Chronic Pathological Conditions Research Articles

The SGLT2 inhibitor empagliflozin exerts neuroprotective effect against hydrogen peroxide-induced toxicity on primary neurons.

Oxidative stress has been implicated in several chronic pathological conditions, leading to cell death and injury. Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) have several overlapping mechanisms as they are both characterized by increased oxidative stress, inflammation, insulin resistance, and autophagy dysfunction. The objective of this study was to elucidate the possible neuroprotective effect of empagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT2i), against hydrogen peroxide-induced neurotoxicity in primary hippocampal neurons derived from wild-type (WT) and transgenic AD rats (TgF344-AD). An in vitro oxidative stress model was established using hydrogen peroxide to induce damage to neurons. Empagliflozin pretreatment was tested on this model initially through a cell viability assay. Flow cytometry and cell sorting were employed to discriminate the apoptotic and necrotic neuronal cell populations. Finally, the morphological and morphometric features of the neurons, including dendritic length and spine density, were evaluated using the SNT ImageJ plug-in following immunostaining with GFP. Sholl analysis was used to evaluate the impact of empagliflozin and hydrogen peroxide on dendritic arborization. Empagliflozin tended to ameliorate hydrogen peroxide-induced toxicity in primary neurons derived from WT rats and led to the preservation of dendritic spine density in both WT and TgF344-AD neurons (one-way ANOVA, p < 0.05). A modest improvement in dendrites' length was also observed. Empagliflozin pretreatment can partially mitigate dendritic and spine alterations induced by hydrogen peroxide in primary neurons. These results underscore the impact of empagliflozin on neuronal morphology and highlight its potential as a candidate for the treatment and/or prevention of AD.

OZONIOTERAPIA EM CONTAMINAÇÃO DE FERIDA CIRÚRGICARELATO DE CASO EM CÃO CAUDECTOMIZADO

Integrative medicine offers a wide variety of therapies that can be associated with conventional medicine, providing patients appropriate treatment with satisfactory results. Among the therapies used in integrative medicine, we have ozone therapy, which is widely used for various purposes due to its bactericidal, fungicidal and virucidal properties and the fact that it has practically no side effects with low toxicity, being used in chronic pathological conditions, in cases of dermatitis, ulcers and redness, burns and wound healing processes. The case report shows a healing process promoted by ozone therapy and associated therapies in a dog, presenting positive results. Ozone is a colorless gas with a characteristic odor and analgesic and anti-inflammatory functions, also contributing to the immune system and body oxygenation of animals. It can be applied in distinct ways, split into local or systemic, and can be subcutaneous, intravaginal, blood therapies, bagging and cupping methods. In addition, the technique offers low cost and promotes an improvement in the animal's quality of life.

OZONIOTERAPIA EM CONTAMINAÇÃO DE FERIDA CIRÚRGICARELATO DE CASO EM CÃO CAUDECTOMIZADO

Integrative medicine offers a wide variety of therapies that can be associated with conventional medicine, providing patients appropriate treatment with satisfactory results. Among the therapies used in integrative medicine, we have ozone therapy, which is widely used for various purposes due to its bactericidal, fungicidal and virucidal properties and the fact that it has practically no side effects with low toxicity, being used in chronic pathological conditions, in cases of dermatitis, ulcers and redness, burns and wound healing processes. The case report shows a healing process promoted by ozone therapy and associated therapies in a dog, presenting positive results. Ozone is a colorless gas with a characteristic odor and analgesic and anti-inflammatory functions, also contributing to the immune system and body oxygenation of animals. It can be applied in distinct ways, split into local or systemic, and can be subcutaneous, intravaginal, blood therapies, bagging and cupping methods. In addition, the technique offers low cost and promotes an improvement in the animal's quality of life.

Features of proinflammatory activation of macrophages in patients with rheumatoid arthritis and systemic lupus erythematosus

Autoimmune rheumatic diseases (ARDs) are chronic pathological conditions that arise from an abnormal immune response and are accompanied by systemic inflammation. The most common ARDs include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). The exact pathogenesis of ARDs remains unclear, but the complex influence of genetic, immunological and external environmental factors leads to the occurrence and further progression of ARDs. It has been shown that the cause of chronic inflammation may be proinflammatory activation of macrophages, in which an increase in the secretion of cytokines is observed. The aim of this study was to evaluate the inflammatory response of macrophages in patients with RA, SLE and SSc. Materials and methods. The study included 143 participants: 47 patients with RA, 45 patients with SLE, 34 patients with SSc, and 17 people without ARDs and other chronic diseases. Isolation of a primary culture of monocytes was carried out by centrifugation in a ficoll gradient using magnetic separation from the whole blood of study participants. Lipopolysaccharide (LPS) was added to stimulate cells along the proinflammatory pathway. Cell cultivation was carried out for 24 hours. Determination of basal and LPS-stimulated secretion of IL-8 by macrophages was carried out in the culture fluid using an enzyme-linked immunosorbent assay (ELISA). Proinflammatory activation of macrophages was calculated as the ratio of LPS-stimulated and basal IL-8 secretion. Research results. Basal secretion of IL-8 by macrophages was statistically significantly higher in the groups of patients with RA and SSc compared with the SLE and control groups. LPS-stimulated secretion of IL-8 by macrophages in the SSc group had statistically higher values compared to the RA and SLE groups. Proinflammatory activation of macrophages was reduced in the group of patients with RA compared to patients with SLE and the control group, and was also statistically significantly lower in patients with SSc compared to the control group.

The processing mechanism of vinegar-processed Curcumae Rhizome enhances anti hepatic fibrotic effects through regulation of PI3K/Akt/mTOR signaling pathway

BackgroundHepatic fibrosis, a chronic pathological condition resulting from various forms of persistent liver injury, in the later stage, it can evolve into cirrhosis and even liver cancer. Curcumae Rhizoma (CR), traditionally recognized for its properties in line qi break blood, eliminate accumulation and relieve pain. According to traditional Chinese medicine (TCM) principles, vinegar-processing enhances CR's ability to enter the liver meridian and act on the blood level, potentially augmenting its therapeutic effects on hepatic diseases. Therefore, vinegar-processed Curcumae Rhizoma (VCR) is frequently employed in treating liver fibrosis and related hepatic conditions. However, the underlying mechanisms of vinegar processing in enhancing its therapeutic efficacy remain unclear. MethodsThe anti-liver fibrosis effects of CR and VCR were verified at individual and cellular levels. Subsequently, HPLC-Q-TOFMS and pharmacokinetic analysis were utilized to elucidate the potential bioactive substances underlying the enhanced anti-fibrotic efficacy of VCR. Building upon these findings, network pharmacology and metabolomics were integrated to screen for key effect components and regulatory pathways. Finally, the mechanisms of action were further analyzed and validated at the tissue and cellular levels through Western blotting (WB) and molecular docking studies. ResultsBoth CR and VCR exhibited therapeutic effects against hepatic fibrosis, with VCR demonstrating enhanced efficacy after vinegar processing. 6 sesquiterpenes including furanodiene and curdione, showed significant alterations in plasma exposure and hepatic distribution post-processing. VCR significantly improved pathological liver conditions, lipid accumulation, and fibrosis severity. Additionally, VCR markedly reduced the expression of α-SMA in the liver and attenuated the elevations in liver function markers such as ALT and AST. Combined network pharmacology, metabolomics, and hepatic tissue WB analysis revealed that the reduced phosphorylation of the PI3K/Akt/mTOR pathway is a critical mechanism in VCR's anti-fibrotic effects. Experiments on LX-2 cells demonstrated that four sesquiterpenes, including furanodiene and curdione, effectively inhibited the proliferation of activated hepatic stellate cells (HSCs). Furanodiene, in particular, promoted apoptosis in activated HSCs by reducing phosphorylation levels of the PI3K/Akt/mTOR pathway proteins, increasing BAX expression, and activating downstream caspase-3 to achieve the effect of anti-liver fibrosis. ConclusionVinegar-processing significantly increases the plasma exposure and hepatic distribution of components such as furanodiene in VCR, enhancing anti-fibrotic efficacy by downregulating the phosphorylation levels of the PI3K/Akt/mTOR pathway and promoting HSC apoptosis. This study provides a comprehensive explanation of the vinegar-processing mechanism and its role in enhancing the anti-fibrotic effects of VCR, offering insights for its clinical application in liver fibrosis treatment and reference for the mechanistic study of other vinegar-processed herbal medicines.

