IntroductionLung cancer remains the leading cause of cancer-related mortality worldwide. Drug resistance is a major limitation of current therapies, prompting the search for new treatment strategies. Lung tumors frequently develop a hypoxic microenvironment associated with aggressive behavior and unfavorable clinical outcomes. Tumor-initiating cells (TICs), also known as cancer stem cells, and hypoxia-driven metabolic adaptations contribute significantly to therapy resistance. Mitochondrial destabilization has emerged as a promising invariant target in TICs. Triphenylphosphonium (TPP+)-conjugated hydroxybenzoates selectively accumulate in the mitochondrial matrix, driven by membrane potential, disrupting organelle function. Additionally, doxycycline inhibits mitochondrial biogenesis and reduces mitochondrial mass. Here, we evaluate a therapeutic strategy combining TPP+-conjugated lipophilic cations with doxycycline to target mitochondrial vulnerability in non-small cell lung cancer.MethodsTPP+ lipophilic cations conjugated to benzoate derivatives, alone or combined with doxycycline, were evaluated for their ability to disrupt mitochondrial function, reduce cell viability, and induce apoptosis in two lung cancer cell lines under normoxic and hypoxic conditions.ResultsOur results demonstrate that these compounds exhibit cytotoxicity in lung cancer cells, particularly under hypoxic conditions, consistent with mitochondrial functional impairment. Combinations of TPP+C10/doxycycline and GA-TPP+C10/doxycycline exhibited synergistic cytotoxicity in both normoxia and hypoxia, and increased apoptotic cell death compared to monotherapies.ConclusionTargeting mitochondrial functions using mitochondria-directed compounds, particularly in combination with doxycycline, represents a promising therapeutic approach for lung cancer. This strategy may be especially effective in hypoxic microenvironments, where conventional therapies often fail. Further in vivo validation is warranted to support the translational potential of this approach.

OBJECTIVE:Oral squamous cell carcinoma (OSCC), a common subtype of head and neck cancer (HNSC), impairs essential functions such as breathing, swallowing, and speech. This study aimed to evaluate the therapeutic potential of targeting mitochondrial pathways via inhibition of Voltage-Dependent Anionic Channel 1 (VDAC1) using itraconazole (ITRA) and to assess the synergistic effect of combining VDAC1 inhibition with autophagy inhibition using hydroxychloroquine (HCQ). METHODS:The effects of ITRA, HCQ, and their combinations with cisplatin were tested in various HNSC models, including monolayer cultures, hypoxic conditions, 3D spheroids, and an in vivo xenograft model. The study also examined the role of the VDAC1-Hexokinase-II complex and the impact of autophagy under metabolic stress. RESULTS:ITRA alone showed limited cytotoxicity, but its combination with HCQ significantly enhanced antitumoral activity. Synergistic effects were observed with HCQ + ITRA, HCQ + cisplatin, and ITRA + cisplatin in all in vitro models. In vivo, HCQ alone and in combination with ITRA reduced tumor growth without adverse effects. CONCLUSIONS:Taken together, these findings support itraconazole as a promising candidate for further in vivo and clinical investigation in selected oral cancers, including HNSCC and OSCC. Nevertheless, the definition of clinical treatment schedules will require additional comprehensive pharmacokinetic, toxicological, and clinical studies.

Kinins, bioactive peptides produced through the proteolytic activity of kallikrein1, are members of the kallikrein-kinin system (KKS) and play crucial roles in regulating physiological processes such as inflammation, blood pressure, vascular permeability, and cell function and growth. In adipose tissue, bradykinin (BK) and des-Arg9-BK (DBK), produced by plasma kallikrein (KLKB1), act via their receptors B2 (B2R) and B1 (B1R), respectively. B1R predominates in preadipocytes, while B2R is expressed during adipogenesis, likely driving adipose tissue expansion and sustaining chronic low-grade inflammation, both hallmarks of obesity and its associated metabolic disorders. Obesity, a multifactorial metabolic disease, is closely linked to adipose tissue dysfunction. This dysfunction is driven by inflammation and oxidative stress, which in turn alter adipogenesis, lipolysis, and insulin and leptin signaling, contributing to obesity and its comorbidities. This review focuses on the role of the KKS in adipose tissue homeostasis and function. Evidence from animal models suggests that B1R ablation or antagonism results in a healthier phenotype, characterized by improved leptin and insulin sensitivity, increased lipid oxidation, reduced adipose hypertrophy, and diminished production of proinflammatory mediators and reactive oxygen species. Conversely, B2R activation may exert protective effects by enhancing insulin signaling and promoting glucose uptake, although its role remains incompletely understood and appears context-dependent. The KKS proposes it as a promising therapeutic target, biomarker, and prognostic indicator in anti-obesity pharmacological strategies. B1R promotes adipose inflammation, making it a promising anti-obesity target. B2R activation supports insulin signaling and may counteract metabolic dysfunction. Kallikrein-kinin system (KKS) components and Kallikrein-related peptidases (KLKs) can serve as biomarkers of obesity-related inflammation.

Obesity leads to an increase in chronic non-communicable diseases. Adipose tissue transdifferentiation opens a treatment possibility against obesity through white adipose tissue (WAT) browning related with uncoupling protein 1 (UCP1). Some foods have a browning effect, which is characterized by their high amounts of polyphenols. Polyphenol-rich fruit extracts have been shown potential browning-inducing effects on WAT. Different food matrixes have been used as treatment for obesity without success in characterizing a particular compound responsible for these effects. The aim of this study is to determine that phenylacetic acid (PAA) has browning activity in mature adipocytes. 3T3-L1 preadipocytes were differentiated and stimulated for 24 h with PAA and later thermogenic genes were evaluated. Epigallocatechin gallate (EGCG) was used as a positive control. PAA was able to induce an increase in UCP1 gene expression levels. New studies are needed to evaluate the timing of PAA treatment in mature adipocytes to elucidate if there are different thermogenesis stimulation pathways.

Cardiac fibroblasts (CFs) play a crucial role in the structural and functional remodeling of the heart, particularly in the development of fibrosis, a condition that can ultimately lead to heart failure. Understanding the signaling pathways that regulate CF proliferation and autophagy is essential for uncovering the mechanisms driving cardiac remodeling. Among these pathways, AMP-activated protein kinase (AMPK) has emerged as a key regulator. This study aimed to elucidate the role of AMPK in catecholamine-induced autophagy and ERK-dependent proliferation of CFs. Cells were stimulated with isoproterenol (ISO), norepinephrine (NE), and cAMP analogs. Levels of cAMP, autophagy markers (LC3-II), and phosphorylation of AMPK, AKT, and S6K, along with [3H]-thymidine incorporation as a marker of proliferation, were assessed. The involvement of AMPK in these processes was investigated using the AMPK inhibitor Compound C (CC) and compared with ERK inhibition. Our findings demonstrate that catecholamines increase cAMP levels in CFs, activating AMPK via PKA and inducing autophagy through an mTOR-dependent mechanism. AMPK activation was also crucial for catecholamine-induced ERK-dependent CF proliferation. Inhibition of AMPK with CC blocked both autophagy and proliferation, underscoring AMPK's central role in these processes. These results provide new insights into the interplay between AMPK-mediated autophagy and ERK-dependent cell proliferation, highlighting potential therapeutic targets for heart failure management.

Background: Betulinic acid (BA) and some derivatives are well-known antiproliferative compounds. Literature precedents suggest that incorporating triphenylphosphonium (TPP+) salts on this triterpenoid scaffold enhances its biological activity. In the present study, we carried out a simple synthesis of C-28 ester derivatives of this triterpenoid conjugated with TPP+ bromide salts through 4- to 6-carbon chains via nucleophilic substitution of the corresponding ω-TPP+bromoalkanes. Tests for antiproliferative activity in nine cancer cell lines and normal human fibroblasts showed that TPP+ incorporation enhanced the potency of BA by more than an order of magnitude, up to 100-fold. BA-C4-TPP+Br−, with a four-carbon chain separating the TPP+ moiety from the BA, showed remarkable antiproliferative effects, sometimes more potent than the reference drug (Etoposide). This compound exhibited the strongest mitochondrial uncoupling effect in human cancer cells. No significant LDH release was noted in colorectal carcinoma cells at low micromolar concentrations of BA-C4-TPP+Br−, and sub-micromolar concentrations were sufficient for inducing apoptosis. The in silico prediction of pharmacokinetic properties suggested high oral absorption (88%), as well as a non-inhibitor and non-substrate profile vs. cytochrome isoenzymes. These results point to this compound as a promising lead for the development of novel anticancer drugs.

Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy.

Cardiac fibroblasts (CF) are mesenchymal-type cells responsible for maintaining the homeostasis of the heart's extracellular matrix (ECM). Their dysfunction leads to excessive secretion of ECM proteins, tissue stiffening, impaired nutrient and oxygen exchange, and electrical abnormalities in the heart. Additionally, CF act as sentinel cells in the cardiac tissue microenvironment, responding to various stimuli that may affect heart function. Deleterious stimuli induce an inflammatory response in CF, increasing the secretion of cytokines such as IL-1β and TNF-α and the expression of cell adhesion molecules like ICAM1 and VCAM1, initially promoting damage resolution by recruiting immune cells. However, constant harmful stimuli lead to a chronic inflammatory process and heart dysfunction. Therefore, it is necessary to study the mechanisms that govern CF inflammation. NFκB is a key regulator of the cardiac inflammatory process, making the search for mechanisms of NFκB regulation and CF inflammatory response crucial for developing new treatment options for cardiovascular diseases. SGK1, a serine-threonine protein kinase, is one of the regulators of NFκB and is involved in the fibrotic effects of angiotensin II and aldosterone, as well as in CF differentiation. However, its role in the CF inflammatory response is unknown. On the other hand, many bioactive natural products have demonstrated anti-inflammatory effects, but their role in CF inflammation is unknown. One such molecule is boldine, an alkaloid obtained from Boldo (Peumus boldus), a Chilean endemic tree with proven cytoprotective effects. However, its involvement in the regulation of SGK1 and CF inflammation is unknown. In this study, we evaluated the role of SGK1 and boldine in the inflammatory response in CF isolated from neonatal Sprague-Dawley rats. The involvement of SGK1 was analyzed using GSK650394, a specific SGK1 inhibitor. Our results demonstrate that SGK1 is crucial for LPS- and IFN-γ-induced inflammatory responses in CF (cytokine expression, cell adhesion molecule expression, and leukocyte adhesion). Furthermore, a conditioned medium (intracellular content of CF subject to freeze/thaw cycles) was used to simulate a sterile inflammation condition. The conditioned medium induced a potent inflammatory response in CF, which was completely prevented by the SGK1 inhibitor. Finally, our results indicate that boldine inhibits both SGK1 activation and the CF inflammatory response induced by LPS, IFN-γ, and CF-conditioned medium. Taken together, our results position SGK1 as an important regulator of the CF inflammatory response and boldine as a promising anti-inflammatory drug in the context of cardiovascular diseases.

Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world. Standard drugs currently used for the treatment of advanced CRC—such as 5-fluorouracil (5FU)—remain unsatisfactory in their results due to their high toxicity, high resistance, and adverse effects. In recent years, mitochondria have become an attractive target for cancer therapy due to higher transmembrane mitochondrial potential. We synthesized gallic acid derivatives linked to a ten-carbon aliphatic chain associated with triphenylphosphonium (TPP+C10), a lipophilic cationic molecule that induces the uncoupling of the electron transport chain (ETC). Other derivatives, such as gentisic acid (GA-TPP+C10), have the same effects on colorectal cancer cells. Although part of our group had previously reported preparing these structures by a convergent synthesis route, including their application via flow chemistry, there was no precedent for a new methodology for preparing these compounds. In this scenario, this study aims to develop a new linear synthesis strategy involving an essential step of Steglich esterification under mild conditions (open flask) and a high degree of reproducibility. Moreover, the study seeks to associate GA-TPP+C10 with 5FU to evaluate synergistic antineoplastic effects. In addition, we assess the antimigratory effect of GA-TPP+C10 and TPP+C10 using human and mouse metastatic CRC cell lines. The results show a new and efficient synthesis route of these compounds, having synergistic effects in combination with 5FU, increasing apoptosis and enhancing cytotoxic properties. Additionally, the results show a robust antimigratory effect of GATPP+C10 and TPP+C10, reducing the activation pathways linked to tumor progression and reducing the expression of VEGF and MMP-2 and MMP-9, common biomarkers of advanced CRC. Moreover, TPP+C10 and GA-TPP+C10 increase the activity of metabolic signaling pathways through AMPK activation. The data allow us to conclude that these compounds can be used for in vivo evaluations and are a promising alternative associated with conventional therapies for advanced colorectal cancer. Additionally, the reported intermediates of the new synthesis route could give rise to analog compounds with improved therapeutic activity.

Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo ( P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo ( P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy.

Introduction:Chronic Chagasic cardiomyopathy (CCC), caused by the protozoan Trypanosoma cruzi, is the most severe manifestation of Chagas disease.CCC is characterized by cardiac inflammation and fibrosis caused by a persistent inflammatory response. Following infection, macrophages secrete inflammatory mediators such as IL-1β, IL-6, and TNF-α to control parasitemia. Although this response contains parasite infection, it causes damage to the heart tissue. Thus, the use of immunomodulators is a rational alternative to CCC. Rho-associated kinase (ROCK) 1 and 2 are RhoA-activated serine/threonine kinases that regulate the actomyosin cytoskeleton. Both ROCKs have been implicated in the polarization of macrophages towards an M1 (pro-inflammatory) phenotype. Statins are FDA-approved lipid-lowering drugs that reduce RhoA signaling by inhibiting geranylgeranyl pyrophosphate (GGPP) synthesis. This work aims to identify the effect of statins on U937 macrophage polarization and cardiac tissue inflammation and its relationship with ROCK activity during T. cruzi infection.Methods:PMA-induced, wild-type, GFP-, CA-ROCK1- and CA-ROCK2-expressing U937 macrophages were incubated with atorvastatin, or the inhibitors Y-27632, JSH-23, TAK-242, or C3 exoenzyme incubated with or without T. cruzi trypomastigotes for 30 min to evaluate the activity of ROCK and the M1 and M2 cytokine expression and secretion profiling. Also, ROCK activity was determined in T. cruzi-infected, BALB/c mice hearts.Results:In this study, we demonstrate for the first time in macrophages that incubation with T. cruzi leads to ROCK activation via the TLR4 pathway, which triggers NF-κB activation. Inhibition of ROCKs by Y-27632 prevents NF-κB activation and the expression and secretion of M1 markers, as does treatment with atorvastatin. Furthermore, we show that the effect of atorvastatin on the NF-kB pathway and cytokine secretion is mediated by ROCK. Finally, statin treatment decreased ROCK activation and expression, and the pro-inflammatory cytokine production, promoting anti-inflammatory cytokine expression in chronic chagasic mice hearts.Conclusion:These results suggest that the statin modulation of the inflammatory response due to ROCK inhibition is a potential pharmacological strategy to prevent cardiac inflammation in CCC.

Aims: To evaluate the antifungal and antibiofilm activity of gallic acid derivatives TPP+-C10 and TPP+-C12 and their effects on mitochondrial function on two Candida albicans reference strains (ATCC 90029 and ATCC 10231).Methods and results: First, we determined minimal inhibitory concentration (MIC) using a microdilution assay. Both compounds exerted antifungal effects, and their MICs ranged from 3.9 to 13 mu M, with no statistically significant differences between them (P > 0.05, t-test). These concentrations served as references for following assays. Subsequently, we measured oxygen consumption with a Clark electrode. Our observations revealed that both drugs inhibited oxygen consumption in both strains with TPP+-C12 exerting a more pronounced inhibitory effect. We then employed flow cytometry with TMRE as a probe to assess mitochondrial membrane potential. For each strain assayed, the compounds induced a decay in transmembrane potential by 75%-90% compared to the control condition (P < 0.05, ANOVA). Then, we measured ATP levels using a commercial kit. TPP+-C12 showed a 50% decrease of ATP content (P < 0.05 ANOVA), while TPP+-C10 exhibited a less pronounced effect. Finally, we assessed the antibiofilm effect using the MTT reduction assay. Both compounds were effective, but TPP+-C12 displayed a greater potency, requiring a lower concentration to inhibit 50% of biofilms viability (P < 0.05, t-test).Conclusions: Derivatives of gallic acid linked to a TPP+ group exert antifungal and antibiofilm activity through impairment of mitochondrial function in C. albicans.

