Altered Cytokine Secretory Fingerprint of the Adipocytes Derived from Stem Cells of Morbidly Obese Patients-A Preliminary Study.

Context: Adipose-derived mesenchymal stem cells (ADMSCs) are progenitor cells that shape the tissue's biological properties. Objective: To examine the adipocytes differentiated from the ADMSCs of lean and obese individuals with/without a metabolic syndrome (MetSx) cytokine secretory profile, as to date, little is known on this topic. Methods: Interleukin, chemokine and growth factor levels in the culture medium were determined using the Human Cytokine kit. Results: We observed a characteristic secretory fingerprint displayed by the cells from the MetSx group and identified a set of putative markers (IL-1ß, IL-6, IL-7, IL-10, IL-12, IL-13, VEGF, FGF, GM-CSF, TNF-α, IFN-γ) of the condition. Surprisingly, the concentrations of most of the molecules (except for IL-6, IFN-γ, IP-10, VEGF) decreased when compared with the cells from the lean group. We postulate that the difference stemmed from the fact that in vivo cytokines were mostly secreted by the activated monocytes/macrophages and not adipocytes per se. This may also suggest that the aforementioned upregulated cytokines (IL-6, IFN-γ, IP-10, VEGF) might have been the ones that attracted monocytes and triggered the vicious cycle of tissue inflammation. Conclusions: Our study indicated that the adipocytes newly derived from the ADMSCs of obese patients with metabolic syndrome displayed a secretory fingerprint that may be characteristic to the early stages of the condition.

High-Fat Diet-Induced Blood-Brain Barrier Dysfunction: Impact on Allodynia and Motor Coordination in Rats.

The associations among increased pain sensitivity, obesity, and systemic inflammation have not been described as related to BBB dysfunctions. To analyze the metabolic, behavioral, and inflammatory effects of a high-fat diet (HFD) and ultrastructural modifications in brain regions, we used an in vivo experimental model. Adult male Wistar rats were randomly assigned to one of two conditions, an ad libitum control group or an HFD (60%)-fed group, for eight weeks. At the end of the protocol, glucose and insulin tolerance tests were performed. Additionally, we analyzed the response to a normally innocuous mechanical stimulus and changes in motor coordination. At the end of the protocol, HFD-fed rats presented increased HOMA-IR and metabolic syndrome (MetS) prevalence. HFD-fed rats also developed an increased nociceptive response to mechanical stimuli and neurological injury, resulting in impaired motor function. Hypothalamus and cerebellum neurons from HFD-fed rats presented with nuclear swelling, an absence of nucleoli, and karyolysis. These results reveal that HFD consumption affects vital brain structures such as the cerebellum, hippocampus, and hypothalamus. This, in turn, could be producing neuronal damage, impairing cellular communication, and consequently altering motricity and pain sensitivity. Although direct evidence of a causal link between BBB dysfunction and sensory-motor changes was not observed, understanding the association uncovered in this study could lead to targeted therapeutic strategies.

Adipose Tissue Dysfunction Determines Lipotoxicity and Triggers the Metabolic Syndrome: Current Challenges and Clinical Perspectives.

The adipose tissue organ is organised as distinct anatomical depots located all along the body axis, and it is constituted of three different types of adipocytes: white, beige and brown, which are integrated with vascular, immune, neural, and extracellular stroma cells. These distinct adipocytes serve different specialised functions. The main function of white adipocytes is to ensure healthy storage of excess nutrients/energy and its rapid mobilisation to supply the demand of energy imposed by physiological cues in other organs, whereas brown and beige adipocytes are designed for heat production through uncoupling lipid oxidation from energy production. The concerted action of the three types of adipocytes/tissues ensures an optimal metabolic status. However, when one or several of these adipose depots become dysfunctional because of sustained lipid/nutrient overload, then insulin resistance and associated metabolic complications ensue. These metabolic alterations close a vicious cycle that negatively affects the adipose tissue functionality and compromises global metabolic homeostasis. Optimising white adipose tissue expandability and ensuring its functional metabolic flexibility and/or promoting brown/beige mediated thermogenic activity are complementary strategies that counteract obesity and its associated lipotoxic metabolic effects. However, the development of these therapeutic approaches requires a deep understanding of adipose tissue in all broad aspects. In this chapter, we will discuss the characteristics of the different adipose tissue depots with respect to origins and precursors recruitment, plasticity, cellular composition, and expandability capacity potential as well as molecular and metabolic characteristic signatures in both physiological and pathophysiological conditions. Current antilipotoxic strategies for future clinical application are also discussed in this chapter.

Evaluation of Peripheral Neuropathy in Rat Models of Metabolic Syndrome and Diabetes Mellitus.

The dynamics of nephropathy development in rats with type 2 diabetes mellitus, caused by a high-fat diet and the streptozotocin administration (25 mg/kg), and metabolic syndrome, caused by addition of 20% fructose solution to the diet, was evaluated during the experiment. Models with moderate severity of metabolic changes without significant changes in body weight were obtained after 24 weeks. To study neuropathy severity, the method of electroneuromyography was used; the velocities of motor and sensory excitation propagation along the caudal nerve fibers were measured. In modeled diabetes mellitus against the background of hyperglycemia, a marked decrease in motor and sensory propagation rates was observed, and an increase in the response durations was noted from week 12 to week 24, indicating pronounced neuropathy. In the fructose model, the motor response duration increased from week 12, which possibly indicates the development of peripheral neuropathy.

Aldehydes alter TGF-ß signaling and induce obesity and cancer.

Obesity and fatty liver diseases-metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH)-affect over one-third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2-/- and Aldh2-/-Sptbn1+/- mice develop phenotypes of human metabolic syndrome (MetS) and MASH with accumulation of endogenous aldehydes such as 4-hydroxynonenal (4-HNE). Mechanistic studies demonstrate aberrant transforming growth factor ß (TGF-ß) signaling through 4-HNE modification of the SMAD3 adaptor SPTBN1 (ß2-spectrin) to pro-fibrotic and pro-oncogenic phenotypes, which is restored to normal SMAD3 signaling by targeting SPTBN1 with small interfering RNA (siRNA). Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human model and, additionally, improves glucose handling in Aldh2-/- and Aldh2-/-Sptbn1+/- mice. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target.

[Forensic characteristic of sudden death cases in subjects with metabolic syndrome]. / Sudebno-meditsinskaya kharakteristika sluchaev vnezapnoi smerti lits s metabolicheskim sindromom.

Comparing pace and standard of living of the world population these days and in the end of the last century, it's quiet true that there has been a significant increase. Therewith, the number of deaths from cardiovascular diseases has increased in recent decades. Scientists around the world attribute this fact to the increase in the number of people with overweight and other metabolic disorders. Unhealthy lifestyle, namely unbalanced diet, stress, bad habits (smoking, alcohol abuse) leads to metabolic disorders and metabolic syndrome development, that, in turn, can be the main risk factor for complications of associated diseases leading to fatal outcome. The present study gives a forensic description of sudden death in metabolic syndrome, its pathomorphological features were investigated, the causes of death were shown, as well as their relationship with biochemical abnormalities in the body.

Association between metabolic syndrome and white matter integrity in young and mid-age post-9/11 adult Veterans.

Metabolic syndrome has been associated with reduced brain white matter integrity in older individuals. However, less is known about how metabolic syndrome might impact white matter integrity in younger populations. This study examined metabolic syndrome-related global and regional white matter integrity differences in a sample of 537 post-9/11 Veterans. Metabolic syndrome was defined as ≥3 factors of: increased waist circumference, hypertriglyceridemia, low high-density lipoprotein cholesterol, hypertension, and high fasting glucose. T1 and diffusion weighted 3 T MRI scans were processed using the FreeSurfer image analysis suite and FSL Diffusion Toolbox. Atlas-based regions of interest were determined from a combination of the Johns Hopkins University atlas and a Tract-Based Spatial Statistics-based FreeSurfer WMPARC white matter skeleton atlas. Analyses revealed individuals with metabolic syndrome (n = 132) had significantly lower global fractional anisotropy than those without metabolic syndrome (n = 405), and lower high-density lipoprotein cholesterol levels was the only metabolic syndrome factor significantly related to lower global fractional anisotropy levels. Lobe-specific analyses revealed individuals with metabolic syndrome had decreased fractional anisotropy in frontal white matter regions compared with those without metabolic syndrome. These findings indicate metabolic syndrome is prevalent in this sample of younger Veterans and is related to reduced frontal white matter integrity. Early intervention for metabolic syndrome may help alleviate adverse metabolic syndrome-related brain and cognitive effects with age.

Ferulic acid restores mitochondrial dynamics and autophagy via AMPK signaling pathway in a palmitate-induced hepatocyte model of metabolic syndrome.

Mitochondrial dysfunction, characterized by elevated oxidative stress, impaired energy balance, and dysregulated mitochondrial dynamics, is a hallmark of metabolic syndrome (MetS) and its comorbidities. Ferulic acid (FA), a principal phenolic compound found in whole grains, has demonstrated potential in ameliorating oxidative stress and preserving energy homeostasis. However, the influence of FA on mitochondrial health within the context of MetS remains unexplored. Moreover, the impact of FA on autophagy, which is essential for maintaining energy homeostasis and mitochondrial integrity, is not fully understood. Here, we aimed to study the mechanisms of action of FA in regulating mitochondrial health and autophagy using palmitate-treated HepG2 hepatocytes as a MetS cell model. We found that FA improved mitochondrial health by restoring redox balance and optimizing mitochondrial dynamics, including biogenesis and the fusion/fission ratio. Additionally, FA was shown to recover autophagy and activate AMPK-related cell signaling. Our results provide new insights into the therapeutic potential of FA as a mitochondria-targeting agent for the prevention and treatment of MetS.

Heterogeneous Pathological Changes in Liver Lobes During Liver Disease: A Perspective Review.

Liver diseases have a global prevalence of 25%, accounting for 4% of all deaths worldwide, and are associated with a 36% increased risk of fatal and nonfatal cardiovascular events. Metabolic dysfunction-associated steatotic liver disease constitutes the liver expression of metabolic syndrome and represents the primary type of liver disease. Microscopical analysis of biopsies, which allows the evaluation of a small portion of tissue with inferences made to the entire organ, is considered the gold standard for determining the presence of liver diseases. However, potential sampling errors in liver biopsies are conceivable because the obtained tissue represents only a tiny fraction of the entire liver mass and may not accurately reflect the true pathological state. Studies have demonstrated the existence of sampling errors in liver biopsies, particularly concerning the severity of inflammation, degree of fibrosis, and the presence of cirrhosis. Also, clinical studies have shown that histopathological abnormalities are better detected in humans when liver samples are collected from both the right and the left lobes. However, a gap exists in clinical investigation to clarify the role of differences between these lobes in improving the diagnostic and prognostic for liver diseases. Building upon the heterogeneous nature of pathological alterations observed in liver lobes, this perspective review provided recommendations to enhance the precision of diagnosis and prognostic accuracy of liver diseases.

Metabolic syndrome-associated murine aortic wall stiffening is associated with premature elastic fibers aging.

Type 2 diabetes (T2D) constitutes a major public health problem, and despite prevention efforts, this pandemic disease is one of the deadliest diseases in the world. In 2022, 6.7 million patients with T2D died prematurely from vascular complications. Indeed, diabetes increases the risk of myocardial infarction or stroke eightfold. The identification of the molecular factors involved in the occurrence of cardiovascular complications and their prevention are therefore major axes. Our hypothesis is that factors brought into play during physiological aging appear prematurely with diabetes progression. Our study focused on the aging of the extracellular matrix (ECM), a major element in the maintenance of vascular homeostasis. We characterized the morphological and functional aspects of aorta, with a focus on the collagen and elastic fibers of diabetic mice aged from 6 mo to nondiabetic mice aged 6 mo and 20 mo. The comparison with the two nondiabetic models (young and old) highlighted an exacerbated activity of proteases, which could explain a disturbance in the collagen accumulation and an excessive degradation of elastic fibers. Moreover, the generation of circulating elastin-derived peptides reflects premature aging of the ECM. These extracellular elements contribute to the appearance of vascular rigidity, often the origin of pathologies such as hypertension and atherosclerosis. In conclusion, we show that diabetic mice aged 6 mo present the same characteristics of ECM wear as those observed in mice aged 20 mo. This accelerated aortic wall remodeling could then explain the early onset of cardiovascular diseases and, therefore, the premature death of patients with T2D.NEW & NOTEWORTHY Aortic elastic fibers of young (6-mo old) individuals with diabetes degrade prematurely and exhibit an appearance like that found in aged (20-mo old) nondiabetic mice. Exacerbated elastolysis and elastin-derived peptide production are characteristic elements, contributing to early aortic wall rigidity and hypertension development. Therefore, limiting this early aging could be a judicious therapeutic approach to reduce cardiovascular complications and premature death in patients with diabetes.

Structural Brain Alterations in Metabolic Syndrome: A Comprehensive MRI Volumetric Analysis of Subcortical and Associated Structures.

Objective: This study aims to elucidate the comprehensive effects of metabolic syndrome (MetS) on the structural integrity of subcortical brain regions and associated structures through high-resolution magnetic resonance imaging (MRI) volumetric analysis, thereby contributing to a deeper understanding of the neuroanatomical dimensions of MetS and its potential implications for cognitive functions and overall brain health. Methods: A cross-sectional design was implemented, involving 25 individuals diagnosed with MetS for at least one year and a healthy control group of 15 individuals at a tertiary hospital's family medicine clinic in Eastern Turkey. Participants underwent a high-resolution MRI scan using a 1.5T Siemens Aera scanner. The MRICloud platform was employed for comprehensive segmentation and quantitative analysis of various brain structures. Results: The study revealed significant volumetric reductions in all measured subcortical brain regions among individuals with MetS compared to the control group (all P < 0.05). Notable differences were observed in key structures such as the substantia nigra, corpus callosum, and thalamus. In subcortical structures, the largest volumetric differences were noted in the basal ganglia L (1322.4 mm³), while the most significant percentage differences were seen in the substantia nigra R (25.24%) and caudate nucleus L (21.02%). Conclusion: The findings from this study underscore the significant neuroanatomical changes associated with MetS, manifesting as volumetric reductions in critical subcortical brain areas. These alterations underscore the necessity for further research into the comprehensive influence of MetS on cognitive processes and the potential for early therapeutic interventions.

Single high-dose intravenous injection of Wharton's jelly-derived mesenchymal stem cell exerts protective effects in a rat model of metabolic syndrome.

BACKGROUND: Metabolic syndrome (MetS) is a significant epidemiological problem worldwide. It is a pre-morbid, chronic and low-grade inflammatory disorder that precedes many chronic diseases. Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) could be used to treat MetS because they express high regenerative capacity, strong immunomodulatory properties and allogeneic biocompatibility. This study aims to investigate WJ-MSCs as a therapy against MetS in a rat model. METHODS: Twenty-four animals were fed with high-fat high-fructose (HFHF) diet ad libitum. After 16 weeks, the animals were randomised into treatment groups (n = 8/group) and received a single intravenous administration of vehicle, that is, 3 × 106 cells/kg or 10 × 106 cells/kg of WJ-MSCs. A healthy animal group (n = 6) fed with a normal diet received the same vehicle as the control (CTRL). All animals were periodically assessed (every 4 weeks) for physical measurements, serum biochemistry, glucose tolerance test, cardiovascular function test and whole-body composition. Post-euthanasia, organs were weighed and processed for histopathology. Serum was collected for C-reactive protein and inflammatory cytokine assay. RESULTS: The results between HFHF-treated groups and healthy or HFHF-CTRL did not achieve statistical significance (α = 0.05). The effects of WJ-MSCs were masked by the manifestation of different disease subclusters and continuous supplementation of HFHF diet. Based on secondary analysis, WJ-MSCs had major implications in improving cardiopulmonary morbidities. The lungs, liver and heart show significantly better histopathology in the WJ-MSC-treated groups than in the untreated CTRL group. The cells produced a dose-dependent effect (high dose lasted until week 8) in preventing further metabolic decay in MetS animals. CONCLUSIONS: The establishment of safety and therapeutic proof-of-concept encourages further studies by improving the current therapeutic model.

Spinal cord injury-induced metabolic impairment and steatohepatitis develops in non-obese rats and is exacerbated by premorbid obesity.

Impaired sensorimotor functions are prominent complications of spinal cord injury (SCI). A clinically important but less obvious consequence is development of metabolic syndrome (MetS), including increased adiposity, hyperglycemia/insulin resistance, and hyperlipidemia. MetS predisposes SCI individuals to earlier and more severe diabetes and cardiovascular disease compared to the general population, which trigger life-threatening complications (e.g., stroke, myocardial infarcts). Although each comorbidity is known to be a risk factor for diabetes and other health problems in obese individuals, their relative contribution or perceived importance in propagating systemic pathology after SCI has received less attention. This could be explained by an incomplete understanding of MetS promoted by SCI compared with that from the canonical trigger diet-induced obesity (DIO). Thus, here we compared metabolic-related outcomes after SCI in lean rats to those of uninjured rats with DIO. Surprisingly, SCI-induced MetS features were equal to or greater than those in obese uninjured rats, including insulin resistance, endotoxemia, hyperlipidemia, liver inflammation and steatosis. Considering the endemic nature of obesity, we also evaluated the effect of premorbid obesity in rats receiving SCI; the combination of DIO + SCI exacerbated MetS and liver pathology compared to either alone, suggesting that obese individuals that sustain a SCI are especially vulnerable to metabolic dysfunction. Notably, premorbid obesity also exacerbated intraspinal lesion pathology and worsened locomotor recovery after SCI. Overall, these results highlight that normal metabolic function requires intact spinal circuitry and that SCI is not just a sensory-motor disorder, but also has significant metabolic consequences.

Soluble epoxide hydrolase inhibition reverses cognitive dysfunction in a mouse model of metabolic syndrome by modulating inflammation.

Midlife metabolic syndrome (MetS) is associated with cognitive impairment in late life. The mechanism of delayed MetS-related cognitive dysfunction (MetSCD) is not clear, but it has been linked to systemic inflammation and chronic cerebral microangiopathy. Currently there is no treatment for late life MetSCD other than early risk factor modification. We investigated the effect of soluble epoxide hydrolase (sEH) inhibitor 4-[[trans-4-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]cyclohexyl]oxy]-benzoic acid (t-AUCB) on cognitive performance, cerebral blood flow (CBF), and central and peripheral inflammation in the high-fat diet (HFD) model of MetS in mice. At 6 weeks of age, male mice were randomly assigned to receive either HFD or standard chow (STD) for 6 months. Mice received either t-AUCB or vehicle for 4 weeks. Cognitive performance was evaluated, followed by CBF measurement using magnetic resonance imaging (MRI). At the end of the study, blood was collected for measurement of eicosanoids and inflammatory cytokines. The brains were then analyzed by immunohistochemistry for glial activation markers. The HFD caused a significant impairment in novel object recognition. Treatment with t-AUCB increased plasma levels of 14,15-EET, prevented this cognitive impairment and modified hippocampal glial activation and plasma cytokine levels, without affecting CBF in mice on HFD. In conclusion, sEH inhibition for four weeks prevents cognitive deficits in mice on chronic HFD by modulating inflammatory processes without affecting CBF.

USP18 Curbs the Progression of Metabolic Hypertension by Suppressing JAK/STAT Pathway.

Hypertension is a pathological state of the metabolic syndrome that increases the risk of cardiovascular disease. Managing hypertension is challenging, and we aimed to identify the pathogenic factors and discern therapeutic targets for metabolic hypertension (MHR). An MHR rat model was established with the combined treatment of a high-sugar, high-fat diet and ethanol. Histopathological observations were performed using hematoxylin-eosin and Sirius Red staining. Transcriptome sequencing was performed to screen differentially expressed genes. The role of ubiquitin-specific protease 18 (USP18) in the proliferation, apoptosis, and oxidative stress of HUVECs was explored using Cell Counting Kit-8, flow cytometry, and enzyme-linked immunosorbent assays. Moreover, USP18 downstream signaling pathways in MHR were screened, and the effects of USP18 on these signaling pathways were investigated by western blotting. In the MHR model, total cholesterol and low-density lipoprotein levels increased, while high-density lipoprotein levels decreased. Moreover, high vessel thickness and percentage of collagen were noted along with increased malondialdehyde, decreased superoxide dismutase and catalase levels. The staining results showed that the MHR model exhibited an irregular aortic intima and disordered smooth muscle cells. There were 78 differentially expressed genes in the MHR model, and seven hub genes, including USP18, were identified. USP18 overexpression facilitated proliferation and reduced apoptosis and oxidative stress in HUVECs treated with Ang in vitro. In addition, the JAK/STAT pathway was identified as a USP18 downstream signaling pathway, and USP18 overexpression inhibited the expression of JAK/STAT pathway-related proteins. Conclusively, USP18 restrained MHR progression by promoting cell proliferation, reversing apoptosis and oxidative stress, and suppressing the JAK/STAT pathway.