Experience with the use of hyaluronic acid solution (Diart) in the treatment of patients with degenerative-dystrophic diseases of the hip joint

Background. Degenerative-dystrophic diseases of the joints are chronic progressive pathological conditions, accompanied by such features as presence of pain syndrome, impaired functional capacity, muscle weakness, deformation and instability of the joints. The high prevalence of degenerative-dystrophic diseases of the hip joint necessitates the search for optimal non-invasive treatment methods. Objectives. This study aims to analyze the clinical results of intra-articular injections of hyaluronic acid solution (Diart) in the treatment of patients with II–III stages of degenerative-dystrophic diseases of the hip joint. Materials and methods. The clinical results of 30 patients with II–III stages of degenerative-dystrophic diseases of the hip joint were analyzed. The group included 11 (36.67%) males and 19 (63.33%) females. The mean age of group was 61.43±7.98 years. All patients underwent a course of drug therapy using hyaluronic acid solution (Diart), which included 3 intra-articular injections of the drug, which were performed with the 7-day interval. Clinical results were evaluated at the initial visit, at 7, 14, 30 and 90 days after the first injection of Diart by objective examination of patients and analysis of subjective data using the WOMAC questionnaire. Statistical analysis was performed using Statistica 13 software package. Results. The high effectiveness of intra-articular injections of hyaluronic acid (Diart) in the treatment of patients with II-III stages of degenerative-dystrophic diseases of the hip joint and the absence of complications associated with intra-articular injection of the drug have been established. Signs of post-injection sy- novitis, discomfort, swelling or other unpleasant sensations weren’t observed in any of the examined patients. Comparing the results established during remote period, on the 90th day of observation, and indicators determined at the initial visit, we proved a decrease in the intensity of the pain syndrome in the hip joint by 30.35%, in stiffness — by 29.57%, an improvement in the indicators characterizing the functional capacity by 21.34 % and the total values of the WOMAC index — by 27.37%, after a treatment course using Diart. Conclusion. The high efficiency of using intra-articular injections of hyaluronic acid solution (Diart) in the treatment of patients with II–III stages of degen- erative-dystrophic diseases of the hip joint has been proven.

Smart Microneedle Arrays Integrating Cell-Free Therapy and Nanocatalysis to Treat Liver Fibrosis.

Liver fibrosis is a chronic pathological condition lacking specific clinical treatments. Stem cells, with notable potential in regenerative medicine, offer promise in treating liver fibrosis. However, stem cell therapy is hindered by potential immunological rejection, carcinogenesis risk, efficacy variation, and high cost. Stem cell secretome-based cell-free therapy offers potential solutions to address these challenges, but it is limited by low delivery efficiency and rapid clearance. Herein, an innovative approach for in situ implantation of smart microneedle (MN) arrays enabling precisely controlled delivery of multiple therapeutic agents directly into fibrotic liver tissues is developed. By integrating cell-free and platinum-based nanocatalytic combination therapy, the MN arrays can deactivate hepatic stellate cells. Moreover, they promote excessive extracellular matrix degradation by more than 75%, approaching normal levels. Additionally, the smart MN arrays can provide hepatocyte protection while reducing inflammation levels by ≈70-90%. They can also exhibit remarkable capability in scavenging almost 100% of reactive oxygen species and alleviating hypoxia. Ultimately, this treatment strategy can effectively restrain fibrosis progression. The comprehensive in vitro and in vivo experiments, supplemented by proteome and transcriptome analyses, substantiate the effectiveness of the approach in treating liver fibrosis, holding immense promise for clinical applications.

A Th2-type immune response and low-grade systemic inflammatory reaction as potential immunotoxic effects in intensive agriculture farmers exposed to pesticides

Pesticides are chemicals widely used in agriculture to keep crops healthy and prevent them from being destroyed by pests, thus contributing to a sustainable food and feed production. However, long-term exposure to these compounds may be harmful to human health as they can affect the function of various organs systems, including the immune system. There is growing evidence that pesticides may increase the risk of developing immune-based diseases and inflammation. This study assessed whether greenhouse farmers occupationally exposed to pesticides presented alterations in immunoregulatory proteins, used as surrogate biomarkers of immune function. The study population consisted of 175 greenhouse workers occupationally exposed to pesticides and 91 non-exposed controls. Serum levels of 27 cytokines, chemokines and growth factors were measured using a magnetic bead-based immunoassay in a subpopulation of 111 greenhouse workers and 79 non-exposed controls. Since analytical determinations were performed in two periods of the same crop season with different use of pesticides (period of high and low pesticide exposure), linear mixed models for repeated measures were used to optimize statistical inference. The increase in IL-13, IL-4 and IL-6 observed in greenhouse workers compared to controls, and in the period of high exposure to pesticides relative to that of low exposure, suggest an altered Th1/Th2 balance towards the Th2 response. This finding points to a type-2 inflammation commonly presented as allergic inflammation, which has often been reported in farm-workers and in which pesticide exposure is considered a risk factor. Furthermore, the increase in IL-1β and VEGF, mediators of inflammation and angiogenesis, may suggest a low-grade systemic inflammation that might underlie chronic pathological conditions linked to pesticide exposure.

ZeroExpander® effectiveness assessment in PEEK or PA12 in a group of paediatric patients with transverse maxillary deficiency.

The aim of this article is to compare the performance of ZeroExpander® realised using PEEK or PA12 for the expansion of the maxilla in paediatric patients, exploring a new concept for approaching maxillary expansion with a metal-free fixed automatic appliance, based on pre-programmed set-up and anchored on deciduous teeth. It is a retrospective comparative study with a sample of 40 children in early or mixed deciduous dentition and transversal maxillary deficit, 20 treated with ZeroExpander® in PEEK and 20 treated with ZeroExpander® in PA12 with a mean age of 7.3 years old. The intraoral scans at T0 and at the end of the expansion were all performed by the same operator to obtain digital models on which were performed measurements by two other different operators. A descriptive analysis was conducted using frequencies and percentages for nominal variables and means and standard deviations for continuous variables. In cases of allergy or hypersensitivity to metals or to specific chronic or acute pathological conditions, which may require periodic magnetic resonance imaging (MRI), it may not be possible to use traditional and metal fixed expansion devices. Moreover the concept of autonomous driving in paediatric orthodontics is not only possible, but it is and will be more real and very useful in the future. The "ortho-paediatric dentistry concept" will increase the range of benefits for children and their families which, in addition to care and thanks to technology, demand well-being, safety, comfort and quality of life beyond clinics.

Uremic sarcopenia: the role of intramuscular adipose tissue as a potential early identifier.

Sarcopenia is a chronic pathological condition, first defined in 2010 and revised in 2018. The most recent definition of sarcopenia focuses mostly on "low muscle strength." A secondary form of sarcopenia is represented by uremic sarcopenia (US), a condition that characterizes end-stage kidney disease (ESKD) patients. The intramuscular adipose tissue (IMAT) seems to impact negatively on muscle strength, as it would seem to replace muscle fibers with a non-contractile component. The study aims to compare body composition parameters-both standardized and innovative-related to the diagnosis of US in hemodialysis (HD) patients, stratified by sarcopenia diagnosis. Furthermore, the different indices of sarcopenia are compared in order to evaluate their predictive capacity. We analyzed 48 ESKD patients according to the sarcopenia diagnosis, obtained using dual-energy X-ray absorptiometry (DXA). Moreover, we assessed the presence of IMAT and calculated the sarcopenia index (SI). For the study, the enrolled population was divided according to the sarcopenia diagnosis: no sarcopenic patients had higher transferrin (p = 0.03), total proteins (p = 0.04), and azotemia pre-dialysis (p = 0.05) values. On the contrary, atherogenic indices were lower in no sarcopenic patients. Moreover, we observed an indirect correlation between the SI and parathyroid hormone (PTH) (p = 0.00138, R 2 = 0.54). Finally, we calculated the prevalence of sarcopenia and sarcopenia adjusted for IMAT. We showed a different prevalence between sarcopenia diagnosed with a standard index and an index adjusted for IMAT (p = 0.043). In conclusion, we believe that the most important result obtained is the indirect correlation between SI and PTH. These data corroborate the theories, in which PTH seems to play a central role in the cachexia genesis. Moreover, the SI adjusted for IMAT seems to be a more reliable parameter for the early identification of subjects at risk of developing US, allowing timely implementation of targeted therapeutic strategies.

