Adipose tissue is now recognized as a heterogeneous endocrine and metabolic organ rather than a passive lipid reservoir. Beyond the classical white, brown, and beige adipocytes, several depot- and organ-specific lipid-storing cell populations, including pink adipocytes, bone marrow (yellow) adipocytes, and hepatic stellate cells, contribute to energy homeostasis, thermogenesis, immune regulation, bone marrow function, and hepatic retinoid storage. Most existing reviews address these populations separately or focus narrowly on classical depots. Here, we integrate classical and non-classical adipocyte populations within a single depot-specific framework, examining how anatomical location and functional specialization jointly determine their contribution to obesity-related non-communicable diseases, including type 2 diabetes mellitus, metabolic-associated fatty liver disease, hypertension, and atherosclerotic cardiovascular disease. We further highlight unresolved mechanistic questions, including macrophage phenotypic heterogeneity beyond the classical M1/M2 model, the translational limits of brown adipose tissue activation, and the paracrine role of perivascular adipose tissue, that represent priority areas for future investigation.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by endothelial dysfunction, vascular remodeling, and a sustained increase in pulmonary vascular resistance, causing cardiopulmonary damage. The apelin receptor (APJ), a member of the G protein-coupled receptor family, has emerged as an essential modulator of vascular homeostasis. Clinical and preclinical studies have demonstrated that its activation exerts beneficial effects on the progression of PAH. Its main actions include the restoration of endothelial function, reactivation of the BMPR2/SMAD axis, induction of nitric oxide-mediated vasodilation, inhibition of autophagy and the migration of the pulmonary artery smooth muscle cells (PASMCs). Furthermore, its expression and functionality are modulated by epitranscriptomic mechanisms, particularly by microRNAs involved in the post-transcriptional regulation of key genes for vascular homeostasis. These findings position the APJ as a relevant therapeutic target in PAH. However, the clinical application of its agonists still faces pharmacokinetic limitations that restrict their therapeutic use. Therefore, the aim of this review is to gather current information on APJ in the pathophysiology of PAH and focus attention on its potential as a therapeutic target.

We evaluated the effects of fenofibrate (FF) in a SU5416/hypoxia model of pulmonary arterial hypertension (PAH) with a specific focus on its influence on the renin-angiotensin system (RAS). We assessed right ventricular systolic pressure (RVSP), mean pulmonary artery pressure (mPAP), medial pulmonary artery wall thickening, right ventricular (RV) hypertrophy, systolic pulmonary artery pressure (SPAP), pulmonary artery effective elastance (PAEa), RV diastolic pressure (RVDP), RV developed pressure (RVDevP), right ventricular-pulmonary arterial coupling index (RVPAC), RV dp/dt max and dp/dt min. Levels of angiotensin II, angiotensin (1-7), angiotensin-converting enzyme 2 (ACE2), Bmpr2, Smad5 and nitrite (NO2-) and nitrate (NO3-) in the lung and RV were evaluated. The expression of AT1R, MAS receptors, and ACE2 in lung tissue was assessed. FF prevented the increase in RVSP, mPAP, RV hypertrophy, reduced pulmonary arterioles remodeling, and attenuated the rise in SPAP, mPAP, and PAEa. In the RV, it reduced RVDevP and prevented the decrease in dp/dt min, without affecting RVDP. RVPAC showed partial improvement. In lung tissue, FF decreased angiotensin II levels, the Ang II/Ang-(1-7) ratio, and reduced angiotensin II receptor type 1 (AT1R) expression, while preserving the receptor for the angiotensin-(1-7) (MAS) and ACE2. FF tended to restore Bmpr2/Smad5 expression. NO2- levels were preserved and tended to preserve (NO3-) levels. In the RV, Ang-(1-7) increased, ACE2 was preserved, and NO2- and NO3 levels were maintained. FF exerts protective effects in Su/Hx-induced PAH.