Novel demands from Earth Observation community have emerged in last years. They are mainly oriented on monitoring geo-information and human activity impact. These applications require satellite systems capable to provide high frequency and sub-metric spatial resolution observations. An hybrid architecture which combines in-space with in-situ measurements emerges as a potential approach. In this scenario, ground sensor devices autonomously perform in-situ measurements that are later on combined with satellite ones. This work extends the research on architecture by presenting two proof-of-concept of potential applications: (1) irrigation monitoring, and (2) livestock tracking. This work focuses on the deployment of IoT devices (developed in previous research activities) to extract data for these applications. The results are discussed, and they demonstrate the viability to monitor the trend of crop metrics, as well as the position of a cow herd over time. These results encourage to keep developing these demonstrations for further applications.

Cardiac cells respond to various pathophysiological stimuli, synthesizing inflammatory molecules that allow tissue repair and proper functioning of the heart; however, perpetuation of the inflammatory response can lead to cardiac fibrosis and heart dysfunction. High concentration of glucose (HG) induces an inflammatory and fibrotic response in the heart. Cardiac fibroblasts (CFs) are resident cells of the heart that respond to deleterious stimuli, increasing the synthesis and secretion of both fibrotic and proinflammatory molecules. The molecular mechanisms that regulate inflammation in CFs are unknown, thus, it is important to find new targets that allow improving treatments for HG-induced cardiac dysfunction. NFκB is the master regulator of inflammation, while FoxO1 is a new participant in the inflammatory response, including inflammation induced by HG; however, its role in the inflammatory response of CFs is unknown. The inflammation resolution is essential for an effective tissue repair and recovery of the organ function. Lipoxin A4 (LXA4) is an anti-inflammatory agent with cytoprotective effects, while its cardioprotective effects have not been fully studied. Thus, in this study, we analyze the role of p65/NFκB, and FoxO1 in CFs inflammation induced by HG, evaluating the anti-inflammatory properties of LXA4. Our results demonstrated that HG induces the inflammatory response in CFs, using an in vitro and ex vivo model, while FoxO1 inhibition and silencing prevented HG effects. Additionally, LXA4 inhibited the activation of FoxO1 and p65/NFκB, and inflammation of CFs induced by HG. Therefore, our results suggest that FoxO1 and LXA4 could be novel drug targets for the treatment of HG-induced inflammatory and fibrotic disorders in the heart.

Cardiac fibroblasts (CFs) activation is a common response to most pathological conditions affecting the heart, characterized by increased cellular secretory capacity and increased expression of fibrotic markers, such as collagen I and smooth muscle actin type alpha (α-SMA). Fibrotic activation of CFs induces the increase in tissue protein content, with the consequent tissue stiffness, diastolic dysfunction, and heart failure. Therefore, the search for new mechanisms of CFs activation is important to find novel treatments for cardiac diseases characterized by fibrosis. In this regard, TGF-β1, a cytokine with proinflammatory and fibrotic properties, is crucial in the CFs activation and the development of fibrotic diseases, whereas its molecular targets are not completely known. Serum and glucocorticoid-regulated kinase (SGK1) is a protein involved in various pathophysiological phenomena, especially cardiac and renal diseases that curse with fibrosis. Additionally, SGK1 phosphorylates and regulates the activity and expression of several targets, highlighting FoxO3a for its role in the regulation of oxidative stress and CFs activation induced by TGF-β1. However, the regulation of SGK1 by TGF-β1 and its role in CFs activation have not been studied. In this work, we evaluate the role of SGK1 in CFs isolated from neonatal Sprague-Dawley rats. The participation of SGK1 in the fibrotic activation of CFs induced by TGF-β1 was analyzed, using an inhibitor or siRNA of SGK1. In addition, the role of SGK1 on the regulation of FoxO3a and oxidative stress induced by TGF-β1 was analyzed. Our results indicate that TGF-β1 increased both the activity and expression of SGK1 in CFs, requiring the activation of MAPKs, ERK1/2, p38 and JNK, while inhibition and silencing of SGK1 prevented TGF-β1-induced fibrotic activation of CFs. In addition, SGK1 inhibition prevented FoxO3a inactivation and expression reduction, catalase and SOD2 expression decrease, and the increase of oxidative stress induced by TGF-β1. Taken together, our results position SGK1 as an important regulator of CFs activation driven by TGF-β1, at least in part, through the regulation of FoxO3a and oxidative stress.

