bims-ripira 2026-05-31 papers

bims-ripira

Biomed News

on RRM2B MDMD in Adults

Issue of 2026–05–31
nineteen papers selected by
Martín Lopo

Machine learning-driven analysis of serum GDF15 trajectories identifies novel sepsis sub-phenotypes and predicts 28-day mortality.
Clinical and Genetic Characteristics of Mitochondrial DNA Depletion Syndrome Associated with SUCLG1 Variants in China.
MNGIE with TYMP and POLG variants presenting as decade-long capsule retention: A case report.
Beyond the Powerhouse: Mitochondrial Crosstalk as a Master Regulator of Cardiac Metabolic Homeostasis and Failure.
Mitochondrial transfer: A comprehensive analysis of mechanistic insights, preclinical applications, and technological innovations.
Energy metabolic dysregulation in heat stroke: from mitochondrial dysfunction to multi-organ failure mechanisms and targeted intervention.
Mitochondrial NAD+ Transport Alleviates Cerebral Ischemia/Reperfusion Injury via Enhancement of Mitochondrial Function.
Mitochondrial myopathy biomarkers.
Alpha-Lipoic Acid and Benfotiamine in Diabetic Peripheral Neuropathy: A Critical Review of Mechanistic Rationale and Clinical Evidence Within a Nutritional Therapeutic Framework.
Circulating biomarkers in older adults with and without sarcopenia: a systematic review and meta-analysis.
Recombinant human brain natriuretic peptide for the recovery stage of septic shock: an interventional study protocol.
Sepsis Dysregulates Mitochondrial microRNA and Biogenesis in the Diaphragm but Not Limb Muscle.
Highlighting the mechanisms through which increased dietary folic acid and choline impact regeneration in the brain after damage.
Uncovering the initial response: Intra-mitochondrial surveillance activates the UPRmt.
PINK1/Parkin-dependent mitophagy mediates astrocytic inflammatory responses to mitochondrial damage.
Role of creatine supplementation in intestinal health: a narrative review of its antioxidant and anti-inflammatory potential.
Isometric Exercises for Tendinopathies: A Systematic Literature Review.
From protector to perpetrator: The cGAS-STING pathway at the intersection of neurodegeneration and neuroinflammation.
Mapping the GDF15 arm of the integrated stress response in human cells and tissues.

Cytokine. 2026 May 25. pii: S1043-4666(26)00067-0. [Epub ahead of print]204 157172

Machine learning-driven analysis of serum GDF15 trajectories identifies novel sepsis sub-phenotypes and predicts 28-day mortality.

Qinxue Wang, Jiawei Wang, Yuhan Zhao, Yuanze Ma, Yong Ji, Yi Han.

   BACKGROUND: Sepsis heterogeneity complicates management and prognosis. Growth differentiation factor 15 (GDF15) may offer novel insights into sepsis sub-phenotyping. This study explored serum GDF15 trajectories for sub-phenotyping and prognostic stratification.
METHODS: A multicenter prospective cohort (March-October 2023) enrolled sepsis patients from four Chinese ICUs. Serum GDF15 was measured on days 1, 3, and 7 post-admission. Group-based trajectory modeling (GBTM) was employed for sub-phenotyping. Prognostic differences were analyzed using logistic regression and survival analysis; XGBoost machine learning determined key discriminators.
RESULTS: This study included 284 sepsis patients, with median age 65 (interquartile range [IQR] 52-75), 66.9% male, and 26.1% 28-day mortality. GBTM identified three distinct GDF15 trajectory subgroups according to levels measured on days 1, 3, and 7: low-level (n = 160, 56.3%), intermediate-level (n = 87, 30.6%), and high-level (n = 37, 13.0%). The 28-day mortality was significantly different across the groups (16.9%, 32.2%, and 51.4%, respectively; p < 0.001). After multivariable adjustment for demographics, disease severity scores, and other key clinical parameters in a series of sensitivity analyses, GDF15 trajectory subgrouping remained a robust, independent predictor of mortality. In the most comprehensively adjusted model, the high-level trajectory was associated with a 7.8-fold increased risk of 28-day mortality compared to the low-level group (95% CI: 3.2-19.1, p < 0.01). XGBoost analysis revealed Sequential Organ Failure Assessment (SOFA) score and lactate as critical discriminators of trajectory sub-phenotypes.
CONCLUSION: Machine learning-driven GDF15 trajectory analysis delineates three sepsis sub-phenotypes with divergent prognoses. The high-level trajectory independently predicts 28-day mortality, highlighting GDF15 as a pathophysiologically anchored biomarker for precision management. These findings warrant validation in larger cohorts to optimize sepsis stratification strategies.

Keywords:  28-day mortality; GDF15; Machine learning; Sepsis; Sub-phenotype; Trajectory

DOI:  https://doi.org/10.1016/j.cyto.2026.157172
Physiol Res. 2026 May 12. 75(2): 293-299

Clinical and Genetic Characteristics of Mitochondrial DNA Depletion Syndrome Associated with SUCLG1 Variants in China.

G-X Zhang, K-J Ji, Z-W Wang, N-N Wang.