Induction of diabetes by Tacrolimus in a phenotypic model of obesity and metabolic syndrome.

Introduction: The pathogenesis of Post-Transplant Diabetes Mellitus (PTDM) is complex and multifactorial and it resembles that of Type-2 Diabetes Mellitus (T2DM). One risk factor specific to PTDM differentiates both entities: the use of immunosuppressive therapy. Specifically, Tacrolimus interacts with obesity and insulin resistance (IR) in accelerating the onset of PTDM. In a genotypic model of IR, the obese Zucker rats, Tacrolimus is highly diabetogenic by promoting the same changes in beta-cell already modified by IR. Nevertheless, genotypic animal models have their limitations and may not resemble the real pathophysiology of diabetes. In this study, we have evaluated the interaction between beta-cell damage and Tacrolimus in a non-genotypic animal model of obesity and metabolic syndrome. Methods: Sprague Dawley rats were fed a high-fat enriched diet during 45 days to induce obesity and metabolic dysregulation. On top of this established obesity, the administration of Tacrolimus (1mg/kg/day) during 15 days induced severe hyperglycaemia and changes in morphological and structural characteristics of the pancreas. Results: Obese animals administered with Tacrolimus showed increased size of islets of Langerhans and reduced beta-cell proliferation without changes in apoptosis. There were also changes in beta-cell nuclear factors such as a decrease in nuclear expression of MafA and a nuclear overexpression of FoxO1A, PDX-1 and NeuroD1. These animals also showed increased levels of pancreatic insulin and glucagon. Discussion: This model could be evidence of the relationship between the T2DM and PTDM physiopathology and, eventually, the model may be instrumental to study the pathogenesis of T2DM.

Bone-derived PDGF-BB enhances hippocampal non-specific transcytosis through microglia-endothelial crosstalk in HFD-induced metabolic syndrome.

BACKGROUND: It is well known that high-fat diet (HFD)-induced metabolic syndrome plays a crucial role in cognitive decline and brain-blood barrier (BBB) breakdown. However, whether the bone-brain axis participates in this pathological process remains unknown. Here, we report that platelet-derived growth factor-BB (PDGF-BB) secretion by preosteoclasts in the bone accelerates neuroinflammation. The expression of alkaline phosphatase (ALPL), a nonspecific transcytosis marker, was upregulated during HFD challenge. MAIN BODY: Preosteoclast-specific Pdgfb transgenic mice with high PDGF-BB concentrations in the circulation recapitulated the HFD-induced neuroinflammation and transcytosis shift. Preosteoclast-specific Pdgfb knockout mice were partially rescued from hippocampal neuroinflammation and transcytosis shifts in HFD-challenged mice. HFD-induced PDGF-BB elevation aggravated microglia-associated neuroinflammation and interleukin-1ß (IL-1ß) secretion, which increased ALPL expression and transcytosis shift through enhancing protein 1 (SP1) translocation in endothelial cells. CONCLUSION: Our findings confirm the role of bone-secreted PDGF-BB in neuroinflammation and the transcytosis shift in the hippocampal region during HFD challenge and identify a novel mechanism of microglia-endothelial crosstalk in HFD-induced metabolic syndrome.

Fennel seeds extract prevents fructose-induced cardiac dysfunction in a rat model of metabolic syndrome via targeting abdominal obesity, hyperuricemia and NF-κß inflammatory pathway.

