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American Journal of Physiology. Renal... Jul 2024Diabetes is closely associated with K disturbances during disease progression and treatment. However, it remains unclear whether K imbalance occurs in diabetes with...
Diabetes is closely associated with K disturbances during disease progression and treatment. However, it remains unclear whether K imbalance occurs in diabetes with normal kidney function. In this study, we examined the effects of dietary K intake on systemic K balance and renal K handling in streptozotocin (STZ)-induced diabetic mice. The control and STZ mice were fed low or high K diet for 7 days to investigate the role of dietary K intake in renal K excretion and K homeostasis and to explore the underlying mechanism by evaluating K secretion-related transport proteins in distal nephrons. K-deficient diet caused excessive urinary K loss, decreased daily K balance, and led to severe hypokalemia in STZ mice compared with control mice. In contrast, STZ mice showed an increased daily K balance and elevated plasma K level under K-loading conditions. Dysregulation of the NaCl cotransporter (NCC), epithelial Na channel (ENaC), and renal outer medullary K channel (ROMK) was observed in diabetic mice fed either low or high K diet. Moreover, amiloride treatment reduced urinary K excretion and corrected hypokalemia in K-restricted STZ mice. On the other hand, inhibition of SGLT2 by dapagliflozin promoted urinary K excretion and normalized plasma K levels in K-supplemented STZ mice, at least partly by increasing ENaC activity. We conclude that STZ mice exhibited abnormal K balance and impaired renal K handling under either low or high K diet, which could be primarily attributed to the dysfunction of ENaC-dependent renal K excretion pathway, despite the possible role of NCC. Neither low dietary K intake nor high dietary K intake effectively modulates renal K excretion and K homeostasis in STZ mice, which is closely related to the abnormality of ENaC expression and activity. SGLT2 inhibitor increases urinary K excretion and reduces plasma K level in STZ mice under high dietary K intake, an effect that may be partly due to the upregulation of ENaC activity.
Topics: Animals; Diabetes Mellitus, Experimental; Potassium; Male; Potassium, Dietary; Epithelial Sodium Channels; Mice, Inbred C57BL; Sodium-Glucose Transporter 2 Inhibitors; Potassium Channels, Inwardly Rectifying; Mice; Diabetic Nephropathies; Kidney; Hypokalemia; Amiloride; Renal Elimination; Homeostasis; Solute Carrier Family 12, Member 3; Glucosides; Streptozocin; Benzhydryl Compounds; Sodium-Glucose Transporter 2
PubMed: 38779755
DOI: 10.1152/ajprenal.00240.2023 -
American Journal of Physiology. Renal... Jul 2024Interleukin (IL)-17A contributes to hypertension in preclinical models. T helper 17 and dendritic cells are activated by NaCl, which could involve the epithelial Na...
Interleukin (IL)-17A contributes to hypertension in preclinical models. T helper 17 and dendritic cells are activated by NaCl, which could involve the epithelial Na channel (ENaC). We hypothesized that the ENaC blocker amiloride reduces plasma IL-17A and related cytokines in patients with hypertension. Concentrations of IL-17A, IFN-γ, TNF, IL-6, IL-1β, and IL-10 were determined by immunoassays in plasma from two patient cohorts before and after amiloride treatment: ) patients with type 2 diabetes mellitus (T2DM) and treatment-resistant hypertension ( = 69, amiloride 5-10 mg/day for 8 wk) and ) patients with hypertension and type 1 diabetes mellitus (T1DM) ( = 29) on standardized salt intake (amiloride 20-40 mg/day, 2 days). Plasma and tissue from ANG II-hypertensive mice with T1DM treated with amiloride (2 mg/kg/day, 4 days) were analyzed. The effect of amiloride and benzamil on macrophage cytokines was determined in vitro. Plasma cytokines showed higher concentrations (IL-17A ∼40-fold) in patients with T2DM compared with T1DM. In patients with T2DM, amiloride had no effect on IL-17A but lowered TNF and IL-6. In patients with T1DM, amiloride had no effect on IL-17A but increased TNF. In both cohorts, blood pressure decline and plasma K increase did not relate to plasma cytokine changes. In mice, amiloride exerted no effect on IL-17A in the plasma, kidney, aorta, or left cardiac ventricle but increased TNF in cardiac and kidney tissues. In lipopolysaccharide-stimulated human THP-1 macrophages, amiloride and benzamil (from 1 nmol/L) decreased TNF, IL-6, IL-10, and IL-1β. In conclusion, inhibition of ENaC by amiloride reduces proinflammatory cytokines TNF and IL-6 but not IL-17A in patients with T2DM, potentially by a direct action on macrophages. ENaC activity may contribute to macrophage-derived cytokine release, since amiloride exerts anti-inflammatory effects by suppression of TNF and IL-6 cytokines in patients with resistant hypertension and type 2 diabetes and in THP-1-derived macrophages in vitro.
