Cell Biochemistry and Function最新文献

Gestational diabetes mellitus (GDM) is a major pregnancy complication that adversely affects fetal development. Emerging evidence implicates inflammation and oxidative stress in its pathogenesis, highlighting the need for in-depth mechanistic insights. Aged garlic extract (AGE) and its active compound, S-allyl-L-cysteine (SAC), possess anti-inflammatory, antioxidant, and antidiabetic properties in type I and II diabetes; however, their therapeutic potential in GDM remains unknown. This study developed a rat model of GDM (n = 40) by administering a high-fat diet before and during pregnancy, inducing GDM with Nicotinamide, and inducing chronic stress. Glycemic parameters, insulin signaling genes (IRS-2, AKT-1, and PCK-1), glucose transporters (GLUT-2 and GLUT-4), proinflammatory cytokines, and antioxidants were assessed on gestational day 5. GDM-induced rats (n = 6 in each group) received different treatments, including SAC, insulin, and their combination. On day 15, significant therapeutic benefits were observed in the SAC + insulin group. The model effectively mimics human GDM by demonstrating insulin resistance and dysregulated signaling pathways. SAC treatment reduced inflammation and oxidative stress and restored insulin signaling. GDM involves inflammatory cascades and insulin signaling dysregulation, whereas SAC, particularly in combination with insulin, shows promise as a therapeutic intervention for GDM. These findings provide valuable insights for future research and the development of novel GDM treatment strategies.

Sarcopenia is an age-associated skeletal muscle disorder characterized by progressive declines in muscle mass, strength, and functional performance. A central feature of sarcopenic remodeling is the preferential loss of fast-twitch (Type II) fibers and alterations in contractile protein composition, leading to reduced force generation and impaired muscle quality. Maintenance of skeletal muscle function depends on the integrity of the contractile apparatus, including myosin heavy chain isoforms, titin, actin, troponin, and associated structural proteins, which undergo quantitative and qualitative changes with aging. Multiple aging-related mechanisms including telomere attrition, epigenetic remodeling, mitochondrial dysfunction, ionic dyshomeostasis, hormonal alterations, and chronic low-grade inflammation converge on fiber-type regulation and sarcomeric stability. These upstream processes impair satellite cell renewal, disrupt excitation-contraction coupling, accelerate proteolysis of contractile proteins, and promote maladaptive fiber-type transitions. Ankyrins and muscle ankyrin repeat proteins (MARPs) further modulate sarcomere organization, mechanotransduction, and adaptive stress signaling. Age-related dysregulation of ankyrin-contractile protein interactions compromises structural stability and regenerative capacity, contributing to muscle weakness and frailty. Viewing sarcopenia through the integrated framework of fiber-type plasticity, contractile protein dynamics, and ankyrin-mediated regulation provides a unifying mechanistic perspective that links systemic aging processes to structural muscle decline. This approach highlights potential biomarkers and therapeutic targets for preserving muscle function in aging populations.

The ~12-h ultradian rhythm (circasemidian) represents an evolutionarily conserved temporal architecture that complements the canonical 24-h circadian clock. Over the past 5 years, mounting evidence has revealed its ubiquity across biological kingdoms, from tidal marine organisms and cyanobacteria to plants, microbiomes, and mammals, including humans, manifesting as intrinsic oscillations in gene expression, metabolism, and behavior that often persist independently of circadian control. In mammals, this rhythm is driven by a cell-autonomous oscillator centered on the XBP1s (X-box binding protein 1)/IRE1α (Inositol requiring enzyme 1 alpha) axis, orchestrating endoplasmic reticulum stress responses and lipid homeostasis through negative feedback regulation, further reinforced by metabolic coupling and bidirectional crosstalk with circadian pathways. Functionally, 12-h oscillations act as a secondary temporal layer that ensures bimodal photostatic and energetic homