Respiratory Capacity Research Articles

Exploratory Ultrasound Analysis of the Diaphragm and Respiratory Capacity in Women with Primary Dysmenorrhea: A Cross-Sectional Observational Study

Primary dysmenorrhea (PD) is a common gynecological condition characterized by menstrual pain without underlying pelvic pathology. It has been linked to functional and structural changes in the core musculature, but limited evidence exists regarding its association with diaphragmatic and respiratory mechanics. This study aimed to elaborate on these potential associations by assessing the diaphragmatic structure and respiratory function in women with PD compared to healthy controls, utilizing ultrasound imaging, spirometry and respiratory pressure measurements. Methods: An observational, cross-sectional study was conducted with 44 female participants (22 with PD and 22 healthy controls). Diaphragmatic structure was evaluated through ultrasound, measuring the intercostal distance, diaphragmatic thickness, and diaphragmatic excursion at rest and during maximum voluntary contraction. Spirometric assessments included forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and the FVC/FEV1 ratio, along with measurements of maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP). Group differences were analyzed using Student’s t-test and effect sizes were reported with Cohen’s d. Results: No significant differences were observed between the groups in diaphragmatic thickness, diaphragmatic excursion, or global respiratory capacity (p > 0.05). However, women with PD presented a significant reduction in the left intercostal distance both at rest (p = 0.035, d = 0.56) and during contraction (p = 0.039, d = 0.54). No other significant group differences were detected. Conclusions: While primary dysmenorrhea does not appear to affect overall diaphragmatic function or respiratory capacity, it is associated with subtle localized changes in the left intercostal dynamics. These findings suggest a potential compensatory mechanical adaptation rather than global respiratory dysfunction. Further longitudinal studies with larger sample sizes are needed to explore the clinical significance of these findings.

CRIP1 inhibits cutaneous melanoma progression through TFAM-mediated mitochondrial biogenesis.

Metastasis is the leading cause of death in patients with cutaneous melanoma. CRIP1 (cysteine-rich protein 1) has been reported to be associated with malignant progression of several cancers. However, the biological function and underlying mechanisms of CRIP1 in melanoma progression are largely unknown. Bioinformatic prediction of CRIP1 expression in melanoma and its association with clinical parameters and prognosis of patients. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blots (WB) were used to detect stable overexpression and knockdown of CRIP1 in melanoma cells. The function of CRIP1 in cutaneous melanoma cells was determined by in vitro functional assays. WB, immunofluorescence, OCR detection, mitochondrial DNA assay, and cytosolic ATP assay were used to determine the relationship between CRIP1 and mitochondrial biogenesis, relationship between TFAM. The expression level of CRIP1 in melanoma tissues is lower than that in normal tissues and suggests a poor prognosis for melanoma patients. Functionally, CRIP1 inhibits the proliferation, migration, and invasion of melanoma cells in vitro. Mechanistic studies revealed that CRIP1 inhibited mitochondrial biogenesis in melanoma cells, which included suppression of relative mitochondrial content, mitochondrial DNA copy number, ATP production, respiratory capacity, and expression levels of oxidative phosphorylation-related proteins. Further studies revealed that CRIP1 inhibits mitochondrial biogenesis and malignant progression in melanoma cells by suppressing the protein levels of TFAM. Our results suggest that CRIP1 inhibits the proliferation and invasive ability of cutaneous melanoma cells by suppressing TFAM-mediated mitochondrial biogenesis. Therefore, CRIP1 may be a potential therapeutic target for melanoma.

Novel insight into TRPV1-induced mitochondrial dysfunction in neuropathic pain.

