Altered dynamics of calcium fluxes and mitochondrial metabolism in platelet activation-related disease and aging.

Understanding the mechanisms controlling platelet function is crucial for exploring potential therapeutic targets related to atherothrombotic pathologies and primary hemostasis disorders. Our research, which focuses on the role of platelet mitochondria and Ca2+ fluxes in platelet activation, the formation of the procoagulant phenotype, and thrombosis, has significant implications for the development of new therapeutic strategies. Traditionally, Ca2+-dependent cellular signaling has been recognized as a determinant process throughout the platelet activation, controlled primarily by store-operated Ca2+ entry and the PLC-PKC signaling pathway. However, despite the accumulated knowledge of these regulatory mechanisms, the effectiveness of therapy based on various commonly used antiplatelet drugs (such as acetylsalicylic acid and clopidogrel, among others) has faced challenges due to bleeding risks and reduced efficacy associated with the phenomenon of high platelet reactivity. Recent evidence suggests that platelet mitochondria could play a fundamental role in these aspects through Ca2+-dependent mechanisms linked to apoptosis and forming a procoagulant phenotype. In this context, the present review describes the latest advances regarding the role of platelet mitochondria and Ca2+ fluxes in platelet activation, the formation of the procoagulant phenotype, and thrombosis.

Phenolic profile, cheminformatics, and antiplatelet aggregation activity of orange and purple sweet potato (Ipomoea batatas L.) storage roots.

Sweet potatoes are rich in cardioprotective phytochemicals with potential anti-platelet aggregation activity, although this benefit may vary among cultivars/genotypes. The phenolic profile [HPLC-ESI(-)-qTOF-MS2], cheminformatics (ADMET properties, affinity toward platelet proteins) and anti-PA activity of phenolic-rich hydroalcoholic extracts obtained from orange (OSP) and purple (PSP) sweet potato storage roots, was evaluated. The phenolic richness [Hydroxycinnamic acids> flavonoids> benzoic acids] was PSP > OSP. Their main chlorogenic acids could interact with platelet proteins (integrins/adhesins, kinases/metalloenzymes) but their bioavailability could be poor. Just OSP exhibited a dose-dependent anti-platelet aggregation activity [inductor (IC50, mg.ml-1): thrombin receptor activator peptide-6 (0.55) > Adenosine-5'-diphosphate (1.02) > collagen (1.56)] and reduced P-selectin expression (0.75-1.0 mg.ml-1) but not glycoprotein IIb/IIIa secretion. The explored anti-PA activity of OSP/PSP seems to be inversely related to their phenolic richness. The poor first-pass bioavailability of its chlorogenic acids (documented in silico) may represent a further obstacle for their anti-PA in vivo.

Effect of frailty status on mortality risk among chilean community-dwelling older adults.

INTRODUCTION: The study of frailty and its effect on the risk of mortality in older people is of utmost importance, but understanding the critical factors is still limited. Our main objective was to analyze the association of frailty with all-cause mortality in a prospective community cohort of older people. METHODS: A five-year longitudinal follow-up study was conducted with 1,174 community-dwelling older adults (men and women≥65 years old) from different Family Health Centers and community groups from Chile. We evaluated the functional risk, socioeconomic status, and anthropometric variables. The frailty status was evaluated by modified Fried criteria. RESULTS: The diagnosis of frailty was reached in 290 older adult participants, who had significantly increased 5-year all-cause mortality independently of age, sex, cognitive impairment, and socioeconomic status (adjusted HR 1.51, 1.06-2.15). CONCLUSION: Frailty is a predictor of increased mortality independently of age, sex, socio-economic and cognitive factors.

RhoA/rho kinase pathway activation in age-associated endothelial cell dysfunction and thrombosis.

