Adipose, skeletal, and hepatic muscle tissues are the main endocrine organs that produce adipokines, myokines, and hepatokines. These biomarkers can be harmful or beneficial to an organism and still ...perform crosstalk, acting through the endocrine, paracrine, and autocrine pathways. This study aims to review the crosstalk between adipokines, myokines, and hepatokines. Far beyond understanding the actions of each biomarker alone, it is important to underline that these cytokines act together in the body, resulting in a complex network of actions in different tissues, which may have beneficial or non-beneficial effects on the genesis of various physiological disorders and their respective outcomes, such as type 2 diabetes mellitus (DM2), obesity, metabolic syndrome, and cardiovascular diseases (CVD). Overweight individuals secrete more pro-inflammatory adipokines than those of a healthy weight, leading to an impaired immune response and greater susceptibility to inflammatory and infectious diseases. Myostatin is elevated in pro-inflammatory environments, sharing space with pro-inflammatory organokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), resistin, and chemerin. Fibroblast growth factor FGF21 acts as a beta-oxidation regulator and decreases lipogenesis in the liver. The crosstalk mentioned above can interfere with homeostatic disorders and can play a role as a potential therapeutic target that can assist in the methods of diagnosing metabolic syndrome and CVD.
The treatment for tuberculosis infection usually involves a prolonged regimen of multiple antibacterial drugs, which might lead to various secondary effects. For preventing drug resistance and ...side-effects of anti-tuberculosis drugs, new methods for improving the bioavailability of APIs were investigated. The strategy proposed consists of the preparation of therapeutic deep eutectic solvents (THEDES), that incorporate l-arginine and ethambutol. The eutectic mixtures were prepared by mixing the components at a certain molar ratio, until a clear liquid solution was formed. The prepared mixtures were characterized by differential scanning calorimetry (DSC), polarized optical microscopy (POM) and nuclear magnetic resonance spectroscopy (¹H and
C-NMR). The solubility and permeability of the drugs when they are in the THEDES form was evaluated at 37 °C, in phosphate buffered saline (PBS). Solubility studies showed an increase of the solubility of ethambutol when incorporated in the eutectic system. The cytotoxicity was evaluated using a model cell line (Caco-2), comparing the cytotoxicity of the API incorporated in the eutectic system. We observed that the cell viability in the THEDES was affected by the presence of citric acid, and higher cytotoxicity values were observed. Nonetheless, these findings do not compromise the possibility to use these systems as new delivery systems for ethambutol and arginine.
In patients with inflammatory bowel disease, proactive therapeutic drug monitoring of infliximab over a 2-year period was associated with higher rates of mucosal healing and lower surgical ...requirements compared with a conventional cohort treated without therapeutic drug monitoring.
Abstract
Background
Increasing evidence supports the use of reactive therapeutic drug monitoring (TDM) in Crohn’s disease (CD) and ulcerative colitis (UC) following secondary loss of response. It is still unknown if proactive TDM can improve clinical outcomes.
Methods
Consecutive patients completing infliximab (IFX) induction therapy were prospectively allocated into a proactive TDM protocol (pTDM). Before the fourth infusion and every 2 infusions, IFX trough levels and antidrug antibodies were measured using a drug-sensitive assay (Theradiag, Lisa Tracker). Treatment was proactively escalated aiming at an IFX trough level between 3 and 7 ug/mL (CD) and 5 and 10 ug/mL (UC). A retrospective cohort treated with IFX but without TDM served as the reference group. End points included the need for surgery, hospitalization, treatment discontinuation, and mucosal healing at 2 years of follow-up.
Results
Two hundred five patients were included, 56 in the proactive regimen. Treatment escalation was more common in pTDM patients (76.8% vs 25.5%; P < 0.001), who also required less surgery (8.9% vs 20.8%; P = 0.032) and presented higher rates of mucosal healing (73.2% vs 38.9%; P < 0.0001). Proactive TDM significantly decreased the odds of reaching any unfavorable outcome (odds ratio, 0.358; 95% confidence interval, 0.188–0.683; P = 0.002).