Neuropathic pain remains one of the leading causes of global disability. The mechanism of neuropathic pain development and maintenance involves mitochondrial dysfunction induced-neuronal apoptosis of peripheral and central nociceptive pathways. The TRPV1 is a non-selective cation channel, which has a high Ca2+ permeability, playing an essential role in neuronal apoptosis in the spinal cord following peripheral nerve injury. However, the mechanism of how TRPV1 activation in the spinal cord induces mitochondrial dysfunction-mediate neuronal apoptosis, resulting in allodynia is unknown. Here, we found that activating the TRPV1 channel in the spinal cord using capsaicin, a TRPV1 agonist, results in mechanical and thermal hypersensitivity that were found to be mediated by neuroinflammation, elevated level of apoptosis, and a reduction in transcription of the mitochondrial complexes in the spinal cord and DRG. Moreover, during the early activation of the TRPV1 (1h, 24h, 48h following the capsaicin injection in the spinal cord) we observed a robust reduction in mitochondrial oxygen consumption in the non-phosphorylated state, ATP-linked respiration, maximal respiration, and electron transfer capacity (ETC). A more advanced experiment, wherein we controlled capsaicin, Ca2+ concentration and the exposure time in isolated spinal cord tissue (Lumbar, L1-L6), unveiled that TRPV1 activation impairing the mitochondrial function in terms of oxygen consumption, collapsing the Ψm and induction of the mitochondrial permeability transition pore (mPTP), which were reversed by the mPTP inhibitor-Cyclosporin A (CsA) during challenging the mitochondria with Ca2+ in a dose-dependent manner. More critically, injection of TRPV1 antagonist AMG9810 in the spinal cord following sciatic nerve crush reversed mechanical allodynia and modulated thermal hypersensitivity. In addition, the presence of TRPV1 antagonist-AMG9810 along with capsaicin and Ca2+ during challenging the spinal cord tissue completely prevents the early mPTP induction, the reduction in oxygen consumption and. In conclusion, our findings suggest that TRPV1 activation induces neuronal apoptosis, neuroinflammation, and mitochondrial dysfunction in the spinal cord, reflected in mechanical and thermal allodynia. Notable, the mitochondrial dysfunction following the TRPV1 activation in the spinal cord includes crucial elements that contribute to neuronal death, including mPTP induction, reduction in Ψm and oxygen consumption. Strikingly, regulating the TRPV1 following sciatic nerve injury reverses hypersensitivity probably via protection of the mitochondrial, suggesting a fundamental role for the TRPV1 pathway in mitochondrial dysfunction-mediated pain development.

306 Exercise training reverses skeletal muscle DRP1 hyperactivation and improves respiratory capacity in patients with type 2 diabetes

306 Exercise training reverses skeletal muscle DRP1 hyperactivation and improves respiratory capacity in patients with type 2 diabetes

Effectiveness of a harmonica-integrated, tele-supervised home-based pulmonary rehabilitation program on lung function and comprehensive health outcomes in patients with chronic obstructive pulmonary disease: a randomized controlled trial protocol

IntroductionHarmonica playing mimics pursed-lip breathing and strengthens respiratory muscles. Combined with music therapy, it may improve both pulmonary and mental health in chronic obstructive pulmonary disease (COPD) patients, though its effects are not well understood. This protocol outlines a randomized controlled trial (RCT) to evaluate the effectiveness of integrating harmonica playing into pulmonary rehabilitation (PR) programs.Methods and analysisThis single-center, two-arm RCT will be conducted at a tertiary hospital in Guangzhou, China. A total of 248 adult patients (with a clinical diagnosis of COPD but without severe comorbidities, significant cognitive impairments, and prior experience with the intervention components) will be randomized in a 1:1 ratio to either a harmonica-integrated PR group (intervention) or a standard PR group (control) for 6 months of home-based, tele-supervised training. The intervention will incorporate harmonica sessions in addition to standard PR exercises (breathing and physical exercises). Both groups will undergo in-hospital training sessions, supplemented by daily home practice under remote supervision by PR staff. The primary outcome is lung function (measured by FEV1%), while secondary outcomes include respiratory muscle strength, exercise capacity, fatigue, dyspnea, symptom burden, mental health, self-efficacy, quality of life, social support, adherence, and patient satisfaction. Statistical analyses will employ mixed-effects models with an intention-to-treat approach.ConclusionThis trial will evaluate the efficacy of a harmonica-integrated, home-based PR program with tele-supervision for COPD patients on lung function, respiratory muscle strength, exercise capacity, and overall health. If effective, it could offer a novel, affordable, and accessible home-based PR approach for COPD management.Trial registration numberClinicalTrials.gov: NCT05995847.