Topics: Amiloride; Humans; Interleukin-17; Animals; Diabetes Mellitus, Type 2; Interleukin-6; Male; Middle Aged; Hypertension; Female; Epithelial Sodium Channel Blockers; Tumor Necrosis Factor-alpha; Aged; Mice; Epithelial Sodium Channels; Mice, Inbred C57BL; Antihypertensive Agents; Macrophages; Blood Pressure; Diabetes Mellitus, Type 1
PubMed: 38779752
DOI: 10.1152/ajprenal.00268.2023 -
Cancer Reports (Hoboken, N.J.) May 2024Thalidomide-containing regimens cause adverse events (AEs) that may require a reduction in treatment intensity or even treatment discontinuation in patients with... (Observational Study)
Observational Study
The efficacy and tolerability of bortezomib, thalidomide, and dexamethasone induction therapy with a thalidomide dose step-up strategy in patients with newly diagnosed multiple myeloma: A prospective observational study.
BACKGROUND
Thalidomide-containing regimens cause adverse events (AEs) that may require a reduction in treatment intensity or even treatment discontinuation in patients with multiple myeloma. As thalidomide toxicity is dose-dependent, identifying the most appropriate dose for each patient is essential.
AIMS
This study aimed to investigate the effects of a thalidomide dose step-up strategy on treatment response and progression-free survival (PFS).
METHODS AND RESULTS
This prospective observational study included 93 patients with newly diagnosed multiple myeloma (NDMM) who received bortezomib, thalidomide, and dexamethasone (VTD). The present study assessed the incidence of thalidomide dose reduction and discontinuation, the overall dose intensity, and their effects on therapeutic efficacy. Furthermore, this study used Cox proportional hazard models to analyze the factors contributing to thalidomide intolerability. The results showed the overall response rates in all patients and the evaluable patients were 78.5% and 98.7%, respectively. The median PFS in the study cohort was not reached. The most common thalidomide-related AEs were constipation (32.3%) and skin rash (23.7%), resulting in dose reduction and discontinuation rates of 22.6% and 21.5%, respectively. The responders had a significantly higher average thalidomide dose intensity than the nonresponders (88.6% vs. 42.9%, p < .001).
CONCLUSION
The thalidomide dose step-up approach is a viable option for patients with NDMM receiving VTD induction therapy with satisfactory efficacy and tolerability. However, thalidomide intolerance may lead to dose reduction or discontinuation due to unpredictable AEs, leading to lower dose intensity and potentially inferior treatment outcomes. In addition to a dose step-up strategy, optimal supportive care is critical for patients with multiple myeloma receiving VTD induction therapy.
Topics: Humans; Multiple Myeloma; Thalidomide; Female; Dexamethasone; Male; Bortezomib; Prospective Studies; Aged; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Adult; Induction Chemotherapy; Progression-Free Survival; Aged, 80 and over; Dose-Response Relationship, Drug
PubMed: 38775249
DOI: 10.1002/cnr2.2102 -
Advanced Materials (Deerfield Beach,... May 2024Visible light is a universal and user-friendly excitation source; however, its use to generate persistent luminescence (PersL) in materials remains a huge challenge....
