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World Journal of Experimental Medicine Mar 2024Diabetes is known damage the liver and kidney, leading to hepatic dysfunction and kidney failure. Honey is believed to help in lowering the blood glucose levels of...
BACKGROUND
Diabetes is known damage the liver and kidney, leading to hepatic dysfunction and kidney failure. Honey is believed to help in lowering the blood glucose levels of diabetic patients and reducing diabetic complications. However, the effect of stingless bee honey (SBH) administration in relieving liver and kidney damage in diabetes has not been well-studied.
AIM
To investigate the effect of SBH administration on the kidney and liver of streptozotocin-induced (STZ; 55 mg/kg) diabetic Sprague Dawley rats.
METHODS
The rats were grouped as follows ( = 6 per group): non-diabetic (ND), untreated diabetic (UNT), metformin-treated (MET), and SBH+metformin-treated (SBME) groups. After successful diabetic induction, ND and UNT rats were given normal saline, whereas the treatment groups received SBH (2.0 g/kg and/or metformin (250 mg/kg) for 12 d. Serum biochemical parameters and histological changes using hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining were evaluated.
RESULTS
On H&E and PAS staining, the ND group showed normal architecture and cellularity of Bowman's capsule and tubules, whereas the UNT and MET groups had an increased glomerular cellularity and thickened basement membrane. The SBH-treated group showed a decrease in hydropic changes and mild cellularity of the glomerulus the ND group based on H&E staining, but the two were similar on PAS staining. Likewise, the SBME-treated group had an increase in cellularity of the glomerulus on H&E staining, but it was comparable to the SBH and ND groups on PAS staining. UNT diabetic rats had tubular hydropic tubules, which were smaller than other groups. Reduced fatty vacuole formation and dilated blood sinusoids in liver tissue were seen in the SBH group. Conversely, the UNT group had high glucose levels, which subsequently increased MDA levels, ultimately leading to liver damage. SBH treatment reduced this damage, as evidenced by having the lowest fasting glucose, serum alanine transaminase, aspartate transaminase, and alkaline phosphatase levels compared to other groups, although the levels of liver enzymes were not statistically significant.
CONCLUSION
The cellularity of the Bowman's capsule, as well as histological alteration of kidney tubules, glomerular membranes, and liver tissues in diabetic rats after oral SBH resembled those of ND rats. Therefore, SBH exhibited a protective hepatorenal effect in a diabetic rat model.
PubMed: 38590306
DOI: 10.5493/wjem.v14.i1.91271 -
CPT: Pharmacometrics & Systems... Apr 2024Pralsetinib, a potent and selective inhibitor of oncogenic RET fusion and RET mutant proteins, is a substrate of the drug metabolizing enzyme CYP3A4 and a substrate of...
Pralsetinib, a potent and selective inhibitor of oncogenic RET fusion and RET mutant proteins, is a substrate of the drug metabolizing enzyme CYP3A4 and a substrate of the efflux transporter P-gp based on in vitro data. Therefore, its pharmacokinetics (PKs) may be affected by co-administration of potent CYP3A4 inhibitors and inducers, P-gp inhibitors, and combined CYP3A4 and P-gp inhibitors. With the frequent overlap between CYP3A4 and P-gp substrates/inhibitors, pralsetinib is a challenging and representative example of the need to more quantitatively characterize transporter-enzyme interplay. A physiologically-based PK (PBPK) model for pralsetinib was developed to understand the victim drug-drug interaction (DDI) risk for pralsetinib. The key parameters driving the magnitude of pralsetinib DDIs, the P-gp intrinsic clearance and the fraction metabolized by CYP3A4, were determined from PBPK simulations that best captured observed DDIs from three clinical studies. Sensitivity analyses and scenario simulations were also conducted to ensure these key parameters were determined with sound mechanistic rationale based on current knowledge, including the worst-case scenarios. The verified pralsetinib PBPK model was then applied to predict the effect of other inhibitors and inducers on the PKs of pralsetinib. This work highlights the challenges in understanding DDIs when enzyme-transporter interplay occurs, and demonstrates an important strategy for differentiating enzyme/transporter contributions to enable PBPK predictions for untested scenarios and to inform labeling.