This study aimed to summarize the genetic variants and clinical characteristics of mitochondrial DNA depletion syndrome (MDS) associated with SUCLG1 mutations in children from China. A systematic review of cases reported in a Chinese literature database was conducted. Clinical data and genetic findings of children with MDS caused by SUCLG1 mutations were analyzed. A total of 13 cases from 9 articles were identified. The primary clinical features included hypotonia, psychomotor retardation, feeding difficulties, growth retardation, hearing impairment, and liver function impairment. Urine organic acid analysis demonstrated a mild increase in methylmalonic acid, while plasma concentrations of propionylcarnitine and/or butyrylcarnitine were elevated. Additionally, increased lactate and pyruvic acid levels were observed in both plasma and cerebrospinal fluid. Brain magnetic resonance imaging identified basal ganglion lesions and/or cerebral atrophy. A total of 14 SUCLG1 variants were identified: c.550G>A, c.751C>T, c.809A>C, c.961C>G, c.826-2A>G, c.713T>C, c.916G>T, c.619T>C, c.980dupT, c.40A>G, c.142C>T, c.601A>G, c.871G>C, and c.721_c.722delGA. Among these, the c.826-2A>G variation was the most frequently detected, present in 4 children, followed by c.550G>A. No significant correlation was found between genotype and phenotype. All 13 children were treated with vitamin B complex and coenzyme Q10. Among them, 2 died, while the remaining children exhibited clinical improvement. MDS associated with SUCLG1 mutations presents with nonspecific clinical manifestations and can affect multiple organ systems. Genetic testing is necessary for diagnosis, and no definitive treatment is currently available.
Neurol Sci. 2026 May 26. pii: 521. [Epub ahead of print]47(6):

MNGIE with TYMP and POLG variants presenting as decade-long capsule retention: A case report.

Yuan Xia, Yufen She, Ruiqi Zhao, Yan Zhang.

   BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystem mitochondrial disorder caused by thymidine phosphorylase (TYMP) deficiency, leading to toxic nucleoside accumulation and mitochondrial DNA instability. Pathogenic variants in POLG, encoding mitochondrial DNA polymerase γ, have been associated with overlapping mitochondrial syndromes. However, the coexistence of TYMP-related MNGIE and a concurrent heterozygous POLG variant has not been reported.
CASE PRESENTATION: A 57-year-old woman presented with a 10-year history of recurrent dizziness, chronic diarrhea, and 20 kg weight loss. Laboratory investigations revealed chronic anemia, hypoproteinemia, and positivity for anti-centromere protein B and anti-mitochondrial M2 antibodies. Abdominal CT revealed multiple small-bowel diverticula, splenomegaly, and a retained capsule endoscope, whereas brain MRI showed diffuse white-matter hyperintensities. Electromyography showed sensorimotor neuropathy, and neurological examination revealed bilateral ptosis, ophthalmoplegia, and distal weakness. Whole-exome sequencing confirmed a homozygous TYMP variant (c.708C>A, p.Phe236Leu) and a heterozygous POLG variant (c.1781 T>C, p.Leu594Pro). Surgical removal of the retained capsule together with supportive therapy, including enteral nutrition and coenzyme Q10, resulted in clinical improvement. To our knowledge, this is the first reported case of MNGIE with a homozygous TYMP variant and a concurrent heterozygous POLG variant.
CONCLUSION: While the homozygous TYMP variant provides the primary molecular basis for the diagnosis, the concurrent heterozygous POLG variant may represent a potential phenotypic modifier. This case expands the genotypic context of MNGIE and highlights the importance of early genetic testing and multidisciplinary management in patients with unexplained gastrointestinal and neurological manifestations.

Keywords:  Capsule endoscopy; Mitochondrial disease; Mitochondrial neurogastrointestinal encephalomyopathy; POLG; TYMP

DOI:  https://doi.org/10.1007/s10072-026-09131-z
J Cardiovasc Transl Res. 2026 May 28. pii: 61. [Epub ahead of print]19(1):

Beyond the Powerhouse: Mitochondrial Crosstalk as a Master Regulator of Cardiac Metabolic Homeostasis and Failure.

Yu-Xin Kang, Yue Hu, Xi-Tong Sun, Xin-Biao Fan, Ao-Lin Li, Wen-Yu Shang, Yun-Feng Jia, Yi-Xuan Zhao, Miao-Miao Wei, Tian-Qi Wang, Zheng Zhang, Bo-Yu Zhu, Yong-Chun Liang, Jun-Ping Zhang.

  Mitochondrial dysfunction has long been recognized as a central driver of heart failure (HF) pathogenesis, and emerging evidence highlights that impaired mitochondrial communication, rather than merely energy metabolism dysfunction, plays a pivotal role in the initiation and progression of HF. These communication networks are critical for maintaining cardiac metabolic homeostasis, and their disruption in HF leads to dysregulated energy metabolism, oxidative stress, lipotoxicity, and impaired cardiomyocyte function. This review examines the functional interactions between mitochondria and these organelles in HF, with particular attention to phenotype-specific differences between HF with preserved ejection fraction and HF with reduced ejection fraction. Finally, we summarize current and emerging therapeutic strategies targeting mitochondrial communication, highlighting the potential for phenotype-tailored interventions that restore organelle interplay and metabolic balance in HF.

Keywords:  Energy metabolism; Heart failure; Lipotoxic substances; Mitochondrial communication; Mitochondrial dysfunction; Reactive oxygen species; Subcellular structures

DOI:  https://doi.org/10.1007/s12265-026-10776-6
Neural Regen Res. 2026 May 14.