Visible light is a universal and user-friendly excitation source; however, its use to generate persistent luminescence (PersL) in materials remains a huge challenge. Herein, the concept of intermolecular charge transfer (xCT) is applied in typical host-guest molecular systems, which allows for a much lower energy requirement for charge separation, thus enabling efficient charging of near-infrared (NIR) PersL in organics by visible light (425-700 nm). Importantly, NIR PersL in organics occurs via the trapping of electrons from charge-transfer aggregates (CTAs) into constructed trap states with trap depths of 0.63-1.17 eV, followed by the detrapping of these electrons by thermal stimulation, resulting in a unique light-storage effect and long-lasting emission up to 4.6 h at room temperature. The xCT absorption range is modulated by changing the electron-donating ability of a series of acenaphtho[1,2-b]pyrazine-8,9-dicarbonitrile-based CTAs, and the organic PersL is tuned from 681 to 722 nm. This study on xCT interaction-induced NIR PersL in organic materials provides a major step forward in understanding the underlying luminescence mechanism of organic semiconductors and these findings are expected to promote their applications in optoelectronics, energy storage, and medical diagnosis.
PubMed: 38773688
DOI: 10.1002/adma.202401000 -
The American Journal of Tropical... Jul 2024The rising prevalence of drug-resistant Mycobacterium tuberculosis (MTB) strains poses a significant challenge to global tuberculosis (TB) control efforts. This study...
The rising prevalence of drug-resistant Mycobacterium tuberculosis (MTB) strains poses a significant challenge to global tuberculosis (TB) control efforts. This study aimed to analyze drug resistance patterns and investigate the molecular characteristics of 193 MTB clinical isolates to shed light on the mechanisms of drug resistance. Of the 193 MTB clinical isolates, 28.5% (n = 53) exhibited mono-drug or multidrug resistance. Pyrazinamide mono-drug resistance (PZAr) was the most prevalent (17%, n = 33), followed by isoniazid mono-drug resistance (3.6%, n = 7). Rifampicin resistance was associated with mutations in the rpoB gene (D435Y, D435V, S450L, L452P). Isoniazid resistance mutations were found in the katG (S315T), inhA (C[-15] T), and ndh (R268H) genes, whereas ethambutol resistance mutations were observed in the embB gene (M306V, M306I, M306L, G406S, Q497R). Surprisingly, 94% of PZAr isolates (n = 31) showed no mutations in the pncA or rpsA genes. The presence of the R268H mutation in the ndh gene, not previously linked to PZAr, was detected in 15% of PZAr isolates (n = 5), suggesting its potential contribution to PZAr in specific cases but not as a predominant mechanism. The specific molecular mechanisms underlying PZAr in the majority of the isolates remain unknown, emphasizing the need for further research to uncover the contributing factors. These findings contribute to the understanding of drug resistance patterns and can guide future efforts in TB control and management.
Topics: Mycobacterium tuberculosis; India; Humans; Antitubercular Agents; Mutation; Tertiary Care Centers; Microbial Sensitivity Tests; Tuberculosis, Multidrug-Resistant; Bacterial Proteins; Isoniazid; Rifampin; Pyrazinamide; Drug Resistance, Multiple, Bacterial; Adult; Female; Male; Ethambutol; Drug Resistance, Bacterial
PubMed: 38772358
DOI: 10.4269/ajtmh.24-0042 -
Chemistry (Weinheim An Der Bergstrasse,... May 2024π‑Conjugated materials are highly attractive owing to their unique optical and electronic properties. Covalent organic frameworks (COFs) offer a great opportunity for...
π‑Conjugated materials are highly attractive owing to their unique optical and electronic properties. Covalent organic frameworks (COFs) offer a great opportunity for precise arrangement of building units in a π-conjugated crystalline matrix and tuning of the properties through choice of functionalities or post-synthetic modification. With this review, we aim at summarizing both the most representative as well as emerging strategies for the synthesis of π-conjugated COFs. We give examples of direct synthesis methods with large, π-extended building blocks. COFs featuring fully conjugated linkages such as vinylene, pyrazine, and azole are discussed. Then, post-synthetic modification methods that result in the extension of the COF p-system are reviewed. Throughout, mechanistic insights are presented when available. In the context of their utilization as film devices, we conduct a concise survey of the prominent COF layer deposition techniques reported and their aptness for the deposition of fused aromatic systems.