Topics: Humans; Cytochrome P-450 CYP3A; Drug Interactions; Pyrimidines; Pyridines; Membrane Transport Proteins; Cytochrome P-450 CYP3A Inhibitors; Models, Biological; Pyrazoles
PubMed: 38481038
DOI: 10.1002/psp4.13114 -
Case Reports in Nephrology and Dialysis 2024Alport syndrome (AS) is a hereditary, progressive kidney disease characterized by structural abnormalities and dysfunction of the glomerular basement membrane (GBM). AS...
INTRODUCTION
Alport syndrome (AS) is a hereditary, progressive kidney disease characterized by structural abnormalities and dysfunction of the glomerular basement membrane (GBM). AS is classified as X-linked, autosomal, and digenic. The number of cases of digenic AS has increased, but the genotype-phenotype correlation of patient with digenic AS is still unclear. Here, we present a case of digenic AS with novel digenic missense variants in (c.827G>C, p.Gly276Ala) and (c.4369G>C, p.Gly1457Arg).
CASE PRESENTATION
The patient was a 29-year-old Japanese man suffering from persistent microscopic hematuria and proteinuria without kidney function impairment. Kidney biopsy showed focal interstitial foam cell infiltration, global and segmental glomerulosclerosis. Immunofluorescence staining for collagen IV α5 was almost negative in the GBM and Bowman's capsule. Electron microscopy revealed irregular thickening with lamellation and segmental thinning of the GBM. Clinical and pathological findings were consistent with AS. Comprehensive next-generation sequencing revealed a heterozygous missense variant in (c.827G>C, p.Gly276Ala) in exon 1 and a hemizygous missense variant in (c.4369G>C, p.Gly1457Arg) in exon 49 on the patient's paternal and maternal alleles, respectively. The same digenic variants were detected in his sister, and she also showed a similar phenotype. After treatment with angiotensin-converting enzyme inhibitors, proteinuria decreased from 2.3 to 1.1 g/g creatinine, but occult blood persisted. During follow-up, kidney function has been preserved.
CONCLUSION
The novel genotype of our case provides more information on the genotype-phenotype correlation of digenic XLAS, although long-term follow-up is required. The findings in the present case also indicate the importance of genetic tests for family members of a patient diagnosed with digenic AS.
PubMed: 38179179
DOI: 10.1159/000535493 -
Frontiers in Physiology 2023The kidney is the key organ responsible for maintaining the body's water and electrolyte homeostasis. About 99% of the primary urine filtered from the Bowman's capsule... (Review)
Review
The kidney is the key organ responsible for maintaining the body's water and electrolyte homeostasis. About 99% of the primary urine filtered from the Bowman's capsule is reabsorbed along various renal tubules every day, with only 1-2 L of urine excreted. Aquaporins (AQPs) play a vital role in water reabsorption in the kidney. Currently, a variety of molecules are found to be involved in the process of urine concentration by regulating the expression or activity of AQPs, such as antidiuretic hormone, renin-angiotensin-aldosterone system (RAAS), prostaglandin, and several nuclear receptors. As the main bile acid receptors, farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor 1 (TGR5) play important roles in bile acid, glucose, lipid, and energy metabolism. In the kidney, FXR and TGR5 exhibit broad expression across all segments of renal tubules, and their activation holds significant therapeutic potential for numerous acute and chronic kidney diseases through alleviating renal lipid accumulation, inflammation, oxidative stress, and fibrosis. Emerging evidence has demonstrated that the genetic deletion of FXR or TGR5 exhibits increased basal urine output, suggesting that bile acid receptors play a critical role in urine concentration. Here, we briefly summarize the function of bile acid receptors in renal water reabsorption and urine concentration.
PubMed: 38033333
DOI: 10.3389/fphys.2023.1322288 -
Glomerular Diseases 2023Anti-glomerular basement membrane (anti-GBM) disease is a rare organ-specific autoimmune disease. The overall and renal outcomes of patients have mostly been reported in...
INTRODUCTION
Anti-glomerular basement membrane (anti-GBM) disease is a rare organ-specific autoimmune disease. The overall and renal outcomes of patients have mostly been reported in small-sized cohorts. We aimed to study the clinical profile, overall survival, and renal survival of anti-glomerular basement membrane disease patients at our center.
METHODS
We conducted a retrospective analysis of the data regarding the clinical profile and renal survival of patients diagnosed with anti-GBM disease from October 2019 to March 2022, having a minimum follow-up of 12 months.