Detection of myeloid-derived suppressor cells by flow cytometry.

Recently discovered heterogeneous myeloid-derived suppressor cells (MDSCs) are some of the most discussed immunosuppressive cells in contemporary immunology, especially in the tumor microenvironment, and are defined primarily by their T cell immunosuppressive function. The importance of these cells extend to other chronic pathological conditions as well, including chronic infection, inflammation, and tissue remodeling. In many of these conditions, their accumulation/expansion correlates with disease progression, poor prognosis, and reduced survival, which highlights the potential of how these cells may be used in a clinical setting as both prognostic factor and therapeutic target. In healthy individuals, these cells are usually not present in the circulation. Therefore, monitoring this cell population is of potential clinical significance, and utility in basic research. However, these cells have a complex phenotype without one single marker of sufficient specificity for their identification. Flow cytometry is a powerful tool allowing multi-parameter analysis of heterogeneous cell populations, which makes it ideally suitable for the complex phenotypic analysis essential for identification and enumeration of circulating MDSCs. This approach has the potential to provide a novel clinically useful tool for assessment of prognosis and treatment outcomes. The protocol in this chapter describes a flow cytometric analysis to identify and quantify MDSCs from human or mouse whole blood leukocytes and peripheral blood mononuclear cells, as well as a single cell suspension from solid tissue, by using multicolor fluorescence-conjugated antibodies against their surface markers.

Inhibition of Pro-Fibrotic Molecules Expression in Idiopathic Pulmonary Fibrosis-Derived Lung Fibroblasts by Lactose-Modified Hyaluronic Acid Compounds.

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory and fibrotic pathological condition with undefined effective therapies and a poor prognosis, partly due to the lack of specific and effective therapies. Galectin 3 (Gal-3), a pro-fibrotic ß-galactoside binding lectin, was upregulated in the early stages of the pathology, suggesting that it may be considered a marker of active fibrosis. In the present in vitro study, we use Hylach®, a lactose-modified hyaluronic acid able to bind Gal-3, to prevent the activation of lung myofibroblast and the consequent excessive ECM protein cell expression. Primary human pulmonary fibroblasts obtained from normal and IPF subjects activated with TGF-β were used, and changes in cell viability, fibrotic components, and pro-inflammatory mediator expression at both gene and protein levels were analyzed. Hylach compounds with a lactosylation degree of about 10% and 30% (Hylach1 and Hylach 2), administrated to TGF-β-stimulated lung fibroblast cultures, significantly downregulated α-smooth muscle actin (α-SMA) gene expression and decreased collagen type I, collagen type III, elastin, fibronectin gene and protein expression to near baseline values. This anti-fibrotic activity is accompanied by a strong anti-inflammatory effect and by a downregulation of the gene expression of Smad2 for both Hylachs in comparison to the native HA. In conclusion, the Gal-3 binding molecules Hylachs attenuated inflammation and TGF-β-induced over-expression of α-SMA and ECM protein expression by primary human lung fibroblasts, providing a new direction for the treatment of pulmonary fibrotic diseases.

Role of the redox state of the Pirin-bound cofactor on interaction with the master regulators of inflammation and other pathways.