PubMed: 38771916
DOI: 10.1002/chem.202401344 -
International Journal of Pharmaceutical... 2024Amiloride is a U.S. Food and Drug Administration-approved diuretic agent used to treat hypertension and congestive heart failure. Recent human and animal studies have...
Amiloride is a U.S. Food and Drug Administration-approved diuretic agent used to treat hypertension and congestive heart failure. Recent human and animal studies have suggested that amiloride may also have a role in treating anxiety through its acid-sensing ion channel antagonism. Intranasal administration of amiloride nasal spray via an extemporaneously compounded preparation has the potential for rapid delivery to the site of action to achieve therapeutic outcomes in individual patients with anxiety disorders. However, these patient-specific preparations do not have the pre-formulation characterization, including chemical stability, that conventional manufactured dosage forms have. The objective of this study was to assess the estimated chemical stability of compounded amiloride nasal spray over 6 months and 12 months utilizing accelerated degradation with high heat and the Arrhenius equation. A stability-indicating highperformance liquid chromatography analytical method was employed at appropriate intervals over a 12-month period to reveal that amiloride remained chemically stable over the period tested and by extrapolation. Physical stability and compatibility with the preservative benzyl alcohol were also confirmed via visual inspection, pH monitoring, and measurement of turbidity.
Topics: Amiloride; Drug Stability; Nasal Sprays; Drug Compounding; Administration, Intranasal; Chromatography, High Pressure Liquid; Hydrogen-Ion Concentration
PubMed: 38768504
DOI: No ID Found -
Hematology (Amsterdam, Netherlands) Dec 2024Examine Bach1 protein expression in bone marrow biopsy specimens obtained from newly diagnosed multiple myeloma (NDMM) and iron deficiency anemia (IDA) patients. Conduct...
OBJECTIVE
Examine Bach1 protein expression in bone marrow biopsy specimens obtained from newly diagnosed multiple myeloma (NDMM) and iron deficiency anemia (IDA) patients. Conduct a thorough analysis to explore the potential connection between Bach1 and the onset as well as treatment response of NDMM.
METHODS
This study investigated Bach1 expression in bone marrow biopsy tissues from NDMM and IDA patients. Immunohistochemical staining and Image-pro Plus software were utilized for quantitatively obtaining the expression level of Bach1 protein. Arrange Bach1 expression levels from high to low, and use its median expression level as the threshold. Samples with Bach1 expression level above the median are categorized as the high-expression group, while those below the median are categorized as the low-expression group. Under this grouping, a detailed discussion was conducted to explore relationship of the Bach1 expression level with the patients' gender, ISS stage, and survival rate based on the Bortezomib (Btz) therapy.
RESULTS
Our experiment indicates that the expression level of Bach1 in NDMM patients is significantly higher than in IDA patients. Furthermore, we discovered that patients in the high-expression group exhibit better prognosis compared to those in the low-expression group after Btz-treatment. Bioinformatics analysis further confirms this conclusion.
CONCLUSION
By categorizing Bach1 expression level as high and low, our study offers a unique perspective on understanding the relationship between Bach1 and NDMM.
Topics: Humans; Multiple Myeloma; Basic-Leucine Zipper Transcription Factors; Male; Female; Middle Aged; Aged; Prognosis; Adult; Anemia, Iron-Deficiency; Bortezomib
PubMed: 38767507
DOI: 10.1080/16078454.2024.2352687 -
Food Research International (Ottawa,... Jul 2024The balance regulation between characteristic aroma and hazards in high-temperature processed fish is a hot spot. This study was aimed to explore the interactive...