The small GTPase RhoA and the downstream Rho kinase (ROCK) regulate several cell functions and pathological processes in the vascular system that contribute to the age-dependent risk of cardiovascular disease, including endothelial dysfunction, excessive permeability, inflammation, impaired angiogenesis, abnormal vasoconstriction, decreased nitric oxide production and apoptosis. Frailty is a loss of physiological reserve and adaptive capacity with advanced age and is accompanied by a pro-inflammatory and pro-oxidative state that promotes vascular dysfunction and thrombosis. This review summarises the role of the RhoA/Rho kinase signalling pathway in endothelial dysfunction, the acquisition of the pro-thrombotic state and vascular ageing. We also discuss the possible role of RhoA/Rho kinase signalling as a promising therapeutic target for the prevention and treatment of age-related cardiovascular disease.

Linking triphenylphosphonium cation to a bicyclic hydroquinone improves their antiplatelet effect via the regulation of mitochondrial function.

Platelets are the critical target for preventing and treating pathological thrombus formation. However, despite current antiplatelet therapy, cardiovascular mortality remains high, and cardiovascular events continue in prescribed patients. In this study, first results were obtained with ortho-carbonyl hydroquinones as antiplatelet agents; we found that linking triphenylphosphonium cation to a bicyclic ortho-carbonyl hydroquinone moiety by a short alkyl chain significantly improved their antiplatelet effect by affecting the mitochondrial functioning. The mechanism of action involves uncoupling OXPHOS, which leads to an increase in mitochondrial ROS production and a decrease in the mitochondrial membrane potential and OCR. This alteration disrupts the energy production by mitochondrial function necessary for the platelet activation process. These effects are responsive to the complete structure of the compounds and not to isolated parts of the compounds tested. The results obtained in this research can be used as the basis for developing new antiplatelet agents that target mitochondria.

Exercise-induced hypoalgesia in chronic neck pain: A narrative review.

Chronic neck pain (CNP) is a worldwide health problem with several risk factors. One of the most widely used treatments for managing this condition is therapeutic exercise, which could generate a response called exercise-induced hypoalgesia (EIH). There is no consensus on the best exercise modality to induce hypoalgesia. Therefore, this review aims to analyze and synthesize the state-of-the-art about the hypoalgesic effect of exercise in subjects with CNP. We included articles on EIH and CNP in patients older than 18 years, with pain for more than three months, where the EIH response was measured. Articles that studied CNP associated with comorbidities or measured the response to treatments other than exercise were excluded. The studies reviewed reported variable results. Exercise in healthy subjects has been shown to reduce indicators of pain sensitivity; however, in people with chronic pain, the response is variable. Some investigations reported adverse effects with increased pain intensity and decreased pain sensitivity, others found no clinical response, and some even reported EIH with decreased pain and increased sensitivity. EIH is an identifiable, stimulable, and helpful therapeutic response in people with pain. More research is still needed on subjects with CNP to clarify the protocols and therapeutic variables that facilitate the EIH phenomenon. In addition, it is necessary to deepen the knowledge of the intrinsic and extrinsic factors that influence EIH in people with CNP.

Enfermedad de Lhermitte-Duclos y síndrome de Cowden. Reporte de un caso / Lhermitte-Duclos Disease and Cowden Syndrome. A Case Report

Presentación del caso. Se trata de una paciente femenina de 45 años con antecedentes de hipertensión arterial y múltiples cirugías por cáncer, entre ellas, cáncer de tiroides, carcinoma de parótida, cáncer de mama y cáncer endometrial. De manera incidental se identificó una lesión en el hemisferio cerebeloso derecho en una tomografía de senos paranasales, que fue confirmada a través de una resonancia magnética cerebral. La lesión presentaba una apariencia estriada, característica de gangliocitoma displásico del cerebelo o enfermedad de Lhermitte-Duclos. Considerando los antecedentes de diversos tipos de cáncer y los criterios de diagnóstico propuestos por el Consorcio Internacional Cowden y la Red Nacional Integral del Cáncer, se estableció el diagnóstico de síndrome de Cowden que había pasado desapercibido hasta el momento. Intervención terapéutica. Posteriormente, la paciente fue hospitalizada debido al crecimiento de una masa metastásica en el hemicuello derecho con afectación del plexo braquial, adenopatías cervicales, infraclaviculares y axilares derechas. Evolución clínica. En la actualidad, se encuentra recibiendo tratamiento paliativo con el objetivo de controlar los síntomas y mejorar su calidad de vida, ya que expresó su negativa a someterse a una intervención quirúrgica de resección tumoral