Persistent cellular stress induced perpetuation and uncontrolled amplification of inflammatory response results in a shift from tissue repair toward collateral damage, significant alterations of tissue functions, and derangements of homeostasis which in turn can lead to a large number of acute and chronic pathological conditions, such as chronic heart failure, atherosclerosis, myocardial infarction, neurodegenerative diseases, diabetes, rheumatoid arthritis, and cancer. Keeping the vital role of balanced inflammation in maintaining tissue integrity in mind, the way to combating inflammatory diseases may be through identification and characterization of mediators of inflammation that can be targeted without hampering normal body function. Pirin (PIR) is a non-heme iron containing protein having two different conformations depending on the oxidation state of the iron. Through exploration of the Pirin interactome and using molecular docking approaches, we identified that the Fe2+-bound Pirin directly interacts with BCL3, NFKBIA, NFIX and SMAD9 with more resemblance to the native binding pose and higher affinity than the Fe3+-bound form. In addition, Pirin appears to have a function in the regulation of inflammation, the transition between the canonical and non-canonical NF-κB pathways, and the remodeling of the actin cytoskeleton. Moreover, Pirin signaling appears to have a critical role in tumor invasion and metastasis, as well as metabolic and neuro-pathological complications. There are regulatory variants in PIR that can influence expression of not only PIR but also other genes, including VEGFD and ACE2. Disparity exists between South Asian and European populations in the frequencies of variant alleles at some of these regulatory loci that may lead to differential occurrence of Pirin-mediated pathogenic conditions.

Regulation of Immune Checkpoint Antigen CD276 (B7-H3) on Human Placenta-Derived Mesenchymal Stromal Cells in GMP-Compliant Cell Culture Media.

Therapies utilizing autologous mesenchymal cell delivery are being investigated as anti-inflammatory and regenerative treatments for a broad spectrum of age-related diseases, as well as various chronic and acute pathological conditions. Easily available allogeneic full-term human placenta mesenchymal stromal cells (pMSCs) were used as a potential pro-regenerative, cell-based therapy in degenerative diseases, which could be applied also to elderly individuals. To explore the potential of allogeneic pMSCs transplantation for pro-regenerative applications, such cells were isolated from five different term-placentas, obtained from the dissected maternal, endometrial (mpMSCs), and fetal chorion tissues (fpMSCs), respectively. The proliferation rate of the cells in the culture, as well as their shape, in vitro differentiation potential, and the expression of mesenchymal lineage and stem cell markers, were investigated. Moreover, we studied the expression of immune checkpoint antigen CD276 as a possible modulation of the rejection of transplanted non-HLA-matched homologous or even xeno-transplanted pMSCs. The expression of the cell surface markers was also explored in parallel in the cryosections of the relevant intact placenta tissue samples. The expansion of pMSCs in a clinical-grade medium complemented with 5% human platelet lysate and 5% human serum induced a significant expression of CD276 when compared to mpMSCs expanded in a commercial medium. We suggest that the expansion of mpMSCs, especially in a medium containing platelet lysate, elevated the expression of the immune-regulatory cell surface marker CD276. This may contribute to the immune tolerance towards allogeneic pMSC transplantations in clinical situations and even in xenogenic animal models of human diseases. The endurance of the injected comparably young human-term pMSCs may promote prolonged effects in clinical applications employing non-HLA-matched allogeneic cell therapy for various degenerative disorders, especially in aged adults.

Intracellular remodeling associated with endoplasmic reticulum stress modifies biomechanical compliance of bladder cells

Bladder cells face a challenging biophysical environment: mechanical cues originating from urine flow and regular contraction to enable the filling voiding of the organ. To ensure functional adaption, bladder cells rely on high biomechanical compliance, nevertheless aging or chronic pathological conditions can modify this plasticity. Obviously the cytoskeletal network plays an essential role, however the contribution of other, closely entangled, intracellular organelles is currently underappreciated. The endoplasmic reticulum (ER) lies at a crucial crossroads, connected to both nucleus and cytoskeleton. Yet, its role in the maintenance of cell mechanical stability is less investigated. To start exploring these aspects, T24 bladder cancer cells were treated with the ER stress inducers brefeldin A (10-40nM BFA, 24 h) and thapsigargin (0.1-100nM TG, 24 h). Without impairment of cell motility and viability, BFA and TG triggered a significant subcellular redistribution of the ER; this was associated with a rearrangement of actin cytoskeleton. Additional inhibition of actin polymerization with cytochalasin D (100nM CytD) contributed to the spread of the ER toward cell periphery, and was accompanied by an increase of cellular stiffness (Young´s modulus) in the cytoplasmic compartment. Shrinking of the ER toward the nucleus (100nM TG, 2 h) was related to an increased stiffness in the nuclear and perinuclear areas. A similar short-term response profile was observed also in normal human primary bladder fibroblasts. In sum, the ER and its subcellular rearrangement seem to contribute to the mechanical properties of bladder cells opening new perspectives in the study of the related stress signaling cascades.AnQ6eoaFZ-G6Rs7Kzp4dpwVideo