Mitochondrial transfer: A comprehensive analysis of mechanistic insights, preclinical applications, and technological innovations.

Yao Wang, Zitong Wang, Jie Zhao, Yimin Zhou, Dong Wei, Jingjing Zhao, Zhongqing Sun, Wen Jiang.

  Mitochondrial transfer, the intercellular exchange of functional mitochondria, is crucial for maintaining cellular homeostasis and promoting tissue repair, particularly in neurological disorders associated with mitochondrial dysfunction. This review addresses the mechanisms through which mitochondrial transfer occurs, including tunneling nanotubes, extracellular vesicles, gap junction channels, and cell fusion. Mitochondrial transfer and transplantation have demonstrated positive therapeutic effects in various disease models, such as cerebral hemorrhage, ischemic stroke, Alzheimer's disease, and multiple sclerosis. Exogenous mitochondria can integrate into recipient cells, enhancing adenosine triphosphate production, restoring redox balance, and improving cellular survival under stress conditions. However, clinical translation faces significant hurdles, including immune rejection, limited recipient cell uptake capacity, a lack of standardized manufacturing protocols, and unresolved ethical concerns regarding mitochondrial sourcing. To address these challenges, cutting-edge biotechnological strategies, such as mitochondrial surface modification, nanocarrier-based delivery, biomaterial-assisted transplantation, and the use of engineered vesicles, are being developed to enhance the precision, stability, and biocompatibility of mitochondrial delivery. Furthermore, innovative approaches, including CRISPR-based genome editing, 3D-bioprinted tissue models, and artificial intelligence-assisted predictive platforms, are being explored to enhance mitochondrial function and delivery efficiency. Current strategies to harness mitochondrial transfer include pharmacological agents that enhance mitochondrial dynamics, stem cell-based delivery of healthy mitochondria, and the aforementioned bioengineered platforms. In conclusion, the integration of mitochondrial transfer as a groundbreaking treatment option for neurological disorders relies on addressing two to three fundamental challenges. These include the establishment of standardized and scalable protocols for production and quality control, formulating approaches to minimize immune reactions and improve the efficiency of mitochondrial integration, and creating a well-defined ethical and regulatory framework for sourcing and utilizing mitochondria. The primary contribution of this work lies in its integrated analysis of mechanistic insights, preclinical applications, and technological innovations, providing a consolidated roadmap for advancing mitochondrial transplantation from bench to bedside.

Keywords:  artificial cells; biomaterial-assisted transplantation; extracellular vesicles; mesenchymal stem cells; mitochondrial dysfunction; mitochondrial surface modification; mitochondrial transfer; mitochondrial transplantation; neurological disorders; tunneling nanotubes

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01156
Front Pharmacol. 2026 ;17 1813630

Energy metabolic dysregulation in heat stroke: from mitochondrial dysfunction to multi-organ failure mechanisms and targeted intervention.

Qiqi Li, Jinquan Wang, Xiaojie Qin, Biaochao Zhong, Qiantong Wei, Chunhui Zeng, Ke Yang.

  Heat stroke (HS) is a life-threatening acute condition characterized by hyperthermia, central nervous system dysfunction, and multiple organ failure. Energy metabolism disruption serves as a pivotal link between hyperthermia and multi-organ injury. This review synthesizes current evidence on the mechanisms of energy metabolism dysregulation in HS and evaluates emerging intervention strategies. Mitochondrial dysfunction-manifested as structural damage, oxidative phosphorylation impairment, and excessive fission-represents an initiating event. This is followed by glucose-lipid metabolic restructuring, impaired substrate utilization, and energy depletion. These metabolic derangements mediate secondary injury in the intestine (barrier disruption and endotoxemia), brain (hypothalamic dysregulation), and lung (oxidative stress and barrier leakage). Intervention strategies are categorized into mitochondrial protection (e.g., astragaloside IV, curcumin), mitophagy modulation (e.g., melatonin, rapamycin), and substrate metabolism regulation (e.g., taurine, acetyl-L-carnitine). Notably, most current evidence for these interventions is derived from preclinical studies, and HS-validated human studies are still needed to confirm their efficacy and safety. While these approaches show promise in preclinical models, translational gaps remain, including limited validation in HS-specific models, lack of biomarker-guided patient stratification, and insufficient data on vulnerable populations. Future priorities include dynamic metabolic monitoring, identification of early-warning biomarkers, and development of personalized interventions tailored to age, comorbidity status, and metabolic phenotype.

Keywords:  energy metabolism; heat stroke; intervention strategies; mitochondria; multiple organ injury

DOI:  https://doi.org/10.3389/fphar.2026.1813630
Antioxid Redox Signal. 2026 May 28. 15230864261455714

Mitochondrial NAD+ Transport Alleviates Cerebral Ischemia/Reperfusion Injury via Enhancement of Mitochondrial Function.

Xiaorong Wang, Yuxin Li, Jinhua Tan, Xiaona Sun, Qidi Zhou, Rui Xu, Xiaoqi Song, Yu Cui, Zhaolong Zhang.

   AIMS: Cerebral ischemia-reperfusion (I/R) injury is a leading cause of neurological disability and is characterized by mitochondrial dysfunction and oxidative stress. Although depletion of nicotinamide adenine dinucleotide (NAD+) is a hallmark of ischemic injury, therapeutic strategies aimed at NAD+ replenishment have shown limited efficacy. Whether impaired mitochondrial NAD+ import contributes to neuronal vulnerability after I/R remains poorly understood.
RESULTS: We found that cerebral I/R disrupts the balance of NAD+ distribution between the cytoplasm and mitochondria in the cortex due to upregulated expression of SLC25A51. Augmenting SLC25A51 expression restored mitochondrial NAD+ pools, improved mitochondrial respiratory function, reduced oxidative lipid damage, and attenuated neuronal injury. In contrast, SLC25A51 deficiency exacerbated mitochondrial dysfunction and heightened susceptibility to I/R stress. These effects occurred independently of global NAD+ biosynthesis, indicating that mitochondrial NAD+ transport rather than NAD+ availability per se is a critical determinant of neuronal survival.
INNOVATION: This study reveals the subcellular distribution change of NAD+-mediated by SLC25A51 and its neuroprotective effects via modulating mitochondrial function after cerebral I/R injury.
CONCLUSION: This study identifies defective mitochondrial NAD+ import as a previously underrecognized mechanism of cerebral I/R injury. By establishing SLC25A51-dependent NAD+ trafficking as a key regulator of mitochondrial redox balance and neuronal resilience, our findings shift the therapeutic paradigm from NAD+ supplementation to restoration of subcellular NAD+ distribution, highlighting mitochondrial NAD+ transport as a promising target for ischemic brain injury. Antioxid. Redox Signal. 00, 000-000.

Keywords:  NAD+; SLC25A51; ischemic-reperfusion injury; mitochondria; neurons; oxidative stress

DOI:  https://doi.org/10.1177/15230864261455714
Adv Clin Chem. 2026 ;pii: S0065-2423(26)00021-1. [Epub ahead of print]133 161-216

Mitochondrial myopathy biomarkers.

Marco Refrigeri, Alessandra Tola, Rosangela Mogavero, Maria Michela Pietracupa, Giulia Gionta, Roberto Scatena.

  Mitochondrial myopathies comprise a heterogeneous group of disorders arising from structural or functional mitochondrial impairments that disrupt oxidative phosphorylation and cellular ATP production. The resulting energy deficit manifests not only in muscle but frequently leads to multi-systemic disease involving the brain, heart, kidneys, and endocrine system, creating a complex and often confounding clinical presentation. A critical, often overlooked aspect of their pathophysiology is that mitochondrial dysfunction extends far beyond bioenergetics. These organelles are vital hubs for biosynthetic pathways, calcium homeostasis, thermogenesis, apoptosis, and redox-sensitive signaling pathways that govern gene expression. The disruption of these integrated functions, whose molecular consequences are still being elucidated, is central to the disease's progression and heterogeneity. This clinical and molecular complexity contributes to significant diagnostic delay, with many remaining undiagnosed. Therefore, the development and strategic implementation of reliable biomarkers are essential. This review critically evaluates current and emerging biomarkers, proposing a diagnostic framework designed to improve diagnostic accuracy, limit unnecessary procedures, and ensure timely access to therapeutic interventions and genetic counseling.

Keywords:  Biomarkers; Cell-free circulating mtDNA; Creatine; Diagnosis; Exercise intolerance; FGF21; GDF-15; Genetics; Mitochondrial disease; Mitochondrial medicine; Mitochondrial myopathy; Neurofilaments; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/bs.acc.2026.01.007
Nutrients. 2026 May 12. pii: 1538. [Epub ahead of print]18(10):

Alpha-Lipoic Acid and Benfotiamine in Diabetic Peripheral Neuropathy: A Critical Review of Mechanistic Rationale and Clinical Evidence Within a Nutritional Therapeutic Framework.

Alin Ciubotaru, Cristina Grosu, Daniel Alexa, Laura-Elena Cucu, Thomas Gabriel Schreiner, Cătălina Elena Bistriceanu, Alexandra Maştaleru, Doina Azoicāi, Albert Vamanu, Alexandru Patrascu, Dan Iulian Cuciureanu, Emilian Bogdan Ignat.

   BACKGROUND: Diabetic peripheral neuropathy (DPN) affects up to 50% of diabetes patients and is driven by hyperglycemia-induced oxidative stress, mitochondrial dysfunction, polyol pathway activation, advanced glycation end-product formation, and inflammation. Current management is largely symptomatic, prompting interest in metabolic/nutritional therapies. This review critically evaluates the mechanistic rationale and clinical evidence for alpha-lipoic acid (ALA) and benfotiamine as adjunctive treatments for DPN.
METHODS: A structured narrative review of PubMed/MEDLINE was conducted using predefined keywords for DPN, oxidative stress, metabolic therapy, and thiamine derivatives. Randomized controlled trials, clinical studies, systematic reviews, and relevant experimental studies were included. Evidence was synthesized qualitatively with emphasis on mechanistic plausibility, clinical efficacy, intervention duration, and methodological rigor.
RESULTS: ALA consistently improves short-term symptoms across multiple randomized trials. The long-term NATHAN 1 trial reported a marginal, borderline significant effect on the primary composite endpoint (NIS-LL, p = 0.05) without significant improvements in nerve conduction studies; therefore, evidence for functional stabilization is very limited and inconclusive. ALA's effects are attributed to antioxidant activity, mitochondrial protection, and improved microvascular function. Benfotiamine has a strong biochemical rationale (transketolase activation, diversion of glycolytic intermediates from damaging pathways), but clinical evidence remains limited to short-duration, symptom-based studies, with no large-scale, long-term trials published.
CONCLUSIONS: Both agents target key pathways in DPN pathogenesis. ALA is the most established adjunctive metabolic therapy for symptomatic DPN, although no study has demonstrated structural nerve regeneration or a definitive disease-modifying effect. Benfotiamine is biologically plausible but requires further validation in long-term randomized trials with structural and biomarker-based endpoints. Outside of documented thiamine deficiency, its routine use cannot be recommended based on current evidence.

