Cellular Functions Research Articles

The significance of mitochondrial DNA changes during the onset and progression of head and neck squamous cell carcinoma.

Mitochondrial DNA (mtDNA) is integral to cellular function. Alterations in mtDNA can lead to significant disruptions in mitochondrial function, including cellular energy production, metabolism, and apoptosis regulation. Mitochondrial dysfunction has emerged as a crucial factor in the progression of cancer, including head and neck squamous cell carcinoma (HNSCC). Based on a literature search conducted from August 2024 to March 2025 on PubMed and Google Scholar, our review summarizes the relevance of mtDNA alterations in HNSCC development. HNSCC has been found to cause significant variations in mtDNA, including mutations, copy number variations (or known as mtDNA content) and large-scale deletions. Notably, these alterations varied by disease stage, different key aspects of mitochondrial function, such as cellular growth, senescence, metabolism and apoptosis, and cell-specific genetic context. We further suggest that drugs that modulate mitochondrial pathways, mitochondrial transplantation, and gene-editing technologies, are future treatment strategies for HNSCC. Lastly, we discuss the potential of co-roles of nuclear DNA mutations with mtDNA alterations in HNSCC to provide a holistic view of HNSCC pathogenesis and the possibility for combined therapeutic strategies in HNSCC.

NSAIDS AS MODULATORS OF CATION CHANNELS: FENAMATES REPURPOSING IN CHANNELOPATHIES.

Cationic ion channels are transmembrane proteins that regulate the flux of cations (potassium, sodium, and calcium) across cell membrane, playing a pivotal role in many cellular functions. Disruptions of their activity can lead to the so-called genetic or acquired channelopathies, a heterogeneous group of diseases that affect multiple human systems. Fenamates, a class of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), has recently emerged as modulators of cationic ion channels highlighting the possibility of their repurposing for the treatment ion channel-related disorders, such as channelopathies, chronic pain, epilepsy, cardiac arrhythmias and cancers. In this review, we describe the ability of fenamates (i.e. niflumic, flufenamic, mefenamic, meclofenamic and tolfenamic acids) to differentially modulate the activity of cationic ion channels. Overall, preclinical and clinical studies suggest that fenamates represent a promising class of compounds for drug repurposing and for the development of new molecules, offering novel therapeutic opportunities for patients affected by ion channel-related disorders.

Assessment of Serum Lactate and Creatinine Kinase to evaluate mitochondrial dysfunction in autistic children

Background: Mitochondrial dysfunction and autistic spectrum disorders (ASDs) are closely related with each other. It has also been mitochondrial dysfunction causes impairment in cellular function which may lead to lack of social communications, language deficits and abnormal energy metabolism in autistic spectrum disorder. These are associated with laboratory evidence of lowered mitochondrial function. Objective: To observe the mitochondrial dysfunction and assess serum lactate and CK to in children with autistic spectrum disorder. Methods: This case-control study was conducted in the Department of Physiology of Bangladesh Medical University (BMU), Shahbag, Dhaka from January, 2013 to December, 2013. For this study a total number of 100 male children with age range 3-8 years were randomly selected, among which 50 were normal children and 50 were diagnosed autistic children. The autistic children were selected from the Parent’s Forum, Directorate Generals of Health Service (DOHS), Mohakhali, Dhaka and normal children were selected from some normal school. Serum lactate and creatine kinase (CK) were estimated in all children by standard laboratory method. For statistical analysis independent sample‘t’ test were done as applicable. Result: The mean of both the measured biochemical parameters were found significantly higher (p<0.001) in autistic spectrum disorder children. In addition, elevated levels of serum lactate and CK were found in 94% and 32% of autistic children respectively. Conclusion: The result of this study revealed that mitochondrial dysfunction may occur in children with autistic spectrum disorder. The severity of the autistic spectrum disorder is directly related to the biochemical abnormality for mitochondrial dysfunction. EWMCJ Vol. 13, No. 2, July 2025: 121-124

Tartary Buckwheat Peptides Prevent Oxidative Damage in Differentiated SOL8 Cells via a Mitochondria-Mediated Apoptosis Pathway