Case presentation. The report is of a 45-year-old female patient with a history of high blood pressure and multiple surgeries for cancer, including thyroid cancer, parotid carcinoma, breast cancer, and endometrial cancer. Incidentally, a lesion in the right cerebellar hemisphere was identified in a tomography of the paranasal sinuses, which was later confirmed in a brain magnetic resonance. The lesion had a striated appearance, characteristic of dysplastic gangliocytoma of the cerebellum or Lhermitte-Duclos disease. Considering the history of various types of cancer and the diagnostic criteria proposed by the International Cowden Consortium and the National Comprehensive Cancer Network, the diagnosis of Cowden syndrome, which had gone unnoticed until now, was established. Treatment. Subsequently, the patient was hospitalized due to the growth of a metastatic mass in the right hemicollar with involvement of the brachial plexus, cervical, infraclavicular, and right axillary lymph nodes. Outcome. She is receiving palliative treatment to control the symptoms and improve her quality of life, since she expressed her refusal to undergo tumor resection surgery

Tumor pseudopapilar sólido de páncreas, una neoplasia inusual / Solid Pseudopapillary Tumor of the Pancreas, an Unusual Neoplasm

Presentación del caso. Se trata de una mujer de 26 años que presentó dolor en epigastrio e hipocondrio izquierdo, con aumento del perímetro abdominal y pérdida de 5 kg de peso corporal. En el examen físico se detectó una masa de gran tamaño en el epigastrio, con bordes regulares, ligeramente dolorosa al tacto y no móvil. Los estudios de imagen revelaron una neoplasia mixta en el cuerpo y cola pancreática. Intervención terapéutica. Se practicó una esplenopancreatectomía corpo-caudal, con extirpación completa del tumor. Evolución clínica. La paciente recibió cuidados especializados y vigilancia estrecha posquirúrgica en la unidad de cuidados intensivos, sin presentar complicaciones relevantes. Tras el alta hospitalaria, la paciente refirió un buen estado general en los controles de seguimiento, que incluyeron una tomografía realizada a los 12 meses, donde no se evidenciaron restos o recidivas tumorales

Case presentation. A 26-year-old woman who presented with pain in the epigastrium and left hypochondrium, with increased abdominal perimeter and loss of 5 kg of body weight. Physical examination revealed a large mass in the epigastrium, with regular borders, slightly painful to the touch and non-mobile. Imaging studies revealed a mixed neoplasm in the pancreatic body and tail. Treatment. A corpo-caudal splenopancreatectomy was performed, with complete removal of the tumor. Outcome. The patient received specialized care and close postoperative surveillance in the intensive care unit, with no relevant complications. After hospital discharge, the patient reported a good general condition in the follow-up controls, which included a computed tomography scan performed after 12 months, where no tumor remnants or recurrences were evidenced

Adipose tissue as a therapeutic target for vascular damage in Alzheimer's disease.

Adipose tissue has recently been recognized as an important endocrine organ that plays a crucial role in energy metabolism and in the immune response in many metabolic tissues. With this regard, emerging evidence indicates that an important crosstalk exists between the adipose tissue and the brain. However, the contribution of adipose tissue to the development of age-related diseases, including Alzheimer's disease, remains poorly defined. New studies suggest that the adipose tissue modulates brain function through a range of endogenous biologically active factors known as adipokines, which can cross the blood-brain barrier to reach the target areas in the brain or to regulate the function of the blood-brain barrier. In this review, we discuss the effects of several adipokines on the physiology of the blood-brain barrier, their contribution to the development of Alzheimer's disease and their therapeutic potential. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.