Hypercaloric intake promotes the development of obesity, a risk factor for cardiovascular disease (CVD). In recent years, it has been suggested that senescent cells have negative implications for the outcome of these chronic pathologies, and senotherapy has emerged as a novel intervention to reduce damage to the organism. However, it is unclear whether the accumulation of senescent cells induces alterations at the cardiac level in rats fed a hypercaloric diet (HD) and if the use of senotherapeutics can reverse it. To address this question, we used middle-aged female rats fed HD from 21 days to 15 months of age. Under our experimental conditions, rats exhibited cardiac hypertrophy and fibrosis, accumulation of senescent cells, changes in mitochondrial morphology, and oxidative stress. Rats were treated for 2 months with senolytic (dasatinib + quercetin, DQ) or senomorphic (sulforaphane, SFN) agents. Interestingly, the HD rats showed cardiac improvement after the treatment. Our data suggest a possible link mechanism between Nrf2 activation and mitochondria-endoplasmic reticulum contact sites (MERCSs) preservation, activated by SFN rather than by the DQ combination, which allowed cardiac structure maintenance in HD rats decreasing the harmful effects of senescent cells.

Hypertension (HP) is a health condition that overloads the heart and increases the risk of heart attack and stroke. In an infarction, the lack of oxygen causes an exclusive use of glycolysis, which becomes a crucial source of ATP for the heart with a higher glucose uptake mediated by glucose transporters (GLUTs). Due to the unpleasant effects of antihypertensives, new drugs need to be researched to treat this disease. This study aimed to evaluate the cardioprotective effect of three novel antihypertensive compounds (LQMs, “Laboratorio de Química Medicinal”) synthesized from Changrolin under hypoxic conditions with the participation of two primary cardiac GLUT1 and GLUT4 using a high-salt diet HP model. The model used a diet with 10% salt to increase arterial blood pressure in Wistar rats. In isolated cardiomyocytes from these rats, glucose uptake was measured during hypoxia, evaluating the participation of GLUTs with or without the animals’ previous treatment with LQM312, 319, and 345 compounds. In silico calculations were performed to understand the affinity of the compounds for the trafficking of GLUTs. Results: Control cells do shift to glucose uptake exclusively in hypoxia (from 1.84 ± 0.09 µg/g/h to 2.67 ± 0.1 µg/g/h). Meanwhile, HP does not change its glucose uptake (from 2.38 ± 0.24 µg/g/h to 2.33 ± 0.26 µg/g/h), which is associated with cardiomyocyte damage. The new compounds lowered the systolic blood pressure (from 149 to 120 mmHg), but only LQM312 and LQM319 improved the metabolic state of hypoxic cardiomyocytes mediated by GLUT1 and GLUT4. In silico studies suggested that Captopril and LQM312 may mimic the interaction with the AMPK γ-subunit. Therefore, these compounds could activate AMPK, promoting the GLUT4 trafficking signaling pathway. These compounds are proposed to be cardioprotective during hypoxia under HP.

Sequences formed by symbols are found in diverse fields, including genome sequences, written texts and computer codes. An interesting question is whether a sequence of symbols contains correlated structures. Existing methods to characterize correlations require a numerical representation of the sequence. In this regard, mapping a sequence of text into a sequence of numerical values is a key step for assessing correlation analysis. This work proposes a methodology to study correlations in a sequence of symbols. In the first step, the sequence of symbols is mapped in a multivariate numerical sequence formed by unit vectors in a vectorial space. The main feature of such mapping is that symbols are equally weighted, thus avoiding the numerical overrepresentation of symbols. In the second step, a multivariate version of the detrended fluctuation analysis is used to quantify correlations in the numerical sequence. Genome sequences (first COVID-19), written English texts and comovements between Bitcoin and gold markets were used to illustrate the proposed methodology's performance. The results showed that the balanced numerical mapping of symbolic sequences and the multivariate DFA provides valuable insights into the correlations in a sequence of symbols.

