Systemic biomarker associated with poor outcome after futile reperfusion.

BACKGROUND: Successful recanalization does not lead to complete tissue reperfusion in a considerable percentage of ischemic stroke patients. This study aimed to identify biomarkers associated with futile recanalization. Leukoaraiosis predicts poor outcomes of this phenomenon. Soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK), which is associated with leukoaraiosis degrees, could be a potential biomarker. METHODS: This study includes two cohorts of ischemic stroke patients in a multicentre retrospective observational study. Effective reperfusion, defined as a reduction of ≥8 points in the National Institutes of Health Stroke Scale (NIHSS) within the first 24 h, was used as a clinical marker of effective reperfusion. RESULTS: In the first cohort study, female sex, age, and high NIHSS at admission (44.7% vs. 81.1%, 71.3 ± 13.7 vs. 81.1 ± 6.7; 16 [13, 21] vs. 23 [17, 28] respectively; p < .0001) were confirmed as predictors of futile recanalization. ROC curve analysis showed that leukocyte levels (sensitivity of 99%, specificity of 55%) and sTWEAK level (sensitivity of 92%, specificity of 88%) can discriminate between poor and good outcomes. Both biomarkers simultaneously are higher associated with outcome after effective reperfusion (OR: 2.17; CI 95% 1.63-4.19; p < .0001) than individually (leukocytes OR: 1.38; CI 95% 1.00-1.64, p = .042; sTWEAK OR: 1.00; C I95% 1.00-1.01, p = .019). These results were validated using a second cohort, where leukocytes and sTWEAK showed a sensitivity of 100% and specificity of 66.7% and 75% respectively. CONCLUSIONS: Leukocyte and sTWEAK could be biomarkers of reperfusion failure and subsequent poor outcomes. Further studies will be necessary to explore its role in reperfusion processes.

A Step Forward for the Treatment of Localized Prostate Cancer Using Gold Nanoparticles Combined with Laser Irradiation.

Prostate cancer (PCA) is the second most common cancer diagnosis in men and the fifth leading cause of death worldwide. The conventional treatments available are beneficial to only a few patients and, in those, some present adverse side effects that eventually affect the quality of life of most patients. Thus, there is an urgent need for effective, less invasive and targeted specific treatments for PCA. Photothermal therapy (PTT) is a minimally invasive therapy that provides a localized effect for tumour cell ablation by activating photothermal agents (PTA) that mediate the conversion of the light beam's energy into heat at the site. As tumours are unable to easily dissipate heat, they become more susceptible to temperature increases. In the PTT field, gold nanoparticles (AuNPs) have been attracting interest as PTA. The aim of this study was to formulate AuNPs capable of remaining retained in the tumour and subsequently generating heat at the tumour site. AuNPs were synthesized and characterized in terms of size, polydispersity index (PdI), zeta potential (ZP), morphology and the surface plasmon resonance (SPR). The safety of AuNPs and their efficacy were assessed using in vitro models. A preliminary in vivo safety assessment of AuNPs with a mean size lower than 200 nm was confirmed. The morphology was spherical-like and the SPR band showed good absorbance at the laser wavelength. Without laser, AuNPs proved to be safe both in vitro (>70% viability) and in vivo. In addition, with laser irradiation, they proved to be relatively effective in PCA cells. Overall, the formulation appears to be promising for use in PTT.

Precision Medicine for Blood Glutamate Grabbing in Ischemic Stroke.

Glutamate grabbers, such as glutamate oxaloacetate transaminase (GOT), have been proposed to prevent excitotoxicity secondary to high glutamate levels in stroke patients. However, the efficacy of blood glutamate grabbing by GOT could be dependent on the extent and severity of the disruption of the blood-brain barrier (BBB). Our purpose was to analyze the relationship between GOT and glutamate concentration with the patient's functional status differentially according to BBB serum markers (soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and leukoaraiosis based on neuroimaging). This retrospective observational study includes 906 ischemic stroke patients. We studied the presence of leukoaraiosis and the serum levels of glutamate, GOT, and sTWEAK in blood samples. Functional outcome was assessed using the modified Rankin Scale (mRS) at 3 months. A significant negative correlation between GOT and glutamate levels at admission was shown in those patients with sTWEAK levels > 2900 pg/mL (Pearson's correlation coefficient: -0.249; p < 0.0001). This correlation was also observed in patients with and without leukoaraiosis (Pearson's correlation coefficients: -0.299; p < 0.001 vs. -0.116; p = 0.024). The logistic regression model confirmed the association of higher levels of GOT with lower odds of poor outcome at 3 months when sTWEAK levels were >2900 pg/mL (OR: 0.41; CI 95%: 0.28-0.68; p < 0.0001) or with leukoaraiosis (OR: 0.75; CI 95%: 0.69-0.82; p < 0.0001). GOT levels are associated with glutamate levels and functional outcomes at 3 months, but only in those patients with leukoaraiosis and elevated sTWEAK levels. Consequently, therapies targeting glutamate grabbing might be more effective in patients with BBB dysfunction.

Neurogenic Background for Emotional Stress-Associated Hypertension.

PURPOSE OF REVIEW: The response to natural stressors involves both cardiac stimulation and vascular changes, primarily triggered by increases in sympathetic activity. These effects lead to immediate flow redistribution that provides metabolic support to priority target organs combined with other key physiological responses and cognitive strategies, against stressor challenges. This extremely well-orchestrated response that was developed over millions of years of evolution is presently being challenged, over a short period of time. In this short review, we discuss the neurogenic background for the origin of emotional stress-induced hypertension, focusing on sympathetic pathways from related findings in humans and animals. RECENT FINDINGS: The urban environment offers a variety of psychological stressors. Real or anticipatory, emotional stressors may increase baseline sympathetic activity. From routine day-to-day traffic stress to job-related anxiety, chronic or abnormal increases in sympathetic activity caused by emotional stressors can lead to cardiovascular events, including cardiac arrhythmias, increases in blood pressure and even sudden death. Among the various alterations proposed, chronic stress could modify neuroglial circuits or compromise antioxidant systems that may alter the responsiveness of neurons to stressful stimuli. These phenomena lead to increases in sympathetic activity, hypertension and consequent cardiovascular diseases. The link between anxiety, emotional stress, and hypertension may result from an altered neuronal firing rate in central pathways controlling sympathetic activity. The participation of neuroglial and oxidative mechanisms in altered neuronal function is primarily involved in enhanced sympathetic outflow. The significance of the insular cortex-dorsomedial hypothalamic pathway in the evolution of enhanced overall sympathetic outflow is discussed.

N-Methyl-(2S,4R)-trans-4-hydroxy-L-proline isolated Sideroxylon obtusifolium attenuates TPA-induced irritant contact dermatitis in mice.

Dermatitis is defined as a set of inflammatory diseases that affect the skin, with varied causes. Among the different types of dermatitis, contact dermatitis is the most prevalent. Although the current therapy is often effective, it is associated with adverse effects and the possibility of drug tolerance. N-Methyl-(2S, 4R)-trans-4-hydroxy-L-proline is a L-proline amino acid derivative found in the leaves of Sideroxylon obtusifolium, a species traditionally used to treat inflammatory diseases. The aim of this study was to investigate the topical anti-inflammatory effect of N-methyl-(2S, 4R)-trans-4-hydroxy-L-proline (NMP) in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced irritant contact dermatitis in mice. Topically administered NMP, at doses of 0.03 - 0.50 mg/ear, reduced TPA-induced ear edema and neutrophil migration, as evidenced by low tissue myeloperoxidase activity and verified by histological examination. In addition, NMP (0.06 mg/ear) reduced tissue levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß, INF-γ and MCP-1) and of the anti-inflammatory cytokine IL-10, and reduced gene expression of TNF-α, IL-6 and IL-1ß increased by TPA. The data suggest that N-methyl-(2S, 4R)-trans-4-hydroxy-L-proline acts as a topical anti-inflammatory agent that decreases the expression of inflammatory cytokines, making it useful for the treatment of skin inflammation. Further investigations are necessary for its development as a therapeutic agent.

Influence of sodium hypochlorite on cyclic fatigue resistance of nickel-titanium instruments: A systematic review and meta-analysis of in vitro studies.

OBJECTIVE: This systematic review/meta-analysis investigated the influence of NaOCl on cyclic fatigue resistance of endodontic NiTi instruments. MATERIALS AND METHODS: A systematic search until July 2022 in PubMed/MEDLINE, Embase, Scopus, Web of Science, SciELO, Cochrane Library, and grey literature was conducted. According to the PECOS strategy, only in vitro studies evaluating the effects of NaOCl on the cyclic fatigue resistance of NiTi instruments were eligible. Cyclic fatigue resistance was the primary outcome. A modified Joanna Briggs Institute's Checklist was used for risk of bias assessment. RESULTS: Of the 2,445 records screened, 37 studies were included. Most studies used simulated canals made of stainless-steel block with severe to moderate curvatures. NaOCl concentration varied from 1-6%, mainly at 37 °C. Regarding fatigue resistance, 23 studies using 1.2% to 6% NaOCl showed a reduction in the resistance compared to the control groups, especially when pre-heated. Four meta-analyses were performed according to the tested NiTi systems. The meta-analyses indicated that the PTU F2 files had higher reduction of fatigue resistance after exposure to 5.25% NaOCl; no differences between NaOCl and no immersion were observed for Reciproc R25, WaveOne 25.08, and WaveOne Gold Primary files. Included studies had low risk of bias. CONCLUSION: NaOCl appears to reduce cyclic fatigue resistance of certain NiTi files, especially when they are pre-heated, particularly in conventional NiTi files compared to some heat-treated instruments. It is possible that the temperature of the solution may have a greater influence on resistance than NaOCl itself. Important to note that an overall tendency toward no significant influence was observed among various systems. CLINICAL RELEVANCE: Precautions are necessary when a pre-heated high-concentration NaOCl is used to enhance its properties during root canal preparation, mainly using conventional wire.

Children and adolescents continue to be exposed to early work in Brazil.

2 million children and adolescents between 11 and 19 years old have not yet finished basic education and had left school. The current Brazilian scenario reflects the reality in which these children and adolescents are inserted, without sufficient resources for the continuity of basic or elementary education, and often the parents' lack of income leads these young people to seek work, as can be seen in several capitals and inland cities: children selling food at traffic lights, bars, restaurants, and similar situations5. According to a study carried out by Abrinq Foundation (Fundação Abrinq), in the last quarter of 2021, there were about 2.36 million adolescents aged between 14 and 17 years old in the labor market or looking for a job, of which 1.2 million were in child labor in disagreement with Brazilian legislation, including work similar to slavery, and activities harmful to health, development, and morality.

Influence of Temperature Chronobiology on Stroke Outcome.

The circadian system regulates numerous physiological variables, including body temperature. Additionally, a circadian patter has been described in stroke onset. Considering this, we hypothesised that the chronobiology of temperature may have an impact on stroke onset and functional outcomes. We also studied the variation of blood biomarkers according to stroke onset time. This is a retrospective observational study. Of the patients included, 2763 had a stroke between midnight and 8:00 h; 1571 between 8:00-14:00 h; and 655 between 14:00 h and midnight. Axillary temperature was measured at admission. At this time, blood samples were collected for biomarker analysis (TNF-α, IL-1ß, IL-6, IL-10, and glutamate). Temperature was higher in patients admitted from 8:00 h to midnight (p < 0.0001). However, the percentage of poor outcome at 3 months was highest in patients from midnight to 8:00 h (57.7%, p < 0.001). The association between temperature and mortality was highest during night time (OR: 2.79; CI 95%: 2.36-3.28; p < 0.001). These patients exhibited high glutamate (220.2 ± 140.2 µM), IL-6 (32.8 ± 14.3 pg/mL) and low IL-10 (9.7 ± 14.3 pg/mL) levels. Therefore, temperature chronobiology could have a significant impact on stroke onset and functional outcome. Superficial body hyperthermia during sleep seems to be more dangerous than during wakefulness. Further studies will be necessary to confirm our data.

Artificial Intelligence in Allergy and Immunology: Comparing Risk Prediction Models to Help Screen Inborn Errors of Immunity.

BACKGROUND: Inborn errors of immunity (IEI) are underdiagnosed disorders, leading to increased morbimortality and expenses for healthcare system. OBJECTIVES: The study aimed to develop and compare risk prediction model to measure the individual chance of a confirmed diagnosis of IEI in children at risk for this disorder. METHOD: Clinical and laboratory data of 128 individuals were used to derive machine learning (ML) and logistic regression risk prediction models, to measure the individual chance of a confirmed diagnosis of IEI in children with suspected disorder, according to previous general pediatrician/clinician judgement. Their performances were compared. RESULTS: Statistically significant variables were mainly leucopenia, neutropenia, lymphopenia, and low levels of immunoglobulins A/G/M. ML models performed better. CONCLUSION: The enhanced predictive power provided by ML models could be a resource to track IEI, providing better healthcare outcomes.

Influence of cyclic loading in NiTi austenitic and R-phase endodontic files from a finite element perspective.

