In order to reduce aldosterone secretory tissue, a laparoscopic adrenalectomy was performed for the left adrenal gland, given the higher level of aldosterone from the left gland compared to the right. Following surgery, the patient's heart failure was successfully controlled despite the persistence of high PAC. Treatment with anti-hypertensive medications was reduced to two drugs (eplerenone 100 mg/day and bisoprolol fumarate 10 mg/day). In order to elucidate the mechanism of drug resistance, immunohistochemistry (IHC) and real time-polymerase chain reaction (RT-PCR) assays were performed to assess the expression of steroidogenic factor 1 (SF-1), a regulator of steroid synthesis in adrenal tissue. IHC and RT-PCR demonstrated that the expression of SF-1 in this patient (at both the protein and mRNA levels) was higher than that observed in unilateral PA cases that showed good responsivity to drug treatment.
CONCLUSIONS
Unilateral adrenalectomy to reduce aldosterone secretory tissue may be useful for patients with drug-refractory, bilateral PA. Elevated expression of SF-1 may be involved in drug resistance in PA.
Topics: Humans; Male; Middle Aged; Adrenal Glands; Adrenalectomy; Aldosterone; Antihypertensive Agents; Bisoprolol; Eplerenone; Heart Failure; Hyperaldosteronism; Hypertension
PubMed: 37932696
DOI: 10.1186/s12902-023-01503-2 -
Heliyon Jan 2024The presented research highlights a novel approach using fmoc-protected peptide hydrogels for the encapsulation and stretching of mesenchymal stem cells (MSCs). This...
The presented research highlights a novel approach using fmoc-protected peptide hydrogels for the encapsulation and stretching of mesenchymal stem cells (MSCs). This study utilized a custom mechanical stretching device with a PDMS chamber to stretch human MSCs encapsulated in Fmoc hydrogels. The study assessed the influence of various solvents on the self-assembly and mechanical properties of the hydrogels, and MSC viability and alignment. Particularly we focused on fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF) prepared in dimethyl sulfoxide (DMSO), hexafluoro-2-propanol (HFP), and deionized water (DiHO). Through molecular self-assembly of the peptide sequence into β-sheets connected by π-π aromatic stacking of F-F groups, the peptide hydrogel was found to form a stiff, hydrated gel with nanofiber morphology and a compressive modulus ranging from 174 to 277 Pa. Therefore, this hydrogel can mimic certain critical features of the extracellular matrix and collagen. Evaluations of MSCs cultured on the peptide hydrogels, including viability, morphology, and alignment assessments using various staining techniques, demonstrated that 3D-cultured MSCs in Fmoc-FF/HFP and Fmoc-FF/DMSO, followed by mechanical stretching, exhibited elongated morphology with distinct microfilament fibers compared to the control cells, which maintained a round and spherical F-actin shape. Notably, peptide gels with a concentration of 5 mM maintained 100 % MSC viability. The findings indicate the potential and specific conditions for successful cell encapsulation and alignment within peptide hydrogels, highlighting a promising tissue engineering platform through the encapsulation of MSCs in peptide nanofibers followed by a stretching process. By enhancing our understanding of MSC-peptide hydrogel interactions, this research contributes to the development of biomaterials tailored for regenerative medicine.
PubMed: 38234902
DOI: 10.1016/j.heliyon.2023.e23953 -
Hepatology Communications Feb 2024It has been suggested that a relevant proportion of patients do not respond to nonselective beta-blockers (NSBB)s, which raises questions regarding the need for... (Meta-Analysis)
Meta-Analysis
BACKGROUND
It has been suggested that a relevant proportion of patients do not respond to nonselective beta-blockers (NSBB)s, which raises questions regarding the need for individualized therapy. The existence of potential heterogeneity in the treatment response can be assessed using the variability ratio (VR) of the outcome measurement (in this case, HVPG) between the treated and placebo groups. We conducted a systematic review and meta-analysis of randomized controlled trials to assess the potential heterogeneity in the portal pressure response to NSBBs.
METHODS
After a systematic search, we quantified the heterogeneity of treatment response with the VR between the treatment and control groups, with VR > 1 indicating potential heterogeneity. We used a similar approach to compare carvedilol with propranolol and statins with placebo.
RESULTS
We identified 18 studies that included 965 patients. A comparison between beta-blockers and placebo showed a pooled VR of 0.99 (95% CI:0.87-1.14), which suggests a homogeneous HVPG response to NSBB at the individual patient level (ie, no evidence to support that some patients responded to beta-blockers and others did not). For the comparison between carvedilol and propranolol, pooled VR was 0.97 (95% CI 0.82-1.14), suggesting that carvedilol achieves a greater average response (rather than an increase in the proportion of responders). There was no evidence of a heterogeneous response to statins.