Role of Mitochondria in Inflammatory Bowel Diseases: A Systematic Review.

Mitochondria are key cellular organelles whose main function is maintaining cell bioenergetics by producing ATP through oxidative phosphorylation. However, mitochondria are involved in a much higher number of cellular processes. Mitochondria are the home of key metabolic pathways like the tricarboxylic acid cycle and ß-oxidation of fatty acids, as well as biosynthetic pathways of key products like nucleotides and amino acids, the control of the redox balance of the cell and detoxifying the cell from H2S and NH3. This plethora of critical functions within the cell is the reason mitochondrial function is involved in several complex disorders (apart from pure mitochondrial disorders), among them inflammatory bowel diseases (IBD). IBD are a group of chronic, inflammatory disorders of the gut, mainly composed of ulcerative colitis and Crohn's disease. In this review, we present the current knowledge regarding the impact of mitochondrial dysfunction in the context of IBD. The role of mitochondria in both intestinal mucosa and immune cell populations are discussed, as well as the role of mitochondrial function in mechanisms like mucosal repair, the microbiota- and brain-gut axes and the development of colitis-associated colorectal cancer.

Mitochondrial Stress Links Environmental Triggers with Pro-Inflammatory Signaling in Crohn's Disease.

Inflammatory Bowel Diseases (IBD) are a group of chronic, inflammatory disorders of the gut. The incidence and activity of IBD are determined by both genetic and environmental factors. Among these factors, polymorphisms in genes related to autophagy and the consumption of non-steroidal anti-inflammatory drugs (NSAIDs) have been consistently associated with IBD. We show that NSAIDs induce mitochondrial stress and mitophagy in intestinal epithelial cells. In an altered mitophagy context simulating that observed in IBD patients, NSAID-induced mitochondrial stress leads to the release of mitochondrial components, which act as Danger Associated Molecular Patterns with pro-inflammatory potential. Furthermore, colonic organoids from Crohn's disease patients and healthy donors show activation of the mitochondrial Unfolded Protein Response (UPRmt) upon treatment with ibuprofen. Finally, colon biopsies from Crohn's disease patients in remission or with low-to-moderate activity also show expression of genes involved in UPRmt, while patients with severe activity show no increase compared to healthy donors. Our results suggest the involvement of mitochondria in the mechanisms triggering inflammation in IBD after NSAID use. Moreover, our results highlight the clinical relevance of mitochondrial stress and activation of the UPRmt pathway in the pathophysiology of Crohn's disease.

MiR-221-3p/222-3p Cluster Expression in Human Adipose Tissue Is Related to Obesity and Type 2 Diabetes.

The progression of obesity and type 2 diabetes (T2D) is intricately linked with adipose tissue (AT) angiogenesis. Despite an established network of microRNAs (miRNAs) regulating AT function, the specific role of angiogenic miRNAs remains less understood. The miR-221/222 cluster has recently emerged as being associated with antiangiogenic activity. However, no studies have explored its role in human AT amidst the concurrent development of obesity and T2D. Therefore, this study aims to investigate the association between the miR-221-3p/222-3p cluster in human AT and its regulatory network with obesity and T2D. MiR-221-3p/222-3p and their target gene (TG) expression levels were quantified through qPCR in visceral (VAT) and subcutaneous (SAT) AT from patients (n = 33) categorized based on BMI as normoweight (NW) and obese (OB) and by glycemic status as normoglycemic (NG) and type 2 diabetic (T2D) subjects. In silico analyses of miR-221-3p/222-3p and their TGs were conducted to identify pertinent signaling pathways. The results of a multivariate analysis, considering the simultaneous expression of miR-221-3p and miR-222-3p as dependent variables, revealed statistically significant distinctions when accounting for variables such as tissue depot, obesity, sex, and T2D as independent factors. Furthermore, both miRNAs and their TGs exhibited differential expression patterns based on obesity severity, glycemic status, sex, and type of AT depot. Our in silico analysis indicated that miR-221-3p/222-3p cluster TGs predominantly participate in angiogenesis, WNT signaling, and apoptosis pathways. In conclusion, these findings underscore a promising avenue for future research, emphasizing the miR-221-3p/222-3p cluster and its associated regulatory networks as potential targets for addressing obesity and related metabolic disorders.