Anti-Atherosclerosis and Anti-Hyperlipidemia Functions of Terminalia catappa Fruit.

Background: Atherosclerosis is a chronic pathological condition that has remained clinically silent for decades, and the epidemic has continued to be on the rise due to risk factors, including diet, lifestyle, hyperlipidemia, pathogenic microorganisms, and aging. Using various synthetic drugs in treating atherosclerosis is associated with a high risk of myositis, angioedema, myoglobinuria, and acute renal failure. Various side effects of the available drugs have been reported; attempts are underway to explore natural sources with antiatherosclerotic activity. Aim and objective: Using a diet-induced atherosclerosis rat model, the current study tested the hypothesis of antiatherosclerotic and antihyperlipidemic roles of Terminalia catappa fruit extracts. Materials and Methods: Atherosclerosis in Wistar rats was induced using an atherogenic diet. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (AP), creatine kinase (CK), and lactate dehydrogenase (LDH) were determined using analytical kits. Results: Quantitative phytochemical analysis of the extracts demonstrated that the plant had flavonoids, saponins, tannins, terpenoids, alkaloids, cardiac glycosides, sterols, phenols, and anthraquinones. Diet-induced atherogenic Wistar rats showed a significant (p < 0.05) increase in total cholesterol, triglyceride, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol compared to the healthy control group; however, the atherogenic lipid profile was reversed by the treatment of T. catappa fruit extracts. The biochemical experiments demonstrate that T. catappa fruit extracts have an antihyperlipidaemic effect, shown by a decreased coronary risk index and the atherogenic index, and an increased cardioprotective index, compared to disease control. Conclusion: The current study indicates that T. catappa fruit extracts may contain bioactive molecules to treat atherosclerosis.

Genes Involved in DNA Damage Cell Pathways and Health of the Oldest-Old (85+).

Some sources report a connection of cellular senescence with chronic pathological conditions; however, the association between particular cellular processes and general health is rarely examined. This study aims to test the relationship of general health with DNA damage pathways that play a crucial role in senescence. The association of ten selected SNPs with subjective and objective general health and functional ability indicators has been tested in 314 oldest-old people from Croatia. Multivariate logistic regression was employed to simultaneously test the impact of variables potentially influencing targeted health and functional ability variables. The best model, explaining 37.1% of the variance, has six independent significant predictors of functional ability scores: rs16847897 in TERC, rs533984 in MRE11A, and rs4977756 in CDKN2B, chronic disease count, Mini-Mental State Examination scores, and age at surveying. In conclusion, the examined ten loci involved in DNA damage repair pathways showed a more significant association with self-rated health and functional ability than with the number of disease or prescribed medicaments. The more frequent, longevity-related homozygote (GG) in rs16847897 was associated with all three aspects of self-assessments-health, mobility, and independence-indicating that this TERC locus might have a true impact on the overall vitality of the oldest-old persons.

Development of muscle weakness in a mouse model of critical illness: does fibroblast growth factor 21 play a role?