Background: Under oxidative stress conditions, the increased levels of reactive oxygen species (ROS) within cells disrupt the intracellular homeostasis. Tartary buckwheat peptides exert their effects by scavenging oxidative free radicals, such as superoxide anion and hydrogen peroxide, thereby reducing oxidative damage within cells. Meanwhile, these peptides safeguard mitochondria by maintaining the mitochondrial membrane potential, decreasing the production of mitochondrial oxygen free radicals, and regulating mitochondrial biogenesis and autophagy to preserve mitochondrial homeostasis. Through these mechanisms, Tartary buckwheat peptides restore the intracellular redox balance, sustain cellular energy metabolism and biosynthesis, and ensure normal cellular physiological functions, which is of great significance for cell survival and adaptation under oxidative stress conditions. Objectives: In this experiment, a classical cellular oxidative stress model was established. Indicators related to antioxidant capacity and mitochondrial membrane potential changes, as well as pathways associated with oxidative stress, were selected for detection. The aim was to elucidate the effects of Tartary buckwheat oligopeptides on the metabolism of cells in response to oxidative stress. Methods: In this study, we established an oxidative damage model of mouse skeletal muscle myoblast (SOL8) cells using hydrogen peroxide (H2O2), investigated the pre-protective effects of Tartary buckwheat oligopeptides on H2O2-induced oxidative stress damage in SOL8 cells at the cellular level, and explored the possible mechanisms. The CCK-8 method is a colorimetric assay based on WST-8-[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodiumsalt], which is used to detect cell proliferation and cytotoxicity. Results: The value of CCK-8 showed that, when the cells were exposed to 0.01 mmol/L H2O2 for 1 h and 10 mg/mL Tartary buckwheat oligopeptides intervention for 48 h, these were the optimal conditions. Compared with the H2O2 group, the intervention group (KB/H2O2 group) showed that the production of ROS was significantly reduced (p < 0.001), the malondialdehyde (MDA) content was significantly decreased (p < 0.05), and the activity of catalase (CAT) was significantly increased (p < 0.01); the mitochondrial membrane potential in the KB/H2O2 group tended to return to the level of the control group, and they all showed dose-dependent effects. Compared with the H2O2 group, the mRNA expression of KEAP1 in the KB/H2O2 group decreased, while the mRNA expression of NRF2α, HO-1, nrf1, PGC-1, P62, and PINK increased. Conclusions: Therefore, Tartary buckwheat oligopeptides have a significant pre-protective effect on H2O2-induced SOL8 cells, possibly by enhancing the activity of superoxide dismutase, reducing ROS attack, balancing mitochondrial membrane potential, and maintaining intracellular homeostasis.

Get ready for short tandem repeats analysis using long reads-the challenges and the state of the art

Short tandem repeats (STRs) are repetitive DNA sequences that contribute to genetic diversity and play a significant role in disease susceptibility. The human genome contains approximately 1.5 million STR loci, collectively covering around 3% of the total sequence. Certain repeat expansions can significantly impact cellular function by altering protein synthesis, impairing DNA repair, and leading to neurodegenerative and neuromuscular diseases. Traditional short-read sequencing struggles to accurately characterize STRs due to its limited read length, which limits the ability to resolve repeat expansions, increases mapping errors, and reduces sensitivity for detecting large insertions or interruptions. This review examines how long-read sequencing technologies, particularly Oxford Nanopore and PacBio, overcome these limitations by enabling direct sequencing of full STR regions with improved accuracy. We discuss challenges in sequencing, bioinformatics workflows, and the latest computational tools for STR detection. Additionally, we highlight the strengths and limitations of different methods, providing deeper insight into the future of STR genotyping.

Molecular Mechanisms of Sepsis-Associated Acute Kidney Injury.

Sepsis-associated acute kidney injury (AKI) is a complex pathological state driven by dynamic interactions between the host and microbes. The rapid progression and the absence of a molecular clock that stages the disease timeline make precise therapeutic interventions highly challenging. In this Review, we aim to refine the timeline of sepsis-associated AKI by dissecting key molecular events that drive disease progression and may inform therapeutic strategies. AKI, initiated by microbes or infection mimicry, involves the rapid and simultaneous activation of inflammatory and anti-inflammatory pathways. This energy-intensive response is further fueled by the loss of distinction between self and non-self, leading to excessive antiviral responses mediated by self-derived nucleic acids. The resulting metabolic burden overwhelms cellular functions, triggering the integrated stress response and profound translation shutdown. While this shutdown response may be necessary for energy preservation and for priming endogenous recovery mechanisms, prolonged inhibition of translation represents a maladaptive feature of septic AKI. Despite these challenges, the kidney exhibits remarkable resilience. Recovery relies on metabolic flexibility and stress-adaptive mechanisms, such as enhanced polyamine biosynthesis and RNA editing. Meanwhile, microbes also demonstrate metabolic adaptability, enabling them to evade host defenses and exploit the host environment. Understanding this dynamic interplay along the timeline of septic AKI is essential for developing rational therapeutic strategies.