МОРФОЛОГИЧЕСКИЙ СТАТУС КРОВИ КРУПНОГО РОГАТОГО СКОТА ЧЕРНО-ПЕСТРОЙ ПОРОДЫ ПРИ ИСПОЛЬЗОВАНИИ ФИТОАДАПТОГЕНОВ

The purpose of research is to study the morphological composition of the blood of heifers, no – calf heifers and first-calf heifers of the black-and-white breed using phytoadaptogens from regional raw materi-als. As phytoadaptogens, an extract of cranberry meal containing 40 % ursolic acid, obtained at the Novo-sibirsk Institute of Organic Chemistry named after N.N. Vorozhtsov SB RAS, dry extract of Rhodiola rosea with up to 3 % glycosides-salidrosides. The object of research is heifers of black-and-white breed (n=30), after fruitful insemination – heifers, after giving birth – cows – first-calf heifers. For research, 3 groups of animals were formed: control (n=10), 1st experimental (n=10) and 2nd experimental (n=10). Ani-mals of all groups were kept separately in group cages, in accordance with the characteristics of feeding, according to a loose-box system. The control group of heifers was fed the main diet in the form of a hay-lage-concentrate feed mixture, the heifers of the 1st experimental group additionally received cranberry meal extract containing 40% ursolic acid at a dose of 250.0 mg per head for 20 days before insemination; 2nd experimental group of heifers - a two-component composition of the same amount of cranberry meal extract and 200.0 mg per head per day of dry extract of Rhodiola rosea; heifers were fed drugs for 10 days at 3 and 7 months of pregnancy; first-calf heifers - immediately after calving for 20 days. The use of phy-toadaptogens 20 days before the insemination of animals, during pregnancy and immediately after calving helps to increase the adaptive capacity of the body by increasing the respiratory capacity of the blood - the number of erythrocytes and hemoglobin, and stabilizing the body's reactivity. A more pronounced reaction of the body was noted when using a two-component composition of phytoadaptogens.

The Effect of Rehabilitation Therapy in Children with Intervened Congenital Heart Disease: A Study Protocol of Randomized Controlled Trial Comparing Hospital and Home-Based Rehabilitation

Background/Objectives: Children who suffer from congenital heart defects (CHDs) have a decreased ability to perform physical exercise and consequently have a decrease in their functional capacity. The main causes of this decrease in functional capacity have been related on the one hand to residual hemodynamic defects and, at the same time, to a situation of physical deconditioning due to inactivity, as well as problems in lung function, especially the presence of restrictive patterns that influence the amount of O2 insufflated (decreased maximum VO2), consequently generating a deficient maximum O2 consumption and maximum work rate. This represents an important prognostic value, since it constitutes an independent predictor of death and hospitalization. This study aims to determine the benefits obtained regarding respiratory function, exercise capacity, and quality of life after implementing a hospital-based cardio-respiratory rehabilitation program compared to a home-based Cardio-respiratory Physical Activity Program in patients with intervened CHDs. Methods: This is a randomized controlled trial on the effectiveness of two different rehabilitation programs on respiratory function, exercise capacity, and quality of life in patients with CHDs conducted at the Child Cardiology and Congenital Heart Disease Unit of the University Hospital Complex of A Coruña (CHUAC). There will be two groups: Cardio-respiratory rehabilitation group program conducted in a face-to-face format at the hospital (n = 26) and a study group that follows a home-based Cardio-respiratory Physical Activity Program (TELEA) (n = 26). The measurement variables will be respiratory function, forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), maximum expiratory flow (PEF), the Tiffeneau index (FEV1 /FVC), forced expiratory flow (FEF25%, FEF50%, FEF75%, FEF25–75%), exercise capacity (peak VO2), and the quality of life of these children and their families. Conclusions: The implementation of cardiac and pulmonary rehabilitation programs in children with CHDs is essential to improve their quality of life, exercise tolerance, and socialization. These programs optimize life expectancy and promote integration, being crucial for their physical and emotional well-being

Lithium compromises the bioenergetic reserve of cardiomyoblasts mitochondria.

Lithium is used in the long-term treatment of bipolar disorder, exhibiting a beneficial effect on the neuronal cells. The concentration of lithium in the blood serum can vary and can easily approach a level that is related to cardiotoxic adverse effects. This is due to its narrow therapeutic index. In this study, we investigated the effect of higher than therapeutic dose of lithium. Rat cardiomyoblast cells were treated with 2 mM LiCl for 48h, after which the mitochondrial parameters of the cells were analyzed. Lithium exposure reduced maximal respiratory capacity by diminishing reserve respiratory capacity (RRC), linked to a decrease in complex I (NADH dehydrogenase) activity and elevated superoxide radical levels. In addition, lithium treatment altered the composition of cellular membranes, including mitochondrial cardiolipin, a lipid essential for mitochondrial function. These findings suggest that impaired complex I activity, oxidative stress, and cardiolipin depletion collectively impair the ability of cells to meet high energy demands.