OBJECTIVES: This study aims to evaluate the effects of cyclic loading on the bending moments and the developed stress state of austenitic and R-phase endodontic files through finite element analysis. MATERIALS AND METHODS: The mechanical properties of two groups of NiTi wires, austenite and R-phase, were measured in samples at two different conditions: uncycled and cycled. The cycled condition was achieved by subjecting samples of the two groups to 80% of the corresponding fatigue life under rotating bending efforts. The measured mechanical properties were then used in the finite element analysis, where the boundary and loading conditions were set to replicate a standard bending test. RESULTS: The results showed that mechanical cycling leads to decreasing stress levels and bending moments in the simulated files, especially in the austenitic ones. In comparison with austenite, R-phase presented a more stable mechanical behavior during cycling. CONCLUSIONS: The results show that the moment and stress calculated for an instrument under bending can be considerably decreased after some cyclic work. CLINICAL RELEVANCE: The fatigue related to the clinical use of an endodontic file decreases the moment (as well as the forces) imposed by the instrument during the shaping of a curved root canal. This decrease is directly related to the type of atomic array present in the alloy.

Need for a Paradigm Shift in the Treatment of Ischemic Stroke: The Blood-Brain Barrier.

Blood-brain barrier (BBB) integrity is essential to maintaining brain health. Aging-related alterations could lead to chronic progressive leakiness of the BBB, which is directly correlated with cerebrovascular diseases. Indeed, the BBB breakdown during acute ischemic stroke is critical. It remains unclear, however, whether BBB dysfunction is one of the first events that leads to brain disease or a down-stream consequence. This review will focus on the BBB dysfunction associated with cerebrovascular disease. An added difficulty is its association with the deleterious or reparative effect, which depends on the stroke phase. We will first outline the BBB structure and function. Then, we will focus on the spatiotemporal chronic, slow, and progressive BBB alteration related to ischemic stroke. Finally, we will propose a new perspective on preventive therapeutic strategies associated with brain aging based on targeting specific components of the BBB. Understanding BBB age-evolutions will be beneficial for new drug development and the identification of the best performance window times. This could have a direct impact on clinical translation and personalised medicine.

Ovarian gene expression in collared peccary (Pecari tajacu Linnaeus, 1758) subjected to gonadotropin stimulation protocols.

Ovarian response of collared peccaries (Pecari tajacu), after hormonal stimulation with gonadotropin association (eCG/hCG), was accessed by both gene expression and follicular development. Thus, collared peccaries (n = 8) were treated with the dose used for sows (swine dose, SWD) or with dose adjusted for peccary's weight (allometric dose, ALD). The gene expression of receptors was evaluated for both gonadotropins (FSHR and LHCGR) and growth factors (proteins codified by TGFßR-1, BMPR1-A and BMPR2 genes) in antral follicles, cortex and corpora haemorrhagica (CH). Five days after gonadotropin injection, all females presented CH. The ovulation rate was similar (p > .05) between SWD (4.00 ± 1.17) and ALD (2.50 ± 0.43) group. The total number of follicles per animal and amounts of small (<3 mm), medium (3-5 mm) and large (>5 mm) follicles was similar among groups. However, SWD produced large follicles heavier than ALD group, as accessed by weight of follicular wall biopsies. Ovarian follicles expressed both gonadotropin and growth factor receptors at levels which are independent from gonadotropin dose. In conclusion, the two gonadotropin doses (SWD and ALD) can be used for ovarian stimulation of collared peccary. Additionally, FSH and growth factors (TGFßR-1, BMPR1-A and BMPR2) receptors are more expressed in the early follicle development, while LH receptor seems to be more important in the final of follicular growth.

Comparison between immediate and delayed post space preparations: a systematic review and meta-analysis.