Depleting retinoic acid synthesis in the nucleus accumbens shell produces a protective phenotype for emotional reactivity and drug-taking in rats.

In previous work, a convergent transcriptomic approach strongly suggested a role for retinoic acid (RA) in controlling the emotion- and reward-related functions of the nucleus accumbens shell (NAcSh). Here, we causally assess the role of NAcSh RA in controlling anxiety-, emotion-, and reward-related behavior in rats and explore cellular mechanisms that may underlie this phenotype. Rats underwent bilateral knockdown of the retinoic acid synthesis enzyme Aldh1a1 in the NAcSh. Anxiety-related behavior was assessed using open-field exploration, elevated plus maze, and sucrose neophobia tests. Emotion-related behavior was assessed via sucrose preference, post-isolation social contact, and forced swim tests. Animals were subsequently allowed to self-administer fentanyl to assess reward- and frustration-related behavior. In parallel, electrophysiological testing of medium spiny neurons (MSNs) in the NAcSh was used to explore the role of RA in NAcSh cellular function. We observed an anxiety-vulnerable, depression-resilient phenotype in knockdown animals compared to controls. During operant tasks, knockdown animals took fewer fentanyl infusions during FR5 maintenance and showed decreased demand intensity in behavioral economics sessions. Finally, electrophysiological assessment of NAcSh MSNs revealed attenuated excitability following Aldh1a1 knockdown. Altogether, our findings reveal a key role for NAcSh RA signaling in determining emotional resilience and drug-taking, likely via decreased MSN excitability. Our results posit the RA synthesis enzyme Aldh1a1 as a promising therapeutic target for depression-, frustration-, and addiction-associated disorders. This is the first report linking RA to frustrative nonreward, the NAcSh to operant frustration, and RA to fentanyl drug-taking behavior.

G-Protein-Coupled Receptor-Microtubule Interactions Regulate Neurite Development and Protect Against β-Amyloid Neurotoxicity.

G-protein-coupled receptors (GPCRs) regulate multiple cellular functions, including neurite formation and maturation, processes often disrupted in neurodegenerative diseases. Like GPCRs, microtubule-associated proteins (MAPs, including MAP2 and Tuj1) and the synaptic vesicle protein synaptophysin are essential for neurite formation, maturation, and organization, which underpin brain development and cognitive function. Despite their importance, the functional crosstalk between GPCRs and MAPs, particularly in neurogenesis and pathological conditions such as Alzheimer's disease (AD), remains poorly understood. We show that somatostatin and dopamine receptors(SSTR and DR) are the structural anchors in developing neurites, enabling MAP recruitment and synaptic protein localization. Our findings reveal a cAMP-dependent interplay involving PTEN and ERK1/2, modulating neurite formation and MAPs organization. Notably, we show that β-amyloid (Aβ) disrupts the constitutive association of MAP2 and Tuj1, inducing an increase in intracellular cAMP levels, loss of neurite integrity, and impaired neuronal viability. The activation of SSTR and DR signaling restores neurite architecture and synaptic integrity via p-AKT activation and PTEN inhibition, highlighting a neuroprotective mechanism. Together, our results reveal a novel role of GPCRs in orchestrating interactions with MAPs to regulate neuronal maturation, neurite formation, and synaptic integrity. This study provides a new mechanistic rationale for therapeutic strategies aimed at preserving cognitive function in neurological disorders such as AD.

Dorothy Hodgkin lecture 2024: Insulin regulation of mitochondrial biogenesis and function-Impact of dysregulation of mitochondrial function in diabetes and its complications.

Skeletal muscle atrophy was a characteristic of type 1 diabetes (T1DM) prior to insulin discovery and replacement. Indirect calorimetry during the post-absorptive state demonstrated that increased fuel oxidation during transient insulin deprivation in T1DM caused depletion of energy stores. Further, insulin has a critical role in preserving muscle mitochondrial content and function by enhancing mitochondrial biogenesis and proteostasis. Insulin deficiency not only inhibits mitochondrial biogenesis but also accelerates the degradation of mitochondrial proteins, causing a decline in mitochondrial content and efficiency. Inefficient mitochondrial respiration, reflected by the uncoupling of oxidative phosphorylation and consequent decline in ATP production, adversely affects many cellular functions and causes high oxidative stress. Oxidative stress adversely affects cardiovascular functions and damages many skeletal muscle proteins, accelerating their degradation and explaining muscle atrophy. Increased degradation of muscle proteins increases amino acid efflux that stimulates the liver to synthesize many non-insulin-dependent proteins, potentially contributing to macrovascular complications. This phenomenon explains a paradoxical increase in whole-body protein synthesis during insulin deficiency. Further, the mitochondrial biology of brain regions rich in insulin receptors concurrent with accelerated transport of ketones and lactate across the blood-brain barrier during insulin deficiency seems to protect the brain from oxidative stress. In contrast, insulin resistance associated with less ketone and lactate production renders the brain susceptible to protein oxidative damage. Oxidative damage and reduced ATP production potentially explain the higher prevalence of dementia in insulin-resistant people. Enhancement of insulin sensitivity by aerobic exercise and metformin in pre-clinical studies prevents mitochondrial dysfunction and oxidative damage to the brain.

Viscoelastic mechanics of living cells.

Viscoelastic mechanics of living cells.

BQU57 suppresses IL-1β-induced apoptosis and extracellular matrix degradation in nucleus pulposus cells by blocking the NF-κB signaling pathway.

BQU57 suppresses IL-1β-induced apoptosis and extracellular matrix degradation in nucleus pulposus cells by blocking the NF-κB signaling pathway.

Lactate Metabolism and Lactylation Modification: New Opportunities and Challenges in Cardiovascular Disease.

Traditionally regarded as a metabolic waste product, lactic acid is now recognized as a crucial molecule in energy metabolism and signal transduction. It regulates various biological processes, including intracellular inflammation and immune responses. Notably, a novel epigenetic modification, lactylation, which is directly linked to lactic acid, was first identified by Professor Zhao Yingming's team in 2019. Lactylation influences gene expression and is associated with inflammation, cancer, and ischemic disease. Despite its potential significance, the precise mechanisms by which lactylation regulates gene expression remain unclear, and its implications in cardiovascular diseases are not yet fully understood. This review elucidates the relationship between lactic acid metabolism and cellular functions, highlighting its significant biological roles. This review provides a comprehensive analysis of the mechanistic role of lactylation in disease progression. It synthesizes research findings and emerging trends concerning lactic acid production and lactylation in the context of cardiovascular diseases. We explored potential therapeutic agents targeting lactylation and identified prospective treatment targets, offering novel insights into and directions for intervention strategies related to lactic acid production and lactylation. Ultimately, this review aims to pave the way for new therapeutic and research avenues in cardiovascular diseases.

Investigating the multifaceted role of nucleolin in cellular function and Cancer: Structure, Regulation, and therapeutic implications.

Investigating the multifaceted role of nucleolin in cellular function and Cancer: Structure, Regulation, and therapeutic implications.

The ER-associated degradation adaptor SEL1L is dispensable for ER homeostasis and the differentiation of spermatogenic cells.

The ER-associated degradation adaptor SEL1L is dispensable for ER homeostasis and the differentiation of spermatogenic cells.

Structural-functional relevance of DNAJBs in protein aggregation and associated neurodegenerative diseases.

Structural-functional relevance of DNAJBs in protein aggregation and associated neurodegenerative diseases.

A novel 68Ga-labeled cyclic peptide: A potential radiotracer for PET imaging of CD36-positive cancers.

A novel 68Ga-labeled cyclic peptide: A potential radiotracer for PET imaging of CD36-positive cancers.

Evaluating Protein Extraction Techniques for Elucidating Proteomic Changes in Yeast Deletion Strains

Background: Alterations in protein abundance profiles in yeast deletion strains are frequently utilized to gain insights into cellular functions and regulatory networks, most of which are conserved in higher eukaryotes. Methods: This study investigates the impact of protein extraction methodologies on the whole proteome analysis of S. cerevisiae, comparing detergent-based lysis versus mechanical lysis with silica beads. We evaluated the proteomic profiles of wild-type and two yeast deletion strains, siz1Δ and nfi1Δ (siz2Δ), which are SUMO E3 ligases. Combining isobaric TMTpro-labeling with mass spectrometry using real-time search MS3, we profiled over 4700 proteins, covering approximately 80% of the yeast proteome. Results: Hierarchical clustering and principal component analyses revealed that the choice of protein extraction method significantly influenced the proteomic data, overshadowing the genetic variances among these strains. Notably, the detergent-based lysis showed superior performance in extracting proteins compared to mechanical lysis. Despite minimal proteomic alterations among strains, we observed consistent changes regardless of the lysis strategy in proteins such as Ino1, Rep1, Rep2, Snz1, and Fdh1 in both SUMO E3 ligase deletion strains, implying potential redundant mechanisms of control for these proteins. Conclusion: These findings underscore the importance of method selection at each step of sample preparation in proteomic studies and enhance our comprehension of cellular adaptations to genetic perturbations.