Case report: The Montgomery T tube may be the preferred transition option for achieving a smooth extubation after tracheotomy when complicating airway pathology is present

Prolonged retention of tracheostomy tubes post-procedure often leads to complications, including granulation tissue overgrowth, airway narrowing, and laryngeal edema, necessitating delayed removal of the tracheostomy tube. Currently, a definitive therapeutic regimen capable of simultaneously resolving these complications and expediting tracheostomy decannulation remains elusive. Herein, we present an efficacious strategy addressing these airway morbidities and facilitating rapid tube removal. A 44-year-old male patient, who had undergone tracheostomy due to underlying disease, demonstrated substantial recovery following rehabilitation and was poised for tracheostomy tube extraction. However, bronchoscopic examination revealed severe granulation tissue at the stoma site and laryngeal edema, posing challenges to immediate decannulation. To tackle these issues concurrently while aiming for swift tube removal, we performed bronchoscopic intervention for granulation tissue excision, subsequently replacing the conventional tracheostomy tube with a Montgomery T tube as a transitional measure to restore normal ventilation. With additional rehabilitation fostering respiratory function enhancement, follow-up bronchoscopies confirmed no recurrence of granulations and significant reduction in laryngeal edema, thereby enabling the successful removal of the Montgomery T tube 2 months later, restoring the patient’s unassisted respiratory capacity. This case underscores a clinically pertinent insight: following resolution of local airway abnormalities impeding tracheostomy decannulation, the strategic implementation of a Montgomery T tube as a transitional phase merits serious consideration among clinicians managing patients with long-term tracheostomies. Our findings contribute to the development of more streamlined approaches to overcoming complexities associated with tracheostomy tube removal in clinical practice.

Semaglutide administration protects cardiomyocytes in db/db mice via energetic improvement and mitochondrial quality control.

Diabetic cardiomyopathycauses end-stage heart failure, resulting in high morbidity and mortality in type 2 diabetes mellitus (T2DM) patients. Long-term treatment targeting metabolism is an emerging field in the treatment of diabetic cardiomyopathy. Semaglutide, an agonist of the glucagon-like peptide 1receptor, is clinically approved for the treatment of T2DM and provides cardiac benefits in patients. However, the cardioprotective mechanism of semaglutide, especially its direct effects on cardiomyocytes (CMs), is not fully understood. Here, we used 8-week diabetic and obese db/db mice treated with semaglutide (200 μg·kg·d-1, i.p.) to study its direct effect on CMs and the underlying mechanisms. Our results revealed that the consecutive application of semaglutide improved cardiac function. Increased AMPK and ULK1 phosphorylation levels were detected, accompanied by elevated [Ca2+]mito. Seahorse analysis revealed that semaglutide increases ATP production via elevated basal and maximum respiration rates as well as spare respiration capacity in CMs. Transmission electron microscopy revealed improved mitochondrial morphology in the cardiomyocytes of db/db mice. On the other hand, Western blot analysis revealed increased Parkin and LC3 protein expression, indicating mitophagy in CMs. Collectively, our findings demonstrate that semaglutide directly protects CMs from high-glucose damage by promoting AMPK-dependent ATP production as well as ULK1-mediated mitophagy in db/db mice.