Sugar transport through the plasma membrane is one of the most critical events in the cellular transport of nutrients; for example, glucose has a central role in cellular metabolism and homeostasis. The way sugars enter the cell involves complex systems. Diverse protein systems participate in the membrane traffic of the sugars from the extracellular side to the cytoplasmic side. This diversity makes the phenomenon highly regulated and modulated to satisfy the different needs of each cell line. The beautiful thing about this process is how evolutionary processes have diversified a single function: to move glucose into the cell. The deregulation of these entrance systems causes some diseases. Hence, it is necessary to study them and search for a way to correct the alterations and utilize these mechanisms to promote health. This review will highlight the various mechanisms for importing the valuable sugars needed to create cellular homeostasis and survival in all kinds of cells.

An approach based on fractal scaling analysis to characterize the organization of the Covid-19 genome sequences is presented in this work. The method is based on a multivariate version of the fractal rescaled range analysis implemented on a sliding window scheme to detect variations of long-range correlations over the genome sequence domains. As a preliminary step, the nucleotide sequence is mapped in a numerical sequence by following a Voss rule, resulting in a multichannel sequence represented as a binary matrix. Fractal correlations, quantified in terms of the Hurst exponent, depending on the region of the sequence, where the Covid-19 genome sequences are predominantly random, with some patches of weak long-range correlations. The analysis shows that the regions of randomness are more abundant in the Covid-19 sequences than in the primitive SARS sequence, which suggests that the Covid-19 virus possesses a more diverse genomic structure for replication and infection. The analysis constrained to the surface glycoprotein region shows that the Covid-19 sequence is less random as compared to the SARS sequence, which indicates that the Covid-19 virus can undergo more ordered replications of the spike protein. The Omicron variation exhibits an interesting pattern with some randomness similarities with the other SARS and the Covid-19 genome sequences. Overall, the results show that the multivariate rescaled range analysis provides a suitable framework to assess long-term correlations hidden in the internal organization of the Covid-19 genome sequence.

Background Chagas disease is considered important and presents intense inflammatory and fibrotic processes induced by the perpetuation of the parasite in the affected tissues and organs. Therefore, it is necessary to inquire about the host defense and attack mechanisms to have a more detailed knowledge about Chagas disease. MicroRNAs are found in blood, tissues and extracellular vesicles. These small regulators of gene expression are involved in physiological and pathological processes in both mammals and parasites. Several microRNAs have deregulated expression in chagasic heart disease, although little is known about their extracellular expression. Our main objective was to evaluate the involvement of miR-21, miR-146a and miR-155 in several samples from mice infected with the TcI Ninoa strain from the acute and indeterminate phases. We also explored a potential functional association of the selected microRNAs using STRING software. This software identified 23 pathways associated with Trypanosoma cruzi infection. In addition, eleven genes were identified through bioinformatics analysis, and we found that SMAD family member 5 was downregulated in both phases. This gene serves as a mediator in the TGF-β signaling pathway. Thus, forty female mice of the CD1 strain were distributed into 4 groups and the expression levels of miR-21, miR-146a and miR-155 were measured in samples of heart tissue, total plasma and plasma extracellular vesicles by quantitative real-time polymerase chain reaction. Results Overexpression of miR-21, miR-146a and miR-155 was observed in heart and plasma in both phases. Moreover, in extracellular vesicles miR-21 and miR-146a were also overexpressed in the acute phase, whereas in the indeterminate chronic phase we found only miR-146a up-regulated. Conclusions The expression of inflammatory microRNAs miR-21, miR-146a and miR-155 were up-regulated in each of the samples from acutely and chronically infected mice. The relevant finding was that miR-146a was up-regulated in each sample in both phases; therefore, this miRNA could be a possible candidate biomarker in Chagas disease.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling. Recent evidence supports that inflammation plays a key role in triggering and maintaining pulmonary vascular remodeling. Recent studies have shown that garlic extract has protective effects in PAH, but the precise role of allicin, a compound derived from garlic, is unknown. Thus, we used allicin to evaluate its effects on inflammation and fibrosis in PAH. Male Wistar rats were divided into three groups: control (CON), monocrotaline (60 mg/kg) (MCT), and MCT plus allicin (16 mg/kg/oral gavage) (MCT + A). Right ventricle (RV) hypertrophy and pulmonary arterial medial wall thickness were determined. IL-1β, IL-6, TNF-α, NFκB p65, Iκβ, TGF-β, and α-SMA were determined by Western blot analysis. In addition, TNF-α and TGF-β were determined by immunohistochemistry, and miR-21-5p and mRNA expressions of Cd68, Bmpr2, and Smad5 were determined by RT-qPCR. Results: Allicin prevented increases in vessel wall thickness due to TNF-α, IL-6, IL-1β, and Cd68 in the lung. In addition, TGF-β, α-SMA, and fibrosis were lower in the MCT + A group compared with the MCT group. In the RV, allicin prevented increases in TNF-α, IL-6, and TGF-β. These observations suggest that, through the modulation of proinflammatory and profibrotic markers in the lung and heart, allicin delays the progression of PAH.

The cellular damage caused by redox imbalance is involved in the pathogenesis of many cardiovascular diseases. Besides, redox imbalance is related to the alteration of protein acetylation processes, causing not only chromatin remodeling but also disturbances in so many processes where protein acetylation is involved, such as metabolism and signal transduction. The modulation of acetylases and deacetylases enzymes aids in maintaining the redox homeostasis, avoiding the deleterious cellular effects associated with the dysregulation of protein acetylation. Of note, regulation of protein acetylation has shown protective effects to ameliorate cardiovascular diseases. For instance, HDAC inhibition has been related to inducing cardiac protective effects and it is an interesting approach to the management of cardiovascular diseases. On the other hand, the upregulation of SIRT protein activity has also been implicated in the relief of cardiovascular diseases. This review focuses on the major protein acetylation modulators described, involving pharmacological and bioactive compounds targeting deacetylase and acetylase enzymes contributing to heart protection through redox homeostasis.

BackgroundCold temperatures can aggravate pulmonary diseases and promote pulmonary arterial hypertension (PAH); however, the underlying mechanism has not been fully explored.AimTo explore the effect of chronic cold exposure on the production of inflammatory cytokines and microRNAs (miRNAs) in a monocrotaline (MCT)-induced PAH model.MethodsMale Sprague Dawley rats were divided into a Control (23.5 ± 2 °C), Cold (5.0 ± 1 °C for ten days), MCT (60 mg/kg body weight i.p.), and MCT + Cold (ten days of cold exposure after 3 weeks of MCT injection). Hemodynamic parameters, right ventricle (RV) hypertrophy, and pulmonary arterial medial wall thickness were determined. IL-1β, IL-6, and TNF-α levels were determined using western blotting. miR-21-5p and -3p, miR-146a-5p and -3p, and miR-155-5p and -3p and plasma extracellular vesicles (EVs) and mRNA expression of Cd68, Cd163, Bmpr2, Smad5, Tgfbr2, and Smad3 were determined using RT-qPCR.ResultsThe MCT + Cold group had aggravated RV hypertrophy hemodynamic parameters, and pulmonary arterial medial wall thickness. In lungs of the MCT + Cold, group the protein levels of TNF-α, IL-1β, and IL-6 were higher than those in the MCT group. The mRNA expression of Cd68 and Cd163 were higher in the MCT + Cold group. miR-146a-5p and miR-155-5p levels were higher in the plasma EVs and lungs of the MCT + Cold group. Cold exposure promoted a greater decrease in miR-21-5p, Bmpr2, Smad5, Tgfbr2, and Smad3 mRNA expression in lungs of the MCT + Cold group.ConclusionCold exposure aggravates MCT-induced PAH with an increase in inflammatory marker and miRNA levels in the plasma EVs and lungs.

Pulmonary arterial hypertension (PAH) is a severe disease characterized by the loss and obstructive remodeling of the pulmonary arterial wall, causing a rise in pulmonary arterial pressure and pulmonary vascular resistance, which is responsible for right heart failure, functional decline, and death. Although many drugs are available for the treatment of this condition, it continues to be life-threatening, and its long-term treatment is expensive. On the other hand, many natural compounds present in food have beneficial effects on several cardiovascular conditions. Several studies have explored many of the potential beneficial effects of natural plant products on PAH. However, the mechanisms by which natural products, such as nutraceuticals, exert protective and therapeutic effects on PAH are not fully understood. In this review, we analyze the current knowledge on nutraceuticals and their potential use in the protection and treatment of PAH, as well as whether nutraceuticals could enhance the effects of drugs used in PAH through similar mechanisms.