Role of MMP-9 and NF-κB in Diabetic Retinopathy: Progression and Potential Role of Bioflavonoids in the Mitigation of Diabetic Retinopathy.

"Diabetes mellitus" is a chronic metabolic disorder manifested by elevated blood glucose levels, primarily due to insufficient insulin production or resistance to insulin. Long-term diabetes results in persistent complications like retinopathy, cardiomyopathy, nephropathy, and neuropathy, causing significant health risks. The most alarming microvascular consequence allied with diabetes is "diabetic retinopathy," distinguished by the proliferation of anomalous blood vessels in the eye, mainly in the retina, resulting in visual impairment, diabetic macular edema, and retinal detachment if left untreated. According to estimates, 27.0% of people with diabetes worldwide have retinopathy, which leads to 0.4 million blindness cases. It is believed that mitochondrial damage and the production of inflammatory mediators are the early indicators of diabetic retinopathy before any histological changes occur in the retina. Moreover, it is evident that augmented oxidative stress in the retina further initiates the NF-κB/MMP-9 downstream signaling pathway. Interestingly, these downstream regulators, Nuclear Factor Kappa B [NF- kB] and matrix metalloproteinases 9 [MMP-9], have been recognized as important regulators of the inception and advancement of diabetic retinopathy. This diabetes and oxidative stress-induced MMP-9 are believed to regulate various cellular functions, including angiogenesis and apoptosis, causing blood-retinal barrier breakdown and tight junction protein degradation that further leads to diabetic retinopathy. Thus, there is an emergency need for the treatment of diabetic retinopathy. Emerging treatment options include anti-VEGF, laser treatment, and eye surgery, but these have certain limitations. This comprehensive review explores the mechanisms of MMP-9 and NF-kB involvement in diabetic retinopathy and bioflavonoids' therapeutic potential and mechanisms of action in inhibiting MMP-9 activity and suppressing NF-kB-mediated inflammation. Clinical evidence supporting the use of bioflavonoids in mitigating diabetic complications and future perspectives are also examined.

RNA-binding proteins as key regulators in pulmonary diseases: A review.

RNA-binding proteins as key regulators in pulmonary diseases: A review.

Quinolinone Derivatives Suppress Angiogenesis in Human Umbilical Vein Endothelial Cells by Blocking the VEGF-Induced VEGFR2 Signaling Pathway.

Targeting the vascular endothelial growth factor (VEGF) pathway is crucial for antiangiogenesis therapy in treating cancers and diseases with abnormal blood vessel growth. Human umbilical vein endothelial cells (HUVECs) activated by VEGF are widely used for exploring the impact of antiangiogenic agents on cellular functions. In this study, seven quinolinone derivatives were successfully synthesized and structurally confirmed through 1H, 13C NMR, and HRMS spectra. Compounds 4 and 5 exhibited significant inhibition of VEGF-induced HUVEC proliferation, with IC50 values of 84.8 and 58.1 μM for 48 h. Compounds 3‒6 effectively suppressed VEGF-induced HUVEC migration and invasion, demonstrating potent inhibitory effects in the Matrigel tube formation assay. Compounds 4 and 5 directly bind to vascular endothelial growth factor receptor 2 (VEGFR2), thereby inhibiting VEGFR2-mediated downstream angiogenic signaling pathways (PI3K/Akt, ERK1/2/p38 MAPK, and FAK). Cell-cycle analysis revealed that compounds 4 and 5 induced substantial G2/M phase arrest in HUVECs, accompanied by increased p53 phosphorylation and upregulation of p21cip1 expression. Compounds 3‒6 also induced apoptosis in HUVECs, as evidenced by nuclear condensation, DNA laddering, and increased Annexin V/PI staining. Western blot analysis showed that compounds 4 and 5 significantly increased the levels of apoptosis-related proteins, particularly cleaved caspase-3 and PARP. Through in vivo experiments utilizing the chicken embryo chorioallantoic membrane (CAM) assay, a marked decline in newly formed microvessels was observed posttreatment with both compounds. These results suggest that compounds 4 and 5 show promise as antiangiogenic agents, warranting further investigation into their therapeutic efficacy in conditions characterized by abnormal angiogenesis.