Efficacy of Inhaled Treprostinil in a Patient with Systemic Sclerosis-Associated Pulmonary Hypertension and Interstitial Lung Diseases Refractory to Conventional Intravenous Epoprostenol

Background: Systemic sclerosis-associated pulmonary hypertension (SSc-PH) is widely recognized as the most severe subtype of connective tissue disease-associated pulmonary hypertension (CTD-PH), particularly in patients with complicating factors such as interstitial lung disease (ILD) and biventricular failure. This condition is associated with the poorest clinical outcomes among PH subtypes, presenting significant challenges in both management and prognosis. Despite the use of conventional therapies, including intravenous administration of epoprostenol, a promising prostacyclin analogue, treatment outcomes for SSc-PH remain suboptimal. While epoprostenol has demonstrated efficacy in reducing pulmonary arterial pressures, its clinical application is often constrained by the risk of ventilation–perfusion (V-Q) mismatch, particularly at higher doses. Case presentation: We report the case of a 73-year-old woman with SSc-PH complicated by ILD, who experienced progressive hemodynamic deterioration despite receiving optimized therapy with intravenous epoprostenol. Efforts to escalate the dose of epoprostenol were limited by the development of severe V-Q mismatch, precluding further dose increases. In light of these challenges, inhaled treprostinil was introduced as an adjunctive therapy. There were significant improvements in her pulmonary hypertension and hemodynamic parameters, ultimately allowing the discontinuation of intravenous dobutamine and stabilization of her hemodynamics, as well as her respiratory function, exercise capacity, and quality of life. Conclusions: This case highlights the potential clinical utility of combining inhaled treprostinil with intravenous epoprostenol for the treatment of SSc-PH in patients with concurrent ILD. By addressing the limitations associated with high-dose intravenous prostacyclin therapy, this combination approach may represent a promising therapeutic strategy for improving outcomes in this difficult-to-treat patient population. Further investigation is warranted to establish the efficacy and feasibility of this combination therapy in larger cohorts of patients with SSc-PH and associated ILD.

Calcitriol Treated Mesenchymal Stem Cells Modulated Immune Response in Collagen-Induced Rheumatoid Arthritis in BALB/c Mice.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily involves synovial joints. During the past decade, disease-modifying antirheumatic drugs and biologic agents have been introduced for the treatment of RA. However, they have limitations, including incomplete treatment response, adverse effects requiring drug withdrawal, fall off in efficacy over time, high cost of biologic agents, and refractory cases. Consequently, there is a need to establish safe and effective advanced therapeutic modalities for RA to overcome the shortcomings of current treatments. MSCs after isolation were exposed to 200 nM calcitriol. Rheumatoid arthritis was induced in BALB/c mice using collagen and Freund's complete adjuvant. One week after immunization, the mice were divided into 3 groups including without treatment, groups treated with untreated and treated MSCs. One week after the last injection, mice sacrificed and samples were taken and the desired evaluations were done. Our results revealed that the respiratory burst capacity, neutrophil phagocytosis, and nitric oxide production in the population of splenocytes were higher in the positive control group compared to the treatment groups. Also, the level of production of IL-4, IL-10 and TGF-β cytokines and INF-γ and IL-17 cytokines showed a significant increase and decrease, respectively, compared to the positive control group. Treatment of MSCs with calcitriol leads to an improvement in regulatory function and inhibitory effects on inflammatory mediators of innate immune cells, particularly splenocytes, in a rheumatoid arthritis model compared to untreated mesenchymal stem cells.

Metabolomic Analysis of the Effects of Canagliflozin on HFpEF Rats and Its Underlying Mechanism.

Heart failure with preserved ejection fraction (HFpEF) represents a challenging cardiovascular condition characterized by normal systolic function but impaired diastolic performance. Despite its increasing prevalence, therapeutic options remain limited. This study investigated the metabolic effects of canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on cardiac function and energy metabolism in HFpEF. We established a rat model of HFpEF using Dahl salt-sensitive rats and evaluated three experimental groups: control (A), HFpEF (B), and canagliflozin-treated HFpEF (C). This study carried out comprehensive analyses of cardiac structure and function, metabolomic profiling, and detailed assessment of myocardial energy metabolism, including mitochondrial respiratory capacity and ATP synthesis. Additionally, we validated our findings using H9C2 cardiomyocytes under controlled conditions. Canagliflozin treatment significantly improved cardiac remodeling markers, including reduced myocardial volume and fibrosis area, while enhancing diastolic function (E/A ratio). Metabolomic analysis revealed normalization of hypermetabolic states, with significant reductions in key metabolites, including L-lysine, D-glucose, and uridine. The treatment restored balance in multiple metabolic pathways, particularly affecting β-alanine metabolism, pyrimidine metabolism, and the citrate cycle. Notably, canagliflozin enhanced mitochondrial respiratory function, increased ATP synthesis, and optimized fatty acid utilization, as evidenced by reduced free fatty acid content. Our findings demonstrated that canagliflozin exerts cardioprotective effects through multiple metabolic pathways, suggesting its potential as a therapeutic option for HFpEF. The ability of the drug to optimize energy metabolism and improve mitochondrial function represents a novel mechanism for treating this challenging condition.