Keywords:  advanced glycation end products; alpha-lipoic acid; benfotiamine; diabetic peripheral neuropathy; metabolic therapy; nutritional intervention; oxidative stress; transketolase

DOI:  https://doi.org/10.3390/nu18101538
J Gerontol A Biol Sci Med Sci. 2026 May 27. pii: glag140. [Epub ahead of print]

Circulating biomarkers in older adults with and without sarcopenia: a systematic review and meta-analysis.

Konstantinos Prokopidis, Colleen S Deane, Zoubayda Baoubbou, Charlotte Beaudart.

   BACKGROUND: Sarcopenia, the age-related loss of muscle mass and strength, poses a significant health and economic burden. This systematic review and meta-analysis evaluates circulating biomarkers (activin A, follistatin, growth differentiation factor (GDF-15), myostatin, growth hormone, insulin growth factor-1 (IGF-1), free and total testosterone) that may be associated with sarcopenia in community-dwelling older adults.
METHODS: Following PRISMA 2020 guidelines, we searched PubMed, Scopus, Web of Science, and Cochrane Library from inception to June 2025. Studies included adults without major comorbidities aged >60 years with sarcopenia defined by established consensus. Standardized mean differences (SMDs) were calculated using a random-effects model. Heterogeneity was assessed via I2 and meta-regressions, while Egger's test was employed for publication bias.
RESULTS: From 3488 records, 26 observational studies were included (n = 1345 adults with sarcopenia, 48.3% females, mean age 67.9-88.1 years). Adults with sarcopenia showed elevated GDF-15 (k = 5, SMD: 0.26, 95% confidence interval (95%CI): 0.03-0.50, I2 = 64%, P = 0.03) and reduced IGF-1 (k = 11, SMD: -0.40, 95%CI: -0.54 - -0.27, I2 = 36%, P < 0.01) compared to controls without sarcopenia. No significant differences were found between groups for the other circulating biomarkers.
CONCLUSIONS: Elevated circulating IGF-1 and, to a lesser extent GDF-15, may be promising biomarkers for sarcopenia. Larger, longitudinal studies are needed to address heterogeneity and causality in this field.

Keywords:  GDF-15; IGF-1; ageing; biomarkers; sarcopenia

DOI:  https://doi.org/10.1093/gerona/glag140
BMJ Open. 2026 May 24. 16(5): e110628

Recombinant human brain natriuretic peptide for the recovery stage of septic shock: an interventional study protocol.

Jing-Chao Luo, Tao Mou, Ma Li, Wen-Tao Feng, Rui-Ming Yue, Chun Pan, Xiao-Bo Huang, Eduardo Kattan, Yi Zhang, Ling-Ai Pan.

   INTRODUCTION: In the de-resuscitation phase of septic shock, resolving vasoplegia and fluid mobilisation can increase venous congestion in patients with sepsis-related myocardial dysfunction. This study will characterise the haemodynamic effects and safety of recombinant human brain natriuretic peptide (rh-BNP) in this population.
METHODS AND ANALYSIS: This single-centre, prospective, single-arm study will enrol 30 adults recovering from septic shock with improving infection/vasopressor trends, sinus rhythm, ongoing pulse-index continuous cardiac output (PiCCO) monitoring and measurable arm-equilibrium pressure (Parm). Eligibility will require cardiac dysfunction (left-ventricular ejection fraction ≤50% and/or ≥10% absolute decline when available) and volume overload (global end-diastolic volume index >800 mL/m² and extravascular lung water index >10 mL/kg). Participants will receive rh-BNP (2 µg/kg intravenous bolus over 15 min, then a 0.01 µg/kg/min infusion for up to 72 hours). Measurements will be obtained at baseline, acute response (30-60 min), 24, 48 and 72 hours. The primary outcome will be within-patient change in venous return pressure gradient (ΔPVR, Parm-central venous pressure) from baseline to acute response. Secondary outcomes will include indices of preload, cardiac function, tissue perfusion and venous congestion. Haemodynamic instability will be the safety endpoint. Paired tests and repeated-measures analyses will estimate within-patient changes over time.
ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Ethics Committee of Sichuan Provincial People's Hospital, Sichuan Academy of Medical Sciences (No. 2024-653-1). Written informed consent will be obtained. Findings will be disseminated via peer-reviewed publications and conferences.
TRIAL REGISTRATION NUMBER: NCT06745206.

Keywords:  Adult intensive & critical care; INTENSIVE & CRITICAL CARE; Intensive Care Units; Sepsis

DOI:  https://doi.org/10.1136/bmjopen-2025-110628
Int J Mol Sci. 2026 May 09. pii: 4222. [Epub ahead of print]27(10):

Sepsis Dysregulates Mitochondrial microRNA and Biogenesis in the Diaphragm but Not Limb Muscle.