The balance regulation between characteristic aroma and hazards in high-temperature processed fish is a hot spot. This study was aimed to explore the interactive relationship between the nutritional value, microstructures, aroma, and harmful substances of hairtail under different frying methods including traditional frying (TF), air frying (AF), and vacuum frying (VF) via chemical pattern recognition. The results indicated that VF-prepared hairtail could form a crunchy mouthfeel and retain the highest content of protein (645.53 mg/g) and the lowest content of fat (242.03 mg/g). Vacuum frying reduced lipid oxidation in hairtail, resulting in the POV reaching 0.02 mg/g, significantly lower than that of TF (0.05 mg/g) and AF (0.21 mg/g), and TBARS reached 0.83 mg/g, significantly lower than that of AF (1.96 mg/g) (P < 0.05), respectively. Notable variations were observedin the aroma profileof hairtail preparedfrom different frying methods. Vacuum frying of hairtail resulted in higher levels of pyrazines and alcohols, whereas traditional frying and air frying were associated with the formation of aldehydes and ketones, respectively. Air frying was not a healthy way to cook hairtail which produced the highest concentration of harmful substances (up to 190.63 ng/g), significantly higher than VF (5.72 ng/g) and TF (52.78 ng/g) (P < 0.05), especially norharman (122.57 ng/g), significantly higher than VF (4.50 ng/g) and TF (32.63 ng/g) (P < 0.05). Norharman and acrylamide were the key harmful substances in hairtail treated with traditional frying. The vacuum frying method was an excellent alternative for deep-fried hairtail as a snack food with fewer harmful substances and a fine aroma, providing a theoretic guidance for preparing healthy hairtail food with high nutrition and superior sensory attraction.
Topics: Animals; Cooking; Odorants; Hot Temperature; Aldehydes; Nutritive Value; Perciformes; Volatile Organic Compounds; Pyrazines; Seafood
PubMed: 38763630
DOI: 10.1016/j.foodres.2024.114323 -
Journal of the American Heart... May 2024Many cardiomyopathy-associated pathogenic variants are heterozygous truncations, and pathogenic variants are associated with arrhythmias. Arrhythmia triggers in...
BACKGROUND
Many cardiomyopathy-associated pathogenic variants are heterozygous truncations, and pathogenic variants are associated with arrhythmias. Arrhythmia triggers in filaminopathy are incompletely understood.
METHODS AND RESULTS
We describe an individual with biallelic pathogenic variants, p.Arg650X and c.970-4A>G, with peripartum cardiomyopathy and ventricular arrhythmias. We also describe clinical findings in probands with variants including Val2715fs87X, Glu2458Serfs71X, Phe106Leu, and c.970-4A>G with hypertrophic and dilated cardiomyopathy, atrial fibrillation, and ventricular tachycardia. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated. The truncation, Arg650X/c.970-4A>G, showed a marked reduction in filamin C protein consistent with biallelic loss of function mutations. To assess loss of filamin C, gene editing of a healthy control iPSC line was used to generate a homozygous disruption in the actin binding domain. Because filamin C has been linked to protein quality control, we assessed the necessity of filamin C in iPSC-CMs for response to the proteasome inhibitor bortezomib. After exposure to low-dose bortezomib, null iPSC-CMs showed an increase in the chaperone proteins BAG3, HSP70 (heat shock protein 70), and HSPB8 (small heat shock protein B8) and in the autophagy marker LC3I/II. null iPSC-CMs had prolonged electric field potential, which was further prolonged in the presence of low-dose bortezomib. null engineered heart tissues had impaired function after low-dose bortezomib.
CONCLUSIONS
pathogenic variants associate with a predisposition to arrhythmias, which can be modeled in iPSC-CMs. Reduction of filamin C prolonged field potential, a surrogate for action potential, and with bortezomib-induced proteasome inhibition, reduced filamin C led to greater arrhythmia potential and impaired function.
Topics: Filamins; Humans; Proteostasis; Female; Induced Pluripotent Stem Cells; Arrhythmias, Cardiac; Myocytes, Cardiac; Cardiomyopathies; Male; Adult; Mutation; Bortezomib
PubMed: 38761081
DOI: 10.1161/JAHA.123.030467