Karnozin EXTRA® causes changes in mitochondrial bioenergetics response in MCF-7 and MRC-5 cell lines.

Numerous studies reported about potential effects of L-carnosine in regulation of tumor growth and metabolism. We evaluated the effects of different concentrations of L-carnosine from Karnozin EXTRA® supplement on mitochondrial respiratory chain complexes of human embryo lung fibroblasts (MRC-5) and human breast cancer cells (MCF-7), with different energy pathways. Also, we analyzed the proliferation index and expression of various markers of oxidative stress. Treatment with Karnozin EXTRA® (concentration of L-carnosine were 2, 5 and 10mM) for 24hours gradually decreased the number of cells and changed their morphological features. In both cell lines, a dose-dependent reduction of cell viability was recorded compared to the control group. Also, experimental groups showed a concentration-dependent decrease in fluorescence intensity of SOD2 expressions in MCF-7, while in MRC-5 we noticed higher fluorescence intensity in Carnosine 2mM group. Treated cells, in both cell lines, showed different intensity of iNOS cytoplasmic immunopositivity in a concentration-dependent manner. In all experimental groups, we noticed an increased expression of marker of oxidative stress-cytochrome P450 2E1 (CYP2E1). The effects of Karnozin EXTRA® capsule on mitochondrial respiration, assessed with the Clark-type electrode, were manifested as a reduction of: basal cell respiration, maximum capacity of electron transport chain and mitochondrial ATP-linked respiration. Also, significant decrease in the activity of complex I (NADH-ubiquinone oxidoreductase), complex II (succinate dehydrogenase) and complex IV (cytochrome c oxidase) was observed in both cell lines. Bearing in mind that Karnozin EXTRA® is a potential regulator of energy metabolism of MCF-7 and MRC-5, these results provide a good basis for further preclinical and clinical research.

Prognosis of bronchopulmonary dysplasia

Children with bronchopulmonary dysplasia (BPD) often exhibit severe respiratory problems and significant pulmonary dysfunction during school age and adulthood. Exercise tests show a decline in cardiopulmonary function and physical performance in children with BPD, who also have a higher incidence of pulmonary hypertension. These children generally perform poorly in terms of intelligence, language, and motor development. As they age, the risk of neurodevelopmental disorders increases, and health-related quality of life is also affected. This article reviews the prognosis of the respiratory system, physical capacity, cardiovascular system, nervous system, and health-related quality of life in children with BPD, aiming to improve the management of these patients and enhance their subsequent quality of life.

Long-term mitochondrial and metabolic impairment in lymphocytes of subjects who recovered after severe COVID-19

The underlying mechanisms explaining the differential course of SARS-CoV-2 infection and the potential clinical consequences after COVID-19 resolution have not been fully elucidated. As a dysregulated mitochondrial activity could impair the immune response, we explored long-lasting changes in mitochondrial functionality, circulating cytokine levels, and metabolomic profiles of infected individuals after symptoms resolution, to evaluate whether a complete recovery could be achieved. Results of this pilot study evidenced that different parameters of aerobic respiration in lymphocytes of individuals recuperated from a severe course lagged behind those shown upon mild COVID-19 recovery, in basal conditions and after simulated reinfection, and they also showed altered glycolytic capacity. The severe groups showed trends to enhanced superoxide production in parallel to lower OPA1-S levels. Unbalance of pivotal mitochondrial fusion (MFN2, OPA1) and fission (DRP1, FIS1) proteins was detected, suggesting a disruption in mitochondrial dynamics, as well as a lack of structural integrity in the electron transport chain. In serum, altered cytokine levels of IL-1β, IFN-α2, and IL-27 persisted long after clinical recovery, and growing amounts of the latter after severe infection correlated with lower basal and maximal respiration, ATP production, and glycolytic capacity. Finally, a trend for higher circulating levels of 3-hydroxybutyrate was found in individuals recovered after severe compared to mild course. In summary, long after acute infection, mitochondrial and metabolic changes seem to differ in a situation of full recovery after mild infection versus the one evolving from severe infection.