Conclusions
Proactive TDM is associated with fewer surgeries and higher rates of mucosal healing than conventional non-TDM-based management.
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Cancer remains a major health problem worldwide, with colorectal cancer (CRC) being the third most incident and the second most lethal. Inflammation, on the other hand, has been ...highly associated with cancer development and maintenance, therefore, the reduction of the inflammatory microenvironment represents a promising therapeutic strategy. Deep eutectic systems (DES) are based on the combination of different components which together, at a certain molar ratio, present a deep decrease in their melting point compared with the individual compounds. When an active pharmaceutical ingredient is part of a DES it is designated by therapeutic deep eutectic system (THEDES). New THEDES combining terpenes with anticancer properties, such as safranal, menthol and linalool, with nonsteroidal anti-inflammatory drugs (NSAIDs), like ibuprofen, ketoprofen and flurbiprofen were produced. To evaluate THEDES anti-CRC therapeutic potential, their physico-chemical properties, bioavailability and bioactivity, were explored. Our results show that safranal:ibuprofen (3:1), safranal:ibuprofen (4:1) and menthol:ibuprofen (3:1) present promising therapeutic activity towards CRC cells due to a selective cytotoxic action towards cancer cells. menthol:ibuprofen (3:1) anti-proliferative action seems to be related with cell membrane disruption, reduction of the inflammation through the reduction of reactive oxygen species (ROS) production, and induction of apoptosis via caspase-3. On the other hand, safranal:ibuprofen (3:1) and safafranal:ibuprofen (4:1) seem to prevent tumour expansion only through the induction of apoptosis via caspase-3. Besides, these systems present an increase in ibuprofen permeability, with menthol:ibuprofen (3:1) increasing also ibuprofen’s solubility thus its overall bioavailability. Knowing that cancer is a huge problematic situation that requires alternative therapies with less side effects, improved efficacy, associated with less costs and environmentally friendly, a new opportunity emerges for DES to be part of the pharmaceutical industry.
What if a new technology based on therapeutic deep eutectic systems would disrupt the current treatment of major economic and socially burden diseases? The classical definition of eutectic systems is ...that they are the combination of two or more compounds that interact via hydrogen bonds, from which results a melting temperature depression in comparison with that of its individual components. Therapeutic deep eutectic systems are defined as eutectic systems in which at least one of the individual components is an active pharmaceutical ingredient, or a eutectic system in which the active pharmaceutical ingredient is dissolved. Current literature reports on tuberculosis have been mostly based on the most common anti-tuberculosis drugs prescribed. Using eutectic systems based on naturally occurring molecules known for their anti-microbial activity may also present a promising therapeutic strategy able to cope with the prevalence of Mycobacterium tuberculosis and prevent the appearance of multidrug resistance strains. With regards to colorectal cancer, literature has been unravelling combinations of terpenes with anti-inflammatory drugs that are selectively cytotoxic towards colorectal cancer cells and do not compromise the viability of normal intestinal cells. This technology could contribute to preventing tumor growth and metastasis while providing a patient compliance therapeutics, which will be crucial to the success of overcoming the challenges presented by cancers.
Transfer RNAs (tRNAs) are widely known for their roles in the decoding of the linear mRNA information into amino acid sequences of proteins. They are also multifunctional platforms in the translation ...process and have other roles beyond translation, including sensing amino acid abundance, interacting with the general stress response machinery, and modulating cellular adaptation, survival, and death. In this mini-review, we focus on the emerging role of tRNA genes in the organization and modification of the genomic architecture of yeast and the role of tRNA misexpression and decoding infidelity in genome stability, evolution, and adaption. We discuss published work showing how quickly tRNA genes can mutate to meet novel translational demands, how tRNAs speed up genome evolution, and how tRNA genes can be sites of genomic instability. We highlight recent works showing that loss of tRNA decoding fidelity and small alterations in tRNA expression have unexpected and profound impacts on genome stability. By dissecting these recent evidence, we hope to lay the groundwork that prompts future investigations on the mechanistic interplay between tRNAs and genome modification that likely triggers genome evolution.