OBJECTIVES: This systematic review and meta-analysis compared the effects of immediate and delayed post space preparation on apical sealing. MATERIALS AND METHOD: Two independent authors conducted a systematic search (PubMed/Medline, Cochrane Library, and other databases, until February 2020) and a risk of bias evaluation. Only in vitro studies that compared the effects of immediate and delayed post space preparations on apical filling and adhesion of the post were eligible. RESULT: Of the 742 articles retrieved, 32 were included. Most of the studies used single-rooted human teeth and rotary files for root canal preparation, a single-cone technique for the filling protocol, and rotary instruments for post space preparation. Various delayed preparation times were evaluated: 8-72 h, 5-30 days (mainly 7 days), and 4 months. In nine studies, the delayed groups showed more apical leakage, while four studies reported more leakage in the immediate groups; ten studies found no significant difference. One study found more bacterial penetration in the delayed group, whereas three studies showed no significant difference. One study reported more voids in the delayed group, while another found no such difference. Three studies showed better post-bond strength in the delayed group, one in the immediate group, whereas three found no significant difference in post-bond strength. Three studies employing varied sealers for root canal fillings were considered for meta-analysis. Two subgroup analyses were also performed (one concerning the use of resin-based sealers (AH Plus), another for zinc oxide-eugenol-based sealers). The results of the meta-analysis showed that a delayed post space preparation led to a significantly higher apical leakage than an immediate preparation (mean difference = 0.41 mm, confidence interval = 0.24-0.59, p < 0.001). CONCLUSION: Delayed post space preparation seems to negatively influence apical sealing; however, further studies are needed to determine the influence of the timing of post space preparation on the other parameters. CLINICAL RELEVANCE: Immediate post space preparation may be the safest clinical choice to prevent apical leakage.

Development of a Topical Insulin Polymeric Nanoformulation for Skin Burn Regeneration: An Experimental Approach.

Insulin is a peptide hormone with many physiological functions, besides its use in diabetes treatment. An important role of insulin is related to the wound healing process-however, insulin itself is too sensitive to the external environment requiring the protective of a nanocarrier. Polymer-based nanoparticles can protect, deliver, and retain the protein in the target area. This study aims to produce and characterize a topical treatment for wound healing consisting of insulin-loaded poly-DL-lactide/glycolide (PLGA) nanoparticles. Insulin-loaded nanoparticles present a mean size of approximately 500 nm and neutral surface charge. Spherical shaped nanoparticles are observed by scanning electron microscopy and confirmed by atomic force microscopy. SDS-PAGE and circular dichroism analysis demonstrated that insulin preserved its integrity and secondary structure after the encapsulation process. In vitro release studies suggested a controlled release profile. Safety of the formulation was confirmed using cell lines, and cell viability was concentration and time-dependent. Preliminary safety in vivo assays also revealed promising results.

In Situ AFM Imaging of Adsorption Kinetics of DPPG Liposomes: A Quantitative Analysis of Surface Roughness.

The adsorption of intact liposomes on surfaces is of great importance for the development of sensors and drug delivery systems and, also, strongly dependent on the surface roughness where the liposomes are adsorbed. In this paper, we analyzed, by using atomic force microscopy in liquid, the evolution of the morphology of gold surfaces and of poly(allylamine hydrochloride) (PAH) surfaces with different roughness during the adsorption of liposomes prepared with the synthetic phospholipid 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)]. Our results reveal the following. On smooth surfaces of Au only and Au with PAH, the liposomes open and deploy on the substrate, creating a supported-lipid bilayer, with the opening process being faster on the Au/PAH surface. On rough substrates of Au coated with polyelectrolyte multilayers, the liposomes were adsorbed intact on the surface. This was corroborated by power spectral density analysis that demonstrates the presence of superstructures with an average lateral size of 43 and 87 nm, in accordance with two and four times the mean liposome hydrodynamic diameter of about 21 nm. In addition, this work presents an adequate and effective methodology for analysis of adsorption phenomena of liposomes on rough surfaces.

Managers and clinicians: Perceptions of the impact of regionalization in two regions in Canada.

The aim of this paper is to examine the approach taken to regionalization in Ontario, Canada, and its impact on health system performance as perceived by managers and clinicians. This is a qualitative study, with thematic analysis, based on interviews with 23 managers and clinicians working in primary healthcare and emergency care in two regions of Ontario. Our findings demonstrate that both sets of actors see regional structures as contributing significantly to improving their respective health system although they also identify areas that require improvement. Managers and clinicians agreed on propositions to focus on health determinants, major considerations specific to the local context (population, geography) and support for a three-level system with well-defined functions. However, they also expressed differing propositions about the political power of hospitals.

Nanoparticulate vaccine inhibits tumor growth via improved T cell recruitment into melanoma and huHER2 breast cancer.

Nanoparticulate vaccines are promising tools to overcome cancer immune evasion. However, a deeper understanding on nanoparticle-immune cell interactions and treatments regime is required for optimal efficacy. We provide a comprehensive study of treatment schedules and mode of antigen-association to nanovaccines on the modulation of T cell immunity in vivo, under steady-state and tumor-bearing mice. The coordinated delivery of antigen and two adjuvants (Monophosphoryl lipid A, oligodeoxynucleotide cytosine-phosphate-guanine motifs (CpG)) by nanoparticles was crucial for dendritic cell activation. A single vaccination dictated a 3-fold increase on cytotoxic memory-T cells and raised antigen-specific immune responses against B16.M05 melanoma. It generated at least a 5-fold increase on IFN-γ cytokine production, and presented over 50% higher lymphocyte count in the tumor microenvironment, compared to the control. The number of lymphocytes at the tumor site doubled with triple immunization. This lymphocyte infiltration pattern was confirmed in mammary huHER2 carcinoma, with significant tumor reduction.