Cardiolipin deficiency disrupts CoQ-complex III interface in steatohepatitis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, mitochondrial cardiolipin (CL) was downregulated with MASLD/MASH in mice and in humans. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous and robust MASH with extensive steatotic and fibrotic phenotype. Loss of CL paradoxically increased mitochondrial respiratory capacity but also reduced the formation of I+III 2 +IV 1 respiratory supercomplex and interfered with the ability of coenzyme Q (CoQ) to transfer electrons to complex III. In turn, the bottleneck at complex III promoted electron leak primarily at site III Q0 as well as other upstream sites in the electron transport chain. Thus, reduction in mitochondrial CL promotes oxidative stress and contributes to pathogenesis of MASH.

Interactive effects of elevated temperature and venlafaxine on mitochondrial respiration and enzymatic capacity in Nile tilapia (Oreochromis niloticus).

Warming events are becoming more frequent and extreme in aquatic environments worldwide. Concurrently, many environments are polluted with biologically active compounds such as pharmaceuticals. Understanding how these challenges interact is critical for understanding the climate crisis, as contaminants may modulate how ectotherms respond to heat stress or vice versa. One potential site for these heat × contaminant interactions is the mitochondrion, which is central to metabolism, implicated in thermal tolerance, and evolutionarily conserved. Using high-resolution respirometry, we investigated how acute warming (to 35 °C, 40 °C, or 45 °C from 25 °C) impacted the respiration, coupling, and metabolic capacity of liver mitochondria isolated from Nile tilapia, and how exposure to environmentally relevant levels of the ubiquitous antidepressant venlafaxine modulated those effects. Mitochondria exposed to hotter temperatures had higher respiration rates and decreased respiratory control ratio compared to mitochondria exposed to cooler temperatures. The depressive effects of venlafaxine on respiration rates through complex I and II or complex II only (State 3 and State 4), as well as complex IV-linked respiration, were mild except in mitochondria exposed to high temperatures, suggesting an interactive effect of warming and contaminant exposure. Finally, we found that the maximal enzyme activity of intact mitochondria (represented by mitochondrial respiration) showed a different pattern of response to warming and venlafaxine compared to its underlying components (as reflected by the activity of succinate dehydrogenase [complex II] and cytochrome c oxidase [complex IV]), demonstrating the value of incorporating both interactive and reductive approaches in understanding how mitochondria cope with anthropogenic changes in the environment.

Optogenetic control of Protein Kinase C-epsilon activity reveals its intrinsic signaling properties with spatiotemporal resolution.

The regulation of PKC epsilon (PKCepsilon) and its downstream effects is still not fully understood, making it challenging to develop targeted therapies or interventions. A more precise tool that enables spatiotemporal control of PKCepsilon activity is thus required. Here, we describe a photo-activatable optogenetic PKCepsilon probe (Opto-PKCepsilon) consisting of an engineered PKCepsilon catalytic domain and a blue-light inducible dimerization domain. Molecular dynamics and AlphaFold simulations enable rationalization of the dark-light activity of the optogenetic probe. We first characterize the binding partners of Opto-PKCepsilon, which are similar to those of PKCepsilon. Subsequent validation of the Opto-PKCepsilon tool is performed with phosphoproteome analysis, which reveals that only PKCepsilon substrates are phosphorylated upon light activation. Opto-PKCepsilon could be engineered for recruitment to specific subcellular locations. Activation of Opto-PKCepsilon in isolated hepatocytes reveals its sustained activation at the plasma membrane is required for its phosphorylation of the insulin receptor at Thr1160. In addition, Opto-PKCepsilon recruitment to the mitochondria results in its lowering of the spare respiratory capacity through phosphorylation of complex I NDUFS4. These results demonstrate that Opto-PKCepsilon may have broad applications for the studies of PKCepsilon signaling with high specificity and spatiotemporal resolution.

Clinical benefit of chronic non-invasive ventilation in severe stable COPD: a matter of persistent hypercapnia improvement

PurposeIn patients with chronic obstructive pulmonary disease (COPD) treated with chronic non-invasive ventilation (NIV), the relation between improvements in nocturnal transcutaneous partial pressure of CO2 (PtcCO2) and daytime arterial partial...