The Relationship between Depressive Symptoms, Quality of Life and miRNAs 8 Years after Bariatric Surgery.

(1) Background: There are conflicting results on whether weight loss after bariatric surgery (BS) might be associated with quality of life (QoL)/depressive symptomatology. We aim to determine whether BS outcomes are associated with QoL/depressive symptomatology in studied patients at the 8-year follow-up after BS, as well as their relationship with different serum proteins and miRNAs. (2) Methods: A total of 53 patients with class III obesity who underwent BS, and then classified into "good responders" and "non-responders" depending on the percentage of excess weight lost (%EWL) 8 years after BS (%EWL ≥ 50% and %EWL < 50%, respectively), were included. Basal serum miRNAs and different proteins were analysed, and patients completed tests to evaluate QoL/depressive symptomatology at 8 years after BS. (3) Results: The good responders group showed higher scores on SF-36 scales of physical functioning, role functioning-physical, role functioning-emotional, body pain and global general health compared with the non-responders. The expression of hsa-miR-101-3p, hsa-miR-15a-5p, hsa-miR-29c-3p, hsa-miR-144-3p and hsa-miR-19b-3p were lower in non-responders. Hsa-miR-19b-3p was the variable associated with the response to BS in a logistic regression model. (4) Conclusions: The mental health of patients after BS is limited by the success of the intervention. In addition, the expression of basal serum miRNAs related to depression/anxiety could predict the success of BS.

Regulation of mitochondrial function by hydroquinone derivatives as prevention of platelet activation.

Platelet activation plays an essential role in the pathogenesis of thrombotic events in different diseases (e.g., cancer, type 2 diabetes, Alzheimer's, and cardiovascular diseases, and even in patients diagnosed with coronavirus disease 2019). Therefore, antiplatelet therapy is essential to reduce thrombus formation. However, the utility of current antiplatelet drugs is limited. Therefore, identifying novel antiplatelet compounds is very important in developing new drugs. In this context, the involvement of mitochondrial function as an efficient energy source required for platelet activation is currently accepted; however, its contribution as an antiplatelet target still has little been exploited. Regarding this, the intramolecular hydrogen bonding of hydroquinone derivatives has been described as a structural motif that allows the reach of small molecules at mitochondria, which can exert antiplatelet activity, among others. In this review, we describe the role of mitochondrial function in platelet activation and how hydroquinone derivatives exert antiplatelet activity through mitochondrial regulation.

Assessing mitochondria-targeted acyl hydroquinones on the mitochondrial platelet function and cytotoxic activity: Role of the linker length.

INTRODUCTION: The use of triphenylphosphonium cation (TPP+) linked to phenolic compounds by alkyl chains has a significant relevance as a mitochondrial delivery strategy in biomedicine because it affects mitochondrial bioenergetics in models of noncommunicable diseases such as cancer and cardiovascular-related conditions. Studies indicate that a long alkyl chain (10-12 carbon) increases the mitochondrial accumulation of TPP+-linked drugs. In contrast, other studies show that these compounds are consistently toxic to micromolar concentrations (as observed in platelets). In the present study, we evaluated the in vitro effect of three series of triphenylphosphonium-linked acyl hydroquinones derivates on the metabolism and function of human platelets using 3-9 carbons for the alkyl linker. Those were assessed to determine the role of the length of the alkyl chain linker on platelet toxicity. METHODS: Human platelets were exposed in vitro to different concentrations (2-40 µM) of every compound; cellular viability, phosphatidylserine exposition, mitochondrial membrane potential (ΔΨm), intracellular calcium release, and intracellular ROS generation were assessed by flow cytometry. An in silico energetic profile was generated with Umbrella sampling molecular dynamics (MD). RESULTS AND CONCLUSIONS: There was an increase in cytotoxic activity directly related to the length of the acyl chain and lipophilicity, as seen by three techniques, and this was consistent with a decrease in ΔΨm. The in silico energetic profiles point out that the permeability of the mitochondrial membrane may be involved in the cytotoxicity of phosphonium salts. This information may be relevant for the design of new TPP+ -based drugs with a safe cardiovascular profile.