In modern societies, high fructose intake from sugar-sweetened beverages has contributed to obesity development. In the diet, sucrose and high fructose corn syrup are the main sources of fructose and can be metabolized in the intestine and transported into the systemic circulation. The liver can metabolize around 70% of fructose intake, while the remaining is metabolized by other tissues. Several tissues including adipose tissue express the main fructose transporter GLUT5. In vivo, chronic fructose intake promotes white adipose tissue accumulation through activating adipogenesis. In vitro experiments have also demonstrated that fructose alone induces adipogenesis by several mechanisms, including (1) triglycerides and very-low-density lipoprotein (VLDL) production by fructose metabolism, (2) the stimulation of glucocorticoid activation by increasing 11β-HSD1 activity, and (3) the promotion of reactive oxygen species (ROS) production through uric acid, NOX and XOR expression, mTORC1 signaling and Ang II induction. Moreover, it has been observed that fructose induces adipogenesis through increased ACE2 expression, which promotes high Ang-(1-7) levels, and through the inhibition of the thermogenic program by regulating Sirt1 and UCP1. Finally, microRNAs may also be involved in regulating adipogenesis in high fructose intake conditions. In this paper, we propose further directions for research in fructose participation in adipogenesis.

Obesity is considered to significantly increase the risk of the development of a vast range of metabolic diseases. However, adipogenesis is a complex physiological process, necessary to sequester lipids effectively to avoid lipotoxicity in other tissues, like the liver, heart, muscle, essential for maintaining metabolic homeostasis and has a crucial role as a component of the innate immune system, far beyond than only being an inert mass of energy storage. In pathophysiological conditions, adipogenesis promotes a pro-inflammatory state, angiogenesis and the release of adipokines, which become dangerous to health. It results in a hypoxic state, causing oxidative stress and the synthesis and release of harmful free fatty acids. In this review, we try to explain the mechanisms occurring at the breaking point, at which adipogenesis leads to an uncontrolled lipotoxicity. This review highlights the types of adipose tissue and their functions, their way of storing lipids until a critical point, which is associated with hypoxia, inflammation, insulin resistance as well as lipodystrophy and adipogenesis modulation by Krüppel-like factors and miRNAs.

Among the last consequences of metabolic syndrome are cardiovascular complications such as infarcts. The hypoxic heart switches its lipid-based metabolism to carbohydrates, and a glucose-insulin-potassium (GIK) solution can be the metabolic support to protect the organ. Due to the physiology and cardiac risks associated with the metabolic syndrome, we studied the effect of GIK solution during hypoxia in a metabolic syndrome model by observing the participation of glucose transporters (GLUTs). The metabolic syndrome characteristics were established by giving a 30% sucrose drinking solution to Wistar rats for 24 weeks. The GIK solution’s effect on myocyte glucose uptake during hypoxia and oxygenation was observed using a colorimetric method, and Western blot technique visualized the GLUT participation. Oxygenated control myocytes consumed 1.7 ± 0.2 µg of glucose per gram of fresh tissue per hour using the GLUT1, and during hypoxia, they incorporated 41.1% more glucose by GLUT1 and GLUT4. The GIK solution improved glucose uptake in oxygenation by 70.5% through GLUT1. In hypoxia, the uptake was 21% more than the hypoxic control group and by both GLUTs too. Oxygenated metabolic syndrome myocytes uptake was similar to control cells but achieved by both carriers in oxygenation and hypoxia. Also, the GIK solution had a better response in both oxygenation (113%) and hypoxia (71%). Despite the metabolic energy disorders of this syndrome, the GIK solution protects cardiomyocytes, in conditions of hypoxia, through the modulation of both GLUTs. So, this solution can be considered a useful resource during a heart attack in cases of metabolic syndrome.