Luther Gill, Patricia Molina, Liz Simon.

  Diaphragm dysfunction that leads to respiratory failure is a significant clinical consequence of sepsis-induced critical illness. Diaphragm muscle weakness contributes to morbidity and mortality in these individuals in part due to impaired mitochondrial function. Restoring normal mitochondrial biogenesis is associated with improved survival and physical function. Therefore, identifying reliable biomarkers of mitochondrial dysfunction in diaphragm muscle will allow for more focused and targeted interventions designed to improve the morbidity of critically ill patients. We used a rodent cecal-ligation and puncture (CLP) model to mimic a moderate grade of sepsis. The diaphragm muscle was harvested from adult mice 48 h following CLP (n = 6) or a sham CLP procedure (n = 6). Our primary finding was that moderate grade CLP increases expression of mitochondria-associated microRNA in the diaphragm. Correspondingly, genes associated with mitochondrial biogenesis decreased. Our study provides evidence for sepsis-mediated dysregulation of mitochondrial homeostasis. This may play a role in diaphragm muscle dysfunction, respiratory failure, and difficult weaning from mechanical ventilation in sepsis-induced critical illness.

Keywords:  diaphragm muscle; microRNA; mitochondrial dysregulation

DOI:  https://doi.org/10.3390/ijms27104222
Neural Regen Res. 2026 May 14.

Highlighting the mechanisms through which increased dietary folic acid and choline impact regeneration in the brain after damage.

Nora Jones, Sumaiya Binte, Nafisa M Jadavji.

  Ischemic stroke is a condition caused by an obstruction of blood flow to the brain. Traditionally, there has been a high prevalence in the aged population, but it is increasingly affecting younger adults, reshaping the traditionally understood demographics. Nutrition is a modifiable risk factor for ischemic stroke. The B-vitamin, folic acid and nutrient, choline have previously been reported to impact ischemic stroke outcomes. The aim of this review is to provide mechanistic insight into how increasing levels of folic acid or choline impact brain function after injury. Our survey of the literature has demonstrated that increasing intake of folic acid after brain injury results in reduced apoptosis and autophagy in the brain, along with diminished inflammation and oxidative stress. There is an increase in cellular proliferation and improved mitochondrial function. Whereas, increasing levels of choline also resulted in improved neurite growth post injury. Prenatal supplementation with choline alleviated Alzheimer's disease phenotype in offspring by enhancing neuronal survival and integrity; this could be applied to stroke models. In recent years, the field of stroke research has faced a reproducibility crisis, in that many preclinical studies do not translate into clinical therapies. We discuss two components of the preclinical research that need to be improved: inclusion of females and the use of model systems at the applicable age. The results of our review demonstrate that increasing dietary levels of folic acid or choline is beneficial after brain injury using model systems. As discussed above, these studies need to undergo rigorous experimental design and analysis using both male and female animals that are the age most applicable to human conditions.

Keywords:  choline; folic acid; ischemic stroke; one-carbon metabolism; scientific rigor; sex differences; spinal cord injury

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01911
Mol Cell. 2026 May 26. pii: S1097-2765(26)00308-4. [Epub ahead of print]

Uncovering the initial response: Intra-mitochondrial surveillance activates the UPRmt.

Asli Aras Taskin, Sahana Shankar, Carlotta Peselj, Annette Flotho, Maria Gomez-Fabra Gala, Daniel Poveda-Huertes, Lisa Myketin, Duygu Mutlu, Adinayarana Marada, Sebastian Schuck, Mandy Jeske, Sabrina Büttner, Marcin Luzarowski, Chris Meisinger, F-Nora Vögtle.

  The mitochondrial unfolded protein response (UPRmt) protects mitochondria from proteotoxic stress. Current models induce acute and severe mitochondrial disruption and propose cytosolic detection following the release of mitochondrial damage signals into the cytosol. However, this mode of toxicity contrasts sharply with physiological stress, such as the gradual accumulation of reactive oxygen species (ROS) during aging or chronic respiratory chain defects. Here, we employ a chemogenetic strategy in yeast to induce low levels of hydrogen peroxide (H2O2) in the mitochondrial matrix and show that mild oxidative stress activates the UPRmt independently of cytosolic damage. We identify the presequence proteases MPP and Oct1 as early ROS targets, thereby linking redox imbalance to UPRmt activation: oxidative stress induces glutathionylation of critical cysteines, impairing protease activity and causing the accumulation of unprocessed precursors in proteotoxic matrix aggregates. These aggregates are detected by intra-mitochondrial surveillance, activating UPRmt signaling. Thus, mitochondrial self-surveillance initiates rapid protective signaling as a primary response to mitochondrial dysfunction.

Keywords:  mitochondria-nucleus communication; mitochondrial protein biogenesis; mitochondrial unfolded protein response; oxidative stress; presequence processing; reactive oxygen species

DOI:  https://doi.org/10.1016/j.molcel.2026.05.002
bioRxiv. 2026 May 13. pii: 2026.05.11.724378. [Epub ahead of print]

PINK1/Parkin-dependent mitophagy mediates astrocytic inflammatory responses to mitochondrial damage.