Novel demands from Earth Observation community have emerged due to current climate situation. These needs are mainly oriented on monitoring hydric stress, climate disasters, among others. These applications require satellite systems capable to provide high frequency and sub-metric spatial resolution observations. An hybrid architecture which combines in-space with in-situ measurements emerges as a potential approach. In this scenario, ground sensor devices autonomously perform in-situ measurements with different spatial and temporal resolutions different from satellite ones. These devices must manage their constrained resources and transfer the generated data. The Direct-to-Satellite Internet of Things paradigm proposes the interconnection of Low Earth Orbit satellites with these devices using standardized protocols. This work presents a proof-of-concept that demonstrates the benefits for Earth Observation applications. Specifically, a sensor system is developed to monitor the soil moisture, and installed in a remote location to perform a measurement campaign. The results demonstrate the feasibility of this hybrid architecture.

Cancer is a complex pathology of great heterogeneity and difficulty that makes the constant search for new therapies necessary. A major advance on the subject has been made by focusing on the development of new drugs aimed to alter the metabolism of cancer cells, by generating a disruption of mitochondrial function. For this purpose, several new compounds with specific mitochondrial action have been tested, leading successfully to cell death. Recently, attention has centered on a group of natural compounds present in plants named polyphenols, among which is caffeic acid, a polyphenol that has proven to be a powerful antitumoral agent and a prominent compound for studies focused on the development of new therapies against cancer.In this review, we revised the antitumoral capacity and mechanisms of action of caffeic acid and its derivatives, with special emphasis in a new class of caffeic acid derivatives that target mitochondria by chemical binding to the lipophilic cation triphenylphosphonium.

In the normal heart, cardiac fibroblasts (CFs) maintain extracellular matrix (ECM) homeostasis, whereas in pathological conditions, such as diabetes mellitus (DM), CFs converse into cardiac myofibroblasts (CMFs) and this CFs phenoconversion increase the synthesis and secretion of ECM proteins, promoting cardiac fibrosis and heart dysfunction. High glucose (HG) conditions increase TGF-β1 expression and FoxO1 activity, whereas FoxO1 is crucial to CFs phenoconversion induced by TGF-β1. In addition, FoxO1 increases CTGF expression, whereas CTGF plays an active role in the fibrotic process induced by hyperglycemia. However, the role of FoxO1 and CTGF in CFs phenoconversion induced by HG is not clear. In this study, we investigated the effects of FoxO1 pharmacological inhibition on CFs phenoconversion in both in vitro and ex vivo models of DM. Our results demonstrate that HG induces CFs phenoconversion and FoxO1 activation. Moreover, AS1842856, a pharmacological inhibitor of FoxO1 activity, prevents CFs phenoconversion and CTGF expression increase induced by HG, whereas these results were corroborated by FoxO1 silencing. Additionally, K252a, a pharmacological blocker of CTGF receptor, prevents HG-induced CFs phenoconversion, which was corroborated with CTGF expression knockdown. Furthermore, through CFs isolation from heart of diabetic rats, we showed that hyperglycemia induces FoxO1 activation, the increase of CTGF expression and CFs phenoconversion, whereas the FoxO1 activity inhibition reverses the effects induced by hyperglycemia on CFs. Altogether, our results demonstrate that FoxO1 and CTGF are necessary for CFs phenoconversion induced by HG and suggest that both proteins are likely to become a potential targeted drug for fibrotic response induced by hyperglycemic conditions.

Cisplatin is a first-line chemotherapeutic drug commonly used to treat patients with head and neck cancer; nevertheless, cisplatin resistance poses a main challenge for its clinical efficacy. Recent studies have shown that kaempferol, a natural flavonoid found in various plants and foods, has an anticancer effect. The following study evaluated the cytotoxic effects of kaempferol on head and neck tumor cells and their mechanism of action, evaluating the effects on proliferation, the oxygen consumption rate, transmembrane potential, tumor cell migration and induction of apoptosis. Moreover, we determined the effects of a combination of kaempferol and cisplatin on head and neck tumor cells. We found that kaempferol inhibited the oxygen consumption rate and decreased the intracellular ATP content in tumor cells. This novel mechanism may inhibit the migratory capacity and promote antiproliferative effects and apoptosis of tumor cells. Additionally, our in vitro data indicated that kaempferol may sensitize head and neck tumor cells to the effects of cisplatin. These effects provide new evidence for the use of a combination of kaempferol and cisplatin in vivo and their future applications in head and neck cancer therapy.