Cell division is characterized by a sequence of events by which a cell gives rise to two daughter cells. Quantitative measurements of cell-cycle dynamics in single cells showed that despite ...variability in G1-, S-, and G2 phases, duration of mitosis is short and remarkably constant. Surprisingly, there is no correlation between cell-cycle length and mitotic duration, suggesting that mitosis is temporally insulated from variability in earlier cell-cycle phases. By combining live cell imaging and computational modeling, we showed that positive feedback is the molecular mechanism underlying the temporal insulation of mitosis. Perturbing positive feedback gave rise to a sluggish, variable entry and progression through mitosis and uncoupled duration of mitosis from variability in cell cycle length. We show that positive feedback is important to keep mitosis short, constant, and temporally insulated and anticipate it might be a commonly used regulatory strategy to create modularity in other biological systems.
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•Duration of mitosis in single cells is short and remarkably constant•Duration of mitosis is temporally insulated from variability in early cell-cycle phases•Positive feedback keeps duration of mitosis short, constant, and insulated•Positive feedback can be a cellular strategy to bring about modularity in signaling
Araujo et al. show by quantitative single cell measurements that mitosis is short, fairly constant, and, surprisingly, uncoupled from the highly variable duration of earlier cell-cycle phases. They propose that positive feedback is responsible for this modularity and predict that it might enable modularity in other biological systems.
Abstract
Background and Aims
Leptin is a hormone responsible for the modulation of the satiety signals and that it is known for being increased in patients undergoing Peritoneal Dialysis (PD) ...treatment. Nevertheless, conclusions about its role in the malnutrition associated with this technique remains to be done. Our study aimed to characterize the nutritional state of a Portuguese program of PD and to establish the impact that leptin levels had on it.
Method
A cross-sectional study was performed involving 28 patients of a PD program. To characterize the patients’ nutritional status we collected the following data: anthropometric measurements (weight, body mass index (BMI), fat tissue index and lean tissue index using Fresenius ® Body Composition Monitor), analytical values (albumin, total proteins, total cholesterol, high-density lipoprotein cholesterol, low-density cholesterol, triglycerides, leptin serum levels), protein metabolism (normalized protein catabolic rate (nPCR), normalized dialysate protein loss (nEPL), normalized urine protein loss (nUPL), normalized total protein loss (nTPL) and normalized dietary protein requirement (nDPR)) and peritoneal dialysis adequacy (total, renal and peritoneal kT/v; total, renal and peritoneal creatinine clearance). The collected data were statistically analyzed and correlations were made using Mann-Whitney U test and Spearman test, depending on the variable type.
Results
7 (25%) patients were females, and the mean age was 59.5 years old (± 14.31). The mean dialysis vintage was 27.04 months (± 20.14) and the majority (n=23, 82,1%) preformed automated peritoneal dialysis (APD). Regarding the nutritional status, the mean BMI, FTI and LTI was 26.64 kg/m2 (±4.39), 14.24 kg/m2 (±5.47) and 11.62 kg/m2 (±2.52) respectively. 57.1% (n=16) had serum albumin below 3.5 mg/dL, with a mean phosphorus of 5.01mg/dl (±0.72) and a mean leptin of 28.58ng/mL (±28.44). The serum leptin was 5.4 times higher than the adjusted value for BMI in the population without kidney disease. The adjusted serum leptin for BMI was different between sex (U=15, P = .001) and it was positively correlated with total (ρ=0.47, P = .012) and high-density lipoprotein (HDL) cholesterol (ρ=0.535, P = .003). It was not associated with the protein metabolism (nPCR, nEPL, nUPL, nTOL and nDPR), albumin or total proteins and PD adequacy.
Conclusion
Leptin values independent of BMI are significantly higher amongst patients on PD. Alike the healthy population, women on PD are also prone to have higher serum leptin values. Although studies are still controversial about the association between this hormone and cholesterol, in this population there is a positive correlation. As so, hyperleptinaemia cannot yet be associated with the malnutrition that is generally present amongst PD patients, but it must be considered as a contribute to the already known increased cardiovascular risk.
Abstract
Background and Aims
Diabetic nephropathy (DN) is the major cause of kidney disease in diabetic patients. However, a significant proportion of diabetic patients may actually have nondiabetic ...renal disease (NDRD). Therefore, it is important to identify patients who can benefit from a renal biopsy in order to establish the correct diagnosis. Our study aims to determine the prevalence and etiology of biopsy proven NDRD and to explore the clinical differences encountered in the diabetic patient with NDRD.
Method
Retrospective study of the medical records of all diabetic patients who underwent a renal biopsy due to suspicion of NDRD from January 2012 to December 2022 at Nephrology department Collected data comprised demographic information, indication and result of renal biopsy, lab results (serum creatinine, Hb1Ac, proteinuria, albuminemia, hematuria, presence of active urinary sediment and presence of auto antibodies) and disease's characteristics (duration of diabetes, presence of diabetic retinopathy). Categorical variables are presented as frequencies and percentages, continuous variables as means and standard deviations, or medians and interquartile ranges (IQR) for variables with skewed distributions. A p-value<0.05 was considered statistically significant. Statistical analysis was performed using SPSS version 28.1 for Mac OS X.
Results
57 patients, 33.3% (n=19) were females, the medium age was 64.9 $\langle {{\rm{italic}}} \rangle \pm \langle {/{\rm{italic}}} \rangle $ 12.1. The most frequent indication for renal biopsy was acute kidney injury (26.3%), followed by rapidly progressive renal failure and nephrotic syndrome (22.8%). In our population, 22.9% had DN and 77.4% had NDRD. Pauciimune Glomerulonephritis (14%) and Membranous Nephropathy (10.5%) were the most common causes of NDRD. A chi-square test was performed to examine the relation between the two groups (ND vs NDRD) and the presence of diabetic retinopathy. There was a statistically significant association between the two variables ($\langle {{\rm{italic}}} \rangle {{\rm{X}}}^2\langle {/{\rm{italic}}} \rangle $= 11.778, p<0.01). Mann-Whitney test was performed to compare the median of duration the diabetes and Hb1Ac in two groups. That showed a statistically significant difference (U = 357, P = .018 and U=335.5 P = .013 respectively).
Conclusion
Since renal biopsy is critical to establish the correct diagnosis and provide an appropriate treatment, it should be performed in patients with high suspicion of NRDN, especially in patients with a recent diagnosis of diabetes, good metabolic control and the absence of diabetic retinopathy.
Wild thyme (
L.) herbal dust has been recognized as a potential underutilized resource for the recovery of antioxidants. The aim of this paper was to optimize natural deep eutectic solvent (NADES) ...extraction of polyphenols to obtain improved antioxidant activity of extracts determined by selected in vitro assays (DPPH, FRAP, and ABTS). Twenty different NADES systems were investigated in the first step of the screening of the extraction solvent and l-proline (Pro)-glycerine (Gly) based solvents provided the best results. Preliminary experiments organized by 2
fractional factorial design narrowed down the number of extraction factors from five (temperature, extraction time, NADES type, water content and L/S ratio) to three and determined their experimental domain for the final step. A face-centered central composite design with temperature (40-55-70 °C), extraction time (60-120-180 min) and L/S ratio (10-20-30 g NADES/g sample) was applied for influence analysis and process optimization. Multi-response optimization suggested a temperature of 65 °C, time of extraction of 180 min and L/S ratio of 28 g NADES/g DW as optimal extraction parameters. Experimental validation confirmed good agreement between experimental and predicted results in the extract obtained at optimal conditions and the interactions in the most suitable NADES (N16; Pro-Gly-H
O; 1:2:1) were confirmed by the
H-NMR.
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