RESULTS
There were 15 patients in the study, with the mean age of presentation being 51.6 ± 13.7 years. The median duration of symptoms onset to the nephrologist opinion was 15 (10-23) days. The extrarenal manifestations were seen in the respiratory, otorhinolaryngological, and neurological systems. The mean serum anti-GBM titers were 154.5 (14.9-263.5) U/mL. Serum anti-GBM titers were present in 13/15 (86.6%) patients, and 12/13 (92.3%) patients had above the reference range. Anti-neutrophil cytoplasm antibody (ANCA) levels were assessed in 12/15 (80%) patients, and 9/12 (75%) had higher levels. Renal biopsy was available in 14 patients with more than 50% crescents. Along with crescents, necrotizing lesions, rupture of the Bowman's capsule, and granulomatous lesions were also seen. Among the initial therapies, the steroid pulse was given to 13 (86.6%) patients, whereas membrane plasmapheresis was given to 8 (53.3%) patients. Inj. cyclophosphamide and inj. rituximab were given to 8 (53.3%) and 4 (26.6%) patients, respectively. No difference was seen in clinical characteristics, renal biopsy features, treatment received, and outcomes with ANCA positivity except for age, where patients who were ANCA positive were older compared to patients who were ANCA negative. One-year renal and patient survival was seen in 4 (26.6%) and 6 (40%) patients, respectively.
CONCLUSION
Most patients of anti-GBM disease have active sediments, raised creatinine, and non-specific symptomatology. There is poor renal and patient outcome as most patients present with advanced renal failure.
PubMed: 38021463
DOI: 10.1159/000534498 -
Journal of Molecular Biology Nov 2023In protein evolution, diversification is generally driven by genetic duplication. The hallmarks of this mechanism are visible in the repeating topology of various...
In protein evolution, diversification is generally driven by genetic duplication. The hallmarks of this mechanism are visible in the repeating topology of various proteins. In outer membrane β-barrels, duplication is visible with β-hairpins as the repeating unit of the barrel. In contrast to the overall use of duplication in diversification, a computational study hypothesized evolutionary mechanisms other than hairpin duplications leading to increases in the number of strands in outer membrane β-barrels. Specifically, the topology of some 16- and 18-stranded β-barrels appear to have evolved through a loop to β-hairpin transition. Here we test this novel evolutionary mechanism by creating a chimeric protein from an 18-stranded β-barrel and an evolutionarily related 16-stranded β-barrel. The chimeric combination of the two was created by replacing loop L3 of the 16-stranded barrel with the sequentially matched transmembrane β-hairpin region of the 18-stranded barrel. We find the resulting chimeric protein is stable and has characteristics of increased strand number. This study provides the first experimental evidence supporting the evolution through a loop to β-hairpin transition.
Topics: Bacterial Outer Membrane Proteins; Directed Molecular Evolution; Porins; Protein Domains; Recombinant Fusion Proteins; Protein Folding; Protein Conformation, beta-Strand
PubMed: 37769963
DOI: 10.1016/j.jmb.2023.168292 -
International Journal of Ophthalmology 2023To report the outcomes of three cases of corneal perforation managed with simultaneous tectonic Descemet stripping endothelial keratoplasty (t-DSEK) and tectonic Bowman...
AIM
To report the outcomes of three cases of corneal perforation managed with simultaneous tectonic Descemet stripping endothelial keratoplasty (t-DSEK) and tectonic Bowman layer transplant (t-BLT) as an alternative to tectonic penetrating keratoplasty (t-PKP).
METHODS
Three eyes of three patients receiving simultaneous t-DSEK and t-BLT for corneal perforation were included. The technique for DSEK was modified depending on individual requirements. The t-BLT technique was standardised using an 8 mm graft and fixated with a running suture. Success was measured by the ability of this procedure to close a corneal perforation.
RESULTS
All three cases achieved tectonic eye globe restoration and remained stable during the minimum 3-month observation period. Reinterventions were relatively common: 2 cases required amniotic membrane transplant for persistent epithelial defects. One case required DSEK rebubbling. One case developed angle closure glaucoma requiring surgical peripheral iridectomy.
CONCLUSION
Simultaneous t-DSEK and t-BLT may be a useful strategy for the management of corneal perforation as an alternative management to t-PKP for selected cases.
PubMed: 37724267
DOI: 10.18240/ijo.2023.09.24