BACKGROUND: Metabolic syndrome (MetS) is commonly associated with increased risk of cardiac disease that affects a large number of world populations. OBJECTIVE: This research attempted to investigate the efficacy of fennel seeds extract (FSE) in preventing development of cardiac dysfunction in rats on fructose enriched diet for 3 months, as a model of MetS. MATERIALS & METHODS: Thirty adult Wistar male rats (160-170 g) were assigned into 5 groups including control, vehicle, FSE (200 mg/kg BW) and fructose (60%) fed rats with and without FSE. Following the last treatment, blood pressure, ECG and heart rate were measured. Next, blood and cardiac tissues were taken for biochemical and histological investigations. RESULTS: Feeding fructose exhibited characteristic features of MetS involving, hypertension, abnormal ECG, elevated heart rate, serum glucose, insulin, lipids and insulin resistance, accompanied by abdominal obesity, cardiac hypertrophy and hyperuricemia. Fructose fed rats also showed significant reduction in cardiac antioxidants (GSH, SOD, CAT) with elevation in oxidative stress indices (NADPH oxidase, O2.-, H2O2, MDA, PCO), NF-κß, pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6), adhesion molecules (ICAM-1, VCAM-1) and serum cardiac biomarkers (AST, LDH, CK-MB, cTn-I). Histopathological changes evidenced by destruction of cardiac myofibrils, cytoplasmic vacuolization, and aggregation of inflammatory cells were also detected. Consumption of FSE showed high ability to alleviate fructose-induced hypertension, ECG abnormalities, cardiac hypertrophy, metabolic alterations, oxidative stress, inflammation and histological injury. CONCLUSION: Findings could suggest FSE as a complementary supplement for preventing MetS and associated cardiac outcomes. However, well controlled clinical studies are still needed.

Metabolic Syndrome and Cardiac Vessel Remodeling Associated with Vessel Rarefaction: A Possible Underlying Mechanism May Result from a Poor Angiogenic Response to Altered VEGF Signaling Pathways.

BACKGROUND: Elevated mortality rates in patients with metabolic syndrome (MetS) are partly due to adverse remodeling of multiple organs, which may lead to cardiovascular disease, nonalcoholic fatty liver disease, kidney failure, or other conditions. MetS symptoms, such as obesity, hypertension, hyperglycemia, dyslipidemia, associated with insulin and leptin resistance, are recognized as major cardiovascular risk factors that adversely affect the heart. SUMMARY: Pathological cardiac remodeling is accompanied by endothelial cell dysfunction which may result in diminished coronary flow, dysregulated oxygen demand/supply balance, as well as vessel rarefaction. The reduced number of vessels and delayed or inhibited formation of collaterals after myocardial infarction in MetS heart may be due to unfavorable changes in endothelial cell metabolism but also to altered expression of vascular endothelial growth factor molecules, their receptors, and changes in signal transduction from the cell membrane, which severely affect angiogenesis. KEY MESSAGES: Given the established role of cardiac vessel endothelial cells in maintaining tissue homeostasis, defining the molecular background underlying vessel dysfunction associated with impaired angiogenesis is of great importance for future therapeutic purposes. Therefore, the aim of this paper was to present current information regarding vascular endothelial growth factor signaling in the myocardium of MetS individuals.

Telmisartan ameliorates nephropathy and restores the hippo pathway in rats with metabolic syndrome.

The main objective of this study was to determine if the telmisartan-ameliorative effects of metabolic syndrome (MetS)-evoked nephropathy are attributed to the Hippo pathway. A secondary objective was to investigate the potential of vitamin D3 to enhance telmisartan-favourable effects. A diet composed of 24% fat and 3% salt, along with drinking water containing 10% fructose, was administered for 12 weeks to induce MetS. MetS-rats were given telmisartan (5 mg/kg/day), vitamin D3 (10 µg/kg/day) or both by gavage, starting in the sixth week of experimental diet administration. Assessments performed at closure included renal function, histological examination, catalase, malondialdehyde (MDA), nuclear factor kappa-B (NF-κB), interleukin-6 (IL-6), peroxisome proliferator-activated receptor-γ (PPAR-γ), phosphatase and tensin homolog (PTEN), and transforming growth factor-ß (TGF-ß). Matrix metalloproteinase-9 (MMP-9) immunostaining was conducted. The expression of the Hippo pathway components, as well as that of angiotensin II type 1 and type 2 (AT1 and AT2), receptors was evaluated. Telmisartan attenuated MetS-evoked nephropathy, as demonstrated by improvement of renal function and histological features, enhancement of catalase, reduction of MDA, inflammation (NF-κB, IL-6), and renal fibrosis (increased PPAR-γ and PTEN and reduced MMP-9 and TGF-ß). Telmisartan downregulated AT1-receptor, upregulated AT2-receptor and restored the Hippo pathway. Vitamin D3 replicated most of the telmisartan-elicited effects and enhanced the antifibrotic actions of telmisartan. The alleviative effects of telmisartan on MetS-evoked nephropathy may be related to the restoration of the Hippo pathway. The combination of vitamin D3 and telmisartan exerted more favourable effects on metabolic and nephropathic biomarkers compared with either one administered alone.