BackgroundCritical illness is hallmarked by severe stress and organ damage. Fibroblast growth factor 21 (FGF21) has been shown to rise during critical illness. FGF21 is a pleiotropic hormone that mediates adaptive responses to tissue injury and repair in various chronic pathological conditions. Animal studies have suggested that the critical illness-induced rise in FGF21 may to a certain extent protect against acute lung, liver, kidney and brain injury. However, FGF21 has also been shown to mediate fasting-induced loss of muscle mass and force. Such loss of muscle mass and force is a frequent problem of critically ill patients, associated with adverse outcome. In the present study, we therefore investigated whether the critical illness-induced acute rise in FGF21 is muscle-protective or rather contributes to the pathophysiology of critical illness-induced muscle weakness.MethodsIn a catheterised mouse model of critical illness induced by surgery and sepsis, we first assessed the effects of genetic FGF21 inactivation, and hence the inability to acutely increase FGF21, on survival, body weight, muscle wasting and weakness, and markers of muscle cellular stress and dysfunction in acute (30 h) and prolonged (5 days) critical illness. Secondly, we assessed whether any effects were mirrored by supplementing an FGF21 analogue (LY2405319) in prolonged critical illness.ResultsFGF21 was not required for survival of sepsis. Genetic FGF21 inactivation aggravated the critical illness-induced body weight loss (p = 0.0003), loss of muscle force (p = 0.03) and shift to smaller myofibers. This was accompanied by a more pronounced rise in markers of endoplasmic reticulum stress in muscle, without effects on impairments in mitochondrial respiratory chain enzyme activities or autophagy activation. Supplementing critically ill mice with LY2405319 did not affect survival, muscle force or weight, or markers of muscle cellular stress/dysfunction.ConclusionsEndogenous FGF21 is not required for sepsis survival, but may partially protect muscle force and may reduce cellular stress in muscle. Exogenous FGF21 supplementation failed to improve muscle force or cellular stress, not supporting the clinical applicability of FGF21 supplementation to protect against muscle weakness during critical illness.

Standardisation and future of preclinical echocardiography.

Echocardiography is a non-invasive imaging technique providing real-time information to assess the structure and function of the heart. Due to advancements in technology, ultra-high-frequency transducers have enabled the translation of ultrasound from humans to small animals due to resolutions down to 30µm. Most studies are performed using mice and rats, with ages ranging from embryonic, to neonatal, and adult. In addition, alternative models such as zebrafish and chicken embryos are becoming more frequently used. With the achieved high temporal and spatial resolution in real-time, cardiac function can now be monitored throughout the lifespan of these small animals to investigate the origin and treatment of a range of acute and chronic pathological conditions. With the increased relevance of in vivo real-time imaging, there is still an unmet need for the standardisation of small animal echocardiography and the appropriate cardiac measurements that should be reported in preclinical cardiac models. This review focuses on the development of standardisation in preclinical echocardiography and reports appropriate cardiac measurements throughout the lifespan of rodents: embryonic, neonatal, ageing, and acute and chronic pathologies. Lastly, we will discuss the future of cardiac preclinical ultrasound.

Mitophagy in metabolic syndrome.

Metabolic syndrome (MS), a chronic and non-communicable pathological condition, is characterized by a constellation of clinical manifestations including insulin resistance, abdominal adiposity, elevated blood pressure, and perturbations in lipid metabolism. The prevalence of MS has increased dramatically in both developed and developing countries and has now become a truly global problem. Excessive energy intake and concomitant obesity are the main drivers of this syndrome. Mitophagy, in which cells degrade damaged mitochondria through a selective form of autophagy, assumes a crucial position in the regulation of mitochondrial integrity and maintenance. Abnormal mitochondrial quality could result in a spectrum of pathological conditions related to metabolic dysfunction, including metabolic syndrome, cardiovascular ailments, and neoplasms. Recently, there has been a proliferation of research pertaining to the process of mitophagy in the context of MS, and there are various regulatory pathways in MS, including pathways like the ubiquitin-dependent mechanism and receptor-mediated mechanisms, among others. Furthermore, studies have uncovered that the process of mitophagy serves a defensive function in the advancement of Metabolic Syndrome, and inhibition of mitophagy exacerbates the advancement of MS. As a result, the regulation of mitophagy holds great promise as a therapeutic approach in the management of Metabolic Syndrome. In this comprehensive analysis, the authors present a synthesis of the diverse regulatory pathways involved in mitophagy in the context of Metabolic Syndrome, as well as its modes of action in metabolic disorders implicated in the development of MS, Including obesity, insulin resistance (IR), and type 2 diabetes mellitus (T2DM), offering novel avenues for the prophylaxis and therapeutic management of MS.