CONCLUSION
Our analysis did not support the existence of a heterogeneous patient-by-patient response to NSBBs in cirrhosis. These findings challenge the concept of personalized therapy based on portal pressure response and indicate that routine portal pressure measurement may not be necessary to guide NSBB therapy.
Topics: Humans; Propranolol; Carvedilol; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Adrenergic beta-Antagonists; Hypertension, Portal
PubMed: 38285880
DOI: 10.1097/HC9.0000000000000321 -
Biotechnology Letters Feb 2024Glucuronoyl esterases (GE, family CE15) catalyse the cleavage of ester linkages in lignin-carbohydrate complexes (LCCs), and this study demonstrate how...
PURPOSE
Glucuronoyl esterases (GE, family CE15) catalyse the cleavage of ester linkages in lignin-carbohydrate complexes (LCCs), and this study demonstrate how transesterification reactions with a fungal GE from Cerrena unicolor (CuGE) can reveal the enzyme's preference for the alcohol-part of the ester-bond.
METHODS
This alcohol-preference relates to where the ester-LCCs are located on the lignin molecule, and has consequences for how the enzymes potentially interact with lignin. It is unknown exactly what the enzymes prefer; either the α-benzyl or the γ-benzyl position. By providing the enzyme with a donor substrate (the methyl ester of either glucuronate or 4-O-methyl-glucuronate) and either one of two acceptor molecules (benzyl alcohol or 3-phenyl-1-propanol) we demonstrate that the enzyme can perform transesterification and it serves as a method for assessing the enzyme's alcohol preferences.
CONCLUSION
CuGE preferentially forms the γ-ester from the methyl ester of 4-O-methyl-glucuronate and 3-phenyl-1-propanol and the enzyme's substrate preferences are primarily dictated by the presence of the 4-O-methylation on the glucuronoyl donor, and secondly on the type of alcohol.
Topics: Esterases; Lignin; Carbohydrates; Esters; Glucuronates; Substrate Specificity; Propanols; Polyporales
PubMed: 38150097
DOI: 10.1007/s10529-023-03456-x -
Scientific Reports Nov 2023Low dose aspirin is routinely taken with antihypertensive drugs such as olmesartan and metoprolol to avoid the cardiovascular and renal outcomes associated with high...
Low dose aspirin is routinely taken with antihypertensive drugs such as olmesartan and metoprolol to avoid the cardiovascular and renal outcomes associated with high blood pressure. The first spectrofluorimetric method for quantifying aspirin, olmesartan, and metoprolol in spiked human plasma is described here. The emission/excitation wavelengths of Aspirin, olmesartan, and metoprolol were 404 nm/290 nm, 372 nm/250 nm, and 302 nm/230 nm, respectively. The native fluorescence spectra of metoprolol do not overlap with those of aspirin or olmesartan, although the spectra of aspirin and olmesartan overlap. As a result, metoprolol could be measured directly in a mixture at 302 nm following excitation at 230 nm. Using synchronous fluorescence spectrometry at Δλ = 110 allowed for the determination of olmesartan at 364 nm with no interference from aspirin and metoprolol. Coupling the synchronous fluorescence spectrometry with second-order derivative allowed for the determination of aspirin at 426 nm with no interference from olmesartan and metoprolol. The suggested approach has been validated using ICH M10 criteria for bioanalytical method validation and was effectively utilized for quantification of tested medications in human plasma with reasonable accuracy and precision findings. Furthermore, using two greenness metrics, the Green Analytical Procedure Index and the Analytical GREEnness, the suggested method obtained a high greenness score.
Topics: Humans; Metoprolol; Aspirin; Spectrometry, Fluorescence; Antihypertensive Agents
PubMed: 37978204
DOI: 10.1038/s41598-023-46042-x -
Synthetic and Systems Biotechnology Dec 2023Plant-originated natural products are important drug sources. However, total biosynthesis of these compounds is often not achievable due to their uncharacterized,...