Tip-Specific Functionalization of Gold Nanorods for Plasmonic Biosensing: Effect of Linker Chain Length.

Gold nanorods are promising platforms for label-free biosensing. We have functionalized gold nanorods with biotin thiol linkers of increasing chain length and evaluated their ability in the molecular detection of streptavidin. We have found an unexpected effect of the increase in linker length, which resulted in a substantial improvement of the plasmon response at surface saturation. The plasmon peak shift increased from 5 to 14 nm, i.e., more than twice the response, between the short and long biotin linkers. This effect is observed only for site-selective tip functionalization, whereas for a full biotin coating there is no improvement observed with the linker length. The improved plasmon response for tip functionalization is attributed to low biotin coverage but is directed to the most sensitive regions, which, combined with a longer chain linker, reduces the steric hindrance for streptavidin binding on the rod's surface. The model sensors were further characterized by measuring their dose-response curves and binding kinetic assays. Simulations of the discrete dipole approximation give theoretical plasmon shifts that compare well with the experimental ones for the long linker but not with those of the short linker, thus suggesting that steric hindrance affects the latter. Our results highlight the importance of specifically functionalizing the plasmonic hot spots in nanoparticle sensors with the adequate density of receptors in order to maximize their response.

Amyrins from Protium heptaphyllum Reduce High-Fat Diet-Induced Obesity in Mice via Modulation of Enzymatic, Hormonal And Inflammatory Responses.

Obesity remains a global problem. In search of phytochemicals that have antiobesity potential, this study evaluated α,ß-amyrin, a triterpenoid mixture from Protium heptaphyllum, on high-fat diet-induced obesity in mice. Groups of mice (n = 8) were fed a normal diet or a high-fat diet, and were orally treated or not treated with either α,ß-amyrin (10 or 20 mg/kg) or sibutramine (10 mg/kg) for 15 weeks. Variables measured at termination were body weight, visceral fat accumulation, adipocyte surface area, peroxisome proliferator-activated receptor gamma, and lipoprotein lipase expressions in adipose tissue, the levels of plasma glucose and insulin, the satiety hormones ghrelin and leptin, the digestive enzymes amylase and lipase, and the inflammatory mediators TNF-α, interleukin-6, and MCP-1. Results showed that α,ß-amyrin treatment resulted in lower high-fat diet-induced increases in body weight, visceral fat content, adipocyte surface area, peroxisome proliferator-activated receptor gamma, and lipoprotein lipase expressions, and blood glucose and insulin levels. Additionally, the markedly elevated leptin and decreased ghrelin levels seen in the high-fat diet-fed control mice were significantly modulated by α,ß-amyrin treatment. Furthermore, α,ß-amyrin decreased serum TNF-α and MCP-1. These results suggest that α,ß-amyrin could be beneficial in reducing high-fat diet-induced obesity and associated disorders via modulation of enzymatic, hormonal, and inflammatory responses.

The role of fibrinogen glycation in ATTR: evidence for chaperone activity loss in disease.

Transthyretin amyloidosis (ATTR) belongs to a class of disorders caused by protein misfolding and aggregation. ATTR is a disabling disorder of autosomal dominant trait, where transthyretin (TTR) forms amyloid deposits in different organs, causing dysfunction of the peripheral nervous system. We previously discovered that amyloid fibrils from ATTR patients are glycated by methylglyoxal. Even though no consensus has been reached about the actual role of methylglyoxal-derived advanced glycation end-products in amyloid diseases, evidence collected so far points to a role for protein glycation in conformational abnormalities, being ubiquitously found in amyloid deposits in Alzheimer's disease, dialysis-related amyloidosis and Parkinson's diseases. Human fibrinogen, an extracellular chaperone, was reported to specifically interact with a wide spectrum of stressed proteins and suppress their aggregation, being an interacting protein with TTR. Fibrinogen is differentially glycated in ATTR, leading to its chaperone activity loss. Here we show the existence of a proteostasis imbalance in ATTR linked to fibrinogen glycation by methylglyoxal.