Dolor torácico agudo en pacientes jóvenes: reporte de dos casos / Acute chest pain in young patients: report of two cases

Se presentan dos casos clínicos de pacientes jóvenes con dolor torácico agudo, en ellos, el enfoque multidisciplinario y la resonancia magnética cardíaca jugaron un papel crucial en el diagnóstico y tratamiento. Presentación del caso 1. Un paciente de 20 años con dolor precordial y palpitaciones que mostró elevación de los niveles de enzimas cardíacas en los exámenes de laboratorio. La angiografía coronaria no reveló estenosis significativas. Sin embargo, se confirmó el diagnóstico de miocarditis a través de la resonancia magnética cardíaca, lo que llevó al inicio del tratamiento con medicamentos para lograr una función cardíaca adecuada y la prevención del progreso de la enfermedad. Su evolución clínica fue favorable. Presentación del caso 2. Un paciente de 19 años que presentó un dolor torácico intenso que se irradiaba al brazo izquierdo y mandíbula. Los exámenes de laboratorio reportaron elevación de los niveles de troponinas, que generaron la sospecha de un síndrome coronario agudo. La resonancia magnética cardíaca confirmó el diagnóstico de un infarto agudo de miocardio, y la angiografía coronaria reveló una estenosis significativa en la arteria descendente anterior y una ectasia subsiguiente. Durante la hospitalización, se brindó un enfoque terapéutico integral con la administración de medicamentos, monitoreo, control del dolor y prevención de complicaciones, y el paciente mostró una evolución clínica favorable

Two clinical cases of young patients with acute chest pain are presented, where the multidisciplinary approach and cardiac magnetic resonance played a crucial role in diagnosis and treatment. Case presentation 1. A 20 year old patient with precordial pain and palpitations showed elevated cardiac enzyme levels on laboratory examination. Coronary angiography revealed no significant stenosis. However, the diagnosis of myocarditis was confirmed by cardiac magnetic resonance imaging, which led to the initiation of drug treatment to achieve adequate cardiac function and prevention of disease progression. His clinical evolution was favorable. Case presentation 2. 19 year old patient presented with severe chest pain radiating to the left arm and jaw. Laboratory tests reported elevated troponin levels, which raised the suspicion of acute coronary syndrome. Cardiac magnetic resonance imaging confirmed the diagnosis of acute myocardial infarction, and coronary angiography revealed significant stenosis in the anterior descending artery and subsequent ectasia. During hospitalization, a comprehensive therapeutic approach with medication administration, monitoring, pain control, and prevention of complications was provided, and the patient showed a favorable clinical evolution

The Use of Triphenyl Phosphonium Cation Enhances the Mitochondrial Antiplatelet Effect of the Compound Magnolol.

Although platelets are anucleated cells, they have fully functional mitochondria, and currently, it is known that several processes that occur in the platelet require the action of mitochondria. There are plenty of mitochondrial-targeted compounds described in the literature related to cancer, however, only a small number of studies have approached their interaction with platelet mitochondria and/or their effects on platelet activity. Recent studies have shown that magnolia extract and mitochondria-targeted magnolol can inhibit mitochondrial respiration and cell proliferation in melanoma and oral cancer cells, respectively, and they can also induce ROS and mitophagy. In this study, the effect of triphenylphosphonium cation, linked by alkyl chains of different lengths, to the organic compound magnolol on human-washed platelets was evaluated. We demonstrated that the addition of triphenylphosphonium by a four-carbon linker to magnolol (MGN4) considerably enhanced the Magnolol antiplatelet effect by a 3-fold decrease in the IC50. Additionally, platelets exposed to MGN4 5 µM showed several differences from the control including increased basal respiration, collagen-induced respiration, ATP-independent respiration, and reduced ATP-dependent respiration and non-mitochondrial respiration.

Hypertension and hypercholesterolemia are predictive factors associated with type 2 diabetes persistence after metabolic surgery: A prospective study.

BACKGROUND: Metabolic surgery is the most effective therapeutic strategy for the management of type 2 diabetes (T2DM). Several preoperative clinical factors have been associated with T2DM remission after metabolic surgery. However, other potential predictors remain unexplored. AIM: To assess the role of basal (pre-surgery) clinical and biochemical parameters in T2DM remission after metabolic surgery. METHODS: A prospective study including 98 patients with T2DM undergoing metabolic surgery was performed. Clinical, anthropometric, and biochemical data were collected at baseline and 1 year following metabolic surgery. RESULTS: Patients without T2DM remission 1 year after metabolic surgery presented a longer duration of diabetes and higher glycated hemoglobin (HbA1c) levels; a higher percentage of these subjects were using insulin therapy, antihypertensive drugs, and lipid-lowering therapies before metabolic surgery, compared to those patients with T2DM remission. A lower percentage of T2DM remission after metabolic surgery was observed among patients with hypertension/hypercholesterolemia before surgery, compared to those patients without hypertension/hypercholesterolemia (51.7 % vs 86.8 %, p < 0.001, and 38.5 % vs 75 %, p < 0.001, respectively), and among patients with longer duration of diabetes (≥5 years vs <5 years; 44.4 % vs 83 %, respectively; p < 0.001). In the logistic regression model, diabetes duration, basal HbA1c, and the presence of hypertension and hypercholesterolemia before surgery were inversely related to T2DM remission following metabolic surgery, after adjusting for sex, age, waist circumference, and type of surgery. CONCLUSIONS: In a cohort of patients with obesity and T2DM, preoperative hypertension and hypercholesterolemia, together with a longer diabetes duration and higher HbA1c concentrations, were independent predictors of T2DM persistence after metabolic surgery.

Membrane Vesicles of Toxigenic Clostridioides difficile Affect the Metabolism of Liver HepG2 Cells.

Clostridioides difficile infection (CDI) appears to be associated with different liver diseases. C. difficile secretes membrane vesicles (MVs), which may be involved in the development of nonalcoholic fatty liver disease (NALFD) and drug-induced liver injury (DILI). In this study, we investigated the presence of C. difficile-derived MVs in patients with and without CDI, and analyzed their effects on pathways related to NAFLD and DILI in HepG2 cells. Fecal extracellular vesicles from CDI patients showed an increase of Clostridioides MVs. C. difficile-derived MVs that were internalized by HepG2 cells. Toxigenic C. difficile-derived MVs decreased mitochondrial membrane potential and increased intracellular ROS compared to non-toxigenic C. difficile-derived MVs. In addition, toxigenic C. difficile-derived MVs upregulated the expression of genes related to mitochondrial fission (FIS1 and DRP1), antioxidant status (GPX1), apoptosis (CASP3), glycolysis (HK2, PDK1, LDHA and PKM2) and ß-oxidation (CPT1A), as well as anti- and pro-inflammatory genes (IL-6 and IL-10). However, non-toxigenic C. difficile-derived MVs did not produce changes in the expression of these genes, except for CPT1A, which was also increased. In conclusion, the metabolic and mitochondrial changes produced by MVs obtained from toxigenic C. difficile present in CDI feces are common pathophysiological features observed in the NAFLD spectrum and DILI.