Plant-originated natural products are important drug sources. However, total biosynthesis of these compounds is often not achievable due to their uncharacterized, lengthy biosynthetic pathways. In nature, phenethylisoquinoline alkaloids (PIAs) such as colchicine are biosynthesized via a common precursor 6,7-dihydroxy-1-(4-hydroxyphenylethyl)-1,2,3,4-tetrahydroisoquinoline (i.e., phenethylisoquinoline scaffold, PIAS). PIAS is naturally synthesized in plants by using two upstream substrates (l-phenylalanine and l-tyrosine) catalyzed by eight enzymes. To shorten this native pathway, here we designed an artificial route to synthesize PIAS with two enzymatic steps from two alternative substrates of 3-(4-hydroxyphenyl) propanol (4-HPP) and dopamine. In the two-step bioconversion, an alcohol dehydrogenase selected from yeast (i.e., ADH7) was able to oxidize its non-native alcohol substrate 4-HPP to form the corresponding aldehyde product, which was then condensed with dopamine by the ()-norcoclaurine synthase (NCS) to synthesize PIAS. After optimization, the final enzymatic reaction system was successfully scaled up by 200 times from 50 μL to 10 mL, generating 5.4 mM of PIAS. We envision that this study will provide an easy and sustainable approach to produce PIAS and thus lay the foundation for large-scale production of PIAS-derived natural products.
PubMed: 37781172
DOI: 10.1016/j.synbio.2023.09.003 -
Journal of Cellular and Molecular... Jan 2024Proranolol has long been recommended to prevent variceal bleeding in patients with cirrhosis. However, the mechanisms of propranolol in liver fibrosis have not yet been...
Proranolol has long been recommended to prevent variceal bleeding in patients with cirrhosis. However, the mechanisms of propranolol in liver fibrosis have not yet been thoroughly elucidated. Autophagic cell death (ACD) of activated hepatic stellate cells (HSCs) is important in the alleviation of liver fibrosis. Our study aims to assess the mechanisms of propranolol regulating HSC ACD and liver fibrosis. ACD of HSCs was investigated using lentivirus transfection. The molecular mechanism was determined using a PCR profiler array. The role of autophagy-related protein 9b (ATG9b) in HSC ACD was detected using co-immunoprecipitation and co-localization of immunofluorescence. Changes in the signalling pathway were detected by the Phospho Explorer antibody microarray. Propranolol induces ACD and apoptosis in HSCs. ATG9b upregulation was detected in propranolol-treated HSCs. ATG9b upregulation promoted ACD of HSCs and alleviated liver fibrosis in vivo. ATG9b enhanced the P62 recruitment to ATG5-ATG12-LC3 compartments and increased the co-localization of P62 with ubiquitinated proteins. The PI3K/AKT/mTOR pathway is responsible for ATG9b-induced ACD in activated HSCs, whereas the p38/JNK pathway is involved in apoptosis. This study provides evidence for ATG9b as a new target gene and propranolol as an agent to alleviate liver fibrosis by regulating ACD of activated HSCs.
Topics: Humans; Hepatic Stellate Cells; Propranolol; Autophagic Cell Death; Up-Regulation; Phosphatidylinositol 3-Kinases; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Liver Cirrhosis; Liver; Autophagy
PubMed: 37970991
DOI: 10.1111/jcmm.18047 -
European Journal of Pharmaceutical... Dec 2023Intrinsic membrane permeability is one of several factors that critically determine the intestinal absorption of a chemical. The intrinsic membrane permeability of a...
Intrinsic membrane permeability is one of several factors that critically determine the intestinal absorption of a chemical. The intrinsic membrane permeability of a chemical is usually extracted from transwell experiments with Caco-2 or MDCK cells, preferably by the pK-Flux method, which is considered the method of choice when aqueous boundary layer effects need to be excluded. The pK-Flux method has two variants, the iso-pH method, where apical and basolateral pH are equal, and the gradient-pH method, where apical and basolateral pH are different. The most commonly used method is the gradient-pH method, as it is intended to reflect the pH-conditions in the gastrointestinal tract. However, concentration-shift effects caused by the applied pH-difference between apical and basolateral compartment in the gradient-pH method have not been considered in the evaluation of the experimental data in the past. Consequently, incorrect intrinsic membrane permeabilities have been determined. In this work, we present a revised method for extracting the intrinsic membrane permeability from gradient-pH data that considers concentration-shift effects in the basolateral aqueous boundary layer and filter as well as in the cytosol. Furthermore, we propose the use of the iso-pH method, where only concentration-shift effects in the cytosol need to be considered, as an alternative to the gradient-pH method. We use the five lipophilic bases amantadine, chloroquine, propranolol, venlafaxine and verapamil as examples to compare gradient-pH method and iso-pH method with regard to the extractability of the intrinsic membrane permeability. For lipophilic bases, the iso-pH method proves to be advantageous. All intrinsic membrane permeabilities determined in this work were substantially higher than the intrinsic membrane permeabilities reported in literature.
Topics: Humans; Caco-2 Cells; Cell Membrane Permeability; Propranolol; Intestinal Absorption; Permeability; Hydrogen-Ion Concentration
PubMed: 37751809
DOI: 10.1016/j.ejps.2023.106592