Julia F Riley, Charity V Robbins, Erika L F Holzbaur.

Astrocytes directly influence neuronal survival and increasingly are understood to contribute to the progression of neurodegenerative diseases including Parkinson's disease (PD). Mitochondrial damage is a hallmark of PD pathology in both neurons and astrocytes. Damaged mitochondria are cleared by PINK1/Parkin-mediated mitophagy; loss-of-function mutations in either PINK1 or Parkin are sufficient to cause PD. Neuronal mitophagy is well-studied, but far less is known about how mitochondrial dysfunction in astrocytes affects neural health. While microglial release of pro-inflammatory cytokines has been shown to induce astrocytes to mount their own inflammatory response, we hypothesize that a more direct pathway is involved, and that mitochondrial damage to astrocytes directly triggers release of proinflammatory cytokines. To address these questions, we treated primary murine cortical astrocytes with oxidative phosphorylation (OXPHOS) inhibitors antimycin A (AA) and oligomycin A (OA) and observed the PINK1-dependent accumulation of Parkin on damaged mitochondria, leading to phospho-ubiquitination of proteins in the outer mitochondrial membrane and the recruitment of the autophagy receptor SQSTM1/p62. To identify transcriptional changes caused by mitochondrial damage and the resulting activation of mitophagic machinery, we performed bulk RNA-sequencing on astrocytes isolated from WT, PINK1 -/- , or Parkin -/- mice treated with AA/OA or a vehicle control. In WT astrocytes, TNF-α signaling via NF-κB was the most significantly upregulated pathway following OXPHOS inhibition. OXPHOS inhibitor treatment also stimulated p62 expression, while NF-κB inhibition prevented this upregulation. Astrocytic secretion of cytokines, including TNF-α, was increased following mitochondrial damage; this secretion was dependent on NF-κB activation and occurred at levels sufficient to induce mitochondrial depolarization in hippocampal neurons. Compared to WT astrocytes, PINK1 -/- astrocytes showed a significant reduction in transcriptional signatures associated with TNF-α signaling following mitochondrial damage, while Parkin -/- astrocytes exhibited upregulation of both IFN-γ and IFN-α signaling. These findings indicate altered inflammatory responses to mitochondrial damage in the absence of functional PINK1 or Parkin. Finally, we analyzed scRNA-sequencing data from substantia nigra astrocytes harvested from human brain tissue from PD-positive or control samples. Distinct clusters comprised predominantly of PD-positive or control astrocytes emerged. Astrocytes in the PD-positive cluster were enriched for NF-κB, IFN-α and IFN-γ responses, consistent with the signaling observed in vitro post-OXPHOS inhibition. Together, these findings identify inflammatory signatures activated by mitochondrial damage in astrocytes, and establish this pathway as a potential contributor to neuroinflammation in PD.

DOI: https://doi.org/10.64898/2026.05.11.724378
Nutrition. 2026 Apr 27. pii: S0899-9007(26)00170-X. [Epub ahead of print]149 113262

Role of creatine supplementation in intestinal health: a narrative review of its antioxidant and anti-inflammatory potential.

Jordan Teixeira Oliveira, Simone Pieniz.

  Inflammatory bowel diseases (IBD) are chronic, idiopathic disorders of the gastrointestinal tract, classified as ulcerative colitis and Crohn's disease. The most common pharmacological therapies include aminosalicylates, glucocorticoids, immunosuppressants, and targeted biological therapies. However, due to their many potential adverse effects, natural compounds such as creatine have also gained attention. Creatine is a compound formed from the amino acids arginine, glycine, and methionine, and can be synthesized endogenously or obtained through food or supplements. Because of its ability to improve cellular energy status, and its antioxidant and anti-inflammatory properties, the aim of this study was to assess its therapeutic potential in IBD and other associated clinical disorders. A literature review was conducted using the PubMed, ScienceDirect and Google Scholar databases. Based on the data found, creatine supplementation demonstrated therapeutic potential in restoring intestinal homeostasis, as well as significant antioxidant and anti-inflammatory activity. Therefore, this compound should to be considered a promising therapeutic agent in IBD, and further studies are needed.

Keywords:  Crohn’s disease; IBD; Intestinal permeability; Leaky gut; Ulcerative colitis

DOI:  https://doi.org/10.1016/j.nut.2026.113262
Clin Ther. 2026 May 27. pii: S0149-2918(26)00146-3. [Epub ahead of print]

Isometric Exercises for Tendinopathies: A Systematic Literature Review.

Ezzat F F Soliman, Deepak Nagra, Su Li Goh, Emmanuel Akingbade, Bako Nouri, Shahriar Amin, Kelvin Chau, Daniel Bulman, Tim Blake, Keir Young, Mark D Rusell, James Galloway.