Cold exposure increases the severity of many cardiovascular and respiratory conditions. The effects of cold stress on the molecular physiopathology involved in Pulmonary hypertension has not been assessed. Thus, we aimed to evaluate the effect of cold exposure on PAH model, and the involvement of miR-21-5p regulation of gene expression in the lung. Four experimental groups were conducted, 24 Male Sprague Dawley weight 250g were divided in control, Monocrotaline (60 mg/kg) four weeks, cold stress 10 day 4 ºC (Cold) and Monocrotaline plus cold stress (MCT+Cold) groups. Weigh of the heart left and right ventricle for ratio RV/BW (g/kg), Fulton index RV/(LV+S) was assessed. microRNA expression of mature miR-21-5p, miR-146a-5p, and miR-155-5p was measured by RT-qPCR. Right ventricle weight normalized against total body weight showed significantly the higher values in MCT treated groups being significantly higher in the MCT+Cold group (Control 0.56±0.02, MCT 1.0± 0.12, Cold 0.76± 0.17 and MCT+Cold 1.5±0.33) p<0.05 vs control. Fulton index was increased in the MCT treated groups (Control 0.35±0.017, MCT 0.62± 0.08, Cold 0.45± 0.12 and MCT+Cold 0.75±0.13) p<0.05. Lower expression of miR-21-5p was found in the MCT with significantly lower levels in the MCT+Cold groups (Control 1.0±0.18, MCT 0.57±0.08, Cold 0.77±0.11 and MCT+Cold 0.21±0.06) p<0.05. Conversely the MCT+Cold group showed higher levels of both miR-146a, and miR-155 p<0.05. In conclusion cold exposure accentuated the right ventricle weight with enhanced repression of miR-21-5p and dysregulation of miR-146a-5p and miR-155-5p.

Metabolic syndrome (MetS) is characterized by a constellation of conditions that increase the risk for heart disease and other health problems. Although multiple organs are affected by this syndrome, research that focuses on the organs that are not directly involved in metabolism is lacking. Because MetS increases the risk for various lung diseases, we explored the effects of MetS on the lung in this study. We observed that the chronic consumption of a high sucrose diet for 24 weeks induced MetS in a rat model. Concomitant expression changes in 1,026 coding genes and two microRNAs were observed in the analyzed lung tissues. A network analysis showed degradation changes in the melatonin pathway, which plays a protective role in the lung; impairments of several inflammatory pathways (i.e., interferon-γ and nuclear factor kappa B) were also revealed. Moreover, multiple olfactory genes were unexpectedly deregulated. Overall, the lungs of MetS mice exhibited an inflammatory phenotype with molecular changes that affected several signaling pathways that were related to melatonin metabolism, olfactory receptors and cytokine production. Additional research will be necessary to dissect a possible mechanism for the effects of this syndrome on the lung.

Maitotoxin (MTX) is the most potent marine toxin known to date. It is responsible for a particular human intoxication syndrome called ciguatera fish poisoning (CFP). Several reports indicate that MTX is an activator of non-selective cation channels (NSCC) in different cell types. The molecular identity of these channels is still an unresolved topic, and it has been proposed that the transient receptor potential (TRP) channels are involved in this effect. In Xenopus laevis oocytes, MTX at picomolar (pM) concentrations induces the activation of NSCC with functional and pharmacological properties that resemble the activity of TRP channels. The purpose of this study was to characterize the molecular identity of the TRP channel involved in the MTX response, using the small interference RNA (siRNA) approach and the two-electrode voltage-clamp technique (TEVC). The injection of a specifically designed siRNA to silence the transient receptor potential canonical type 1 (TRPC1) protein expression abolished the MTX response. MTX had no effect on oocytes, even at doses 20-fold higher compared to cells without injection. Total mRNA and protein levels of TRPC1 were notably diminished. The TRPC4 siRNA did not change the MTX effect, even though it was important to note that the protein level was reduced by the silencing of TRPC4. Our results suggest that MTX could be a selective activator of TRPC1 channels in X. laevis oocytes and a useful pharmacological tool for further studies on these TRP channels.