   PURPOSE: Musculoskeletal disorders are among the most common reasons for medical consultation, with tendinopathies accounting for up to 30% of such presentations. Although exercise remains the cornerstone of management, the most effective modality continues to be debated. Eccentric exercise has long been the mainstay, but the role of isometric exercise in pain modulation and functional recovery remains unclear. This systematic review aims to evaluate the current evidence on the efficacy of isometric exercises in the management of tendinopathies across various anatomic sites.
METHODS: A systematic search was conducted in PubMed, MEDLINE, Embase, and the Cochrane Library from inception to August 1, 2025. Eligible studies included randomized controlled trials and prospective or retrospective cohort studies assessing isometric exercise interventions for tendinopathy, with or without comparator groups. Case series and case reports were excluded. Data extracted included participant demographic characteristics, site of tendinopathy, symptom duration, treatment duration, adherence, and outcome measures such as Victorian Institute of Sports Assessment (A, P, or G), visual analog scale, Patient-Specific Functional Scale, 36 item short form health survey (SF-36), and EuroQol 5-Dimension questionnaires. Imaging outcomes (ultrasound or magnetic resonance imaging) were recorded where available. Methodological quality and risk of bias were assessed using the Cochrane Risk of Bias tool in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.
FINDINGS: The search identified 304 articles, of which 13 randomized controlled trials met the inclusion criteria, encompassing 336 participants (40% female). Tendinopathy sites included the patellar (n = 4), Achilles (n = 3), lateral elbow (n = 2), rotator cuff (n = 2), wrist extensor (n = 1), and gluteal (n = 1) tendons. Median symptom duration was 23 months (interquartile range, 3-51 months). Intervention periods ranged from a single 45-minute session to 4-month exercise programs. Treatment adherence was high initially (nearly 100%) but declined over time, with 70% of participants in the isometric and 58% in the control (isotonic) groups completing ≥80% of sessions. Pain reduction and functional improvement were statistically significant in only 3 studies. Imaging-based outcomes were inconsistently reported, and study heterogeneity precluded meta-analysis. Overall methodological quality was rated as good in 3 studies and poor in 10.
IMPLICATIONS: Current evidence provides limited support for the superiority of isometric exercise in tendinopathy management. Although isometric regimens appear tolerable and may confer short-term analgesic benefits, their long-term efficacy relative to eccentric or isotonic protocols remains uncertain. Future research should prioritize standardized outcome measures, longer follow-up, and uniform diagnostic criteria to strengthen the evidence base for exercise prescription in tendinopathies.

Keywords:  Concentric; Eccentric; Exercise; Isometric; Tendinopathy

DOI:  https://doi.org/10.1016/j.clinthera.2026.04.027
Brain Res Bull. 2026 May 25. pii: S0361-9230(26)00249-2. [Epub ahead of print]241 111963

From protector to perpetrator: The cGAS-STING pathway at the intersection of neurodegeneration and neuroinflammation.

Ghaleb Oriquat, Abdulqader Faris Abdulqader, Hamrayev Farid, Zarifjon Ashurov, Abduvali Sottarov, Nghm Yhya Ghafl, Neeraj Bainsal, Ritesh Singh.

  The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a cornerstone of the innate immune system designed to combat pathogens, is now implicated as a critical driver of sterile inflammation in the brain. This review synthesizes compelling evidence that in the aging and diseased central nervous system, endogenous cytosolic DNA, sourced from genomic instability, mitochondrial dysfunction, and activated retrotransposons, hijacks this pathway. Chronic cGAS-STING activation transforms microglia into inflammatory amplifiers, instigates neurotoxic astrocyte programs, and directly compromises neuronal health, creating a self-perpetuating cycle of neuroinflammation. We dissect the cell-type specific consequences within the neurovascular unit and establish the pathway's role in the pathogenesis of ALS/FTD, Alzheimer's, Parkinson's, and Huntington's diseases. Crucially, we evaluate the therapeutic potential of targeting this axis, discussing small-molecule inhibitors, oligonucleotide therapies, and upstream interventions to quell the source of immunogenic DNA. We also explicitly examine contradictory preclinical data, including the retracted PINK1-Parkin-STING report and context-dependent neurovascular findings, to provide a balanced appraisal of STING biology in the CNS. By reconciling its dual protective and pathogenic roles, this review posits cGAS-STING as a pivotal mechanism-based therapeutic node for halting the progression of neurodegenerative disorders.

Keywords:  Innate Immunity; Mitochondrial DNA; Neurodegenerative Diseases; Neuroinflammation; cGAS-STING Pathway

DOI:  https://doi.org/10.1016/j.brainresbull.2026.111963
Commun Biol. 2026 May 27.

Mapping the GDF15 arm of the integrated stress response in human cells and tissues.

Janell L M Smith, Kamaryn T Tanner, Jack Devine, Anna S Monzel, Taivan Batjargal, Maxwell Z Wilson, Alan A Cohen, Martin Picard.

Mitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through the secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to eleven metabolic perturbations, including genetic and pharmacological mitochondrial OxPhos defects, we show that the ISR has multiple arms. To quantify the GDF15 arm of ISR activation in human cells, we developed an ISRGDF15 index. We validate the ISRGDF15 index in datasets from optogenetic and small molecule activation of ISR kinases, demonstrating its rapid kinetics preceding to GDF15 gene expression. We then deploy the ISRGDF15 index across 44 postmortem human tissues, confirm its correlation with age, and report that the ISRGDF15 is upregulated in the heart of individuals with acute causes of death in the emergency room, whereas it was upregulated in the brain of individuals who died after protracted hospital inpatient stays. These data highlight distinct arms of the ISR and clarify genes related to the GDF15 ISR arm, yielding an ISRGDF15 index that can be used to investigate tissue-specific and age-related ISR activation in both in vitro cultures and human tissues.

DOI: https://doi.org/10.1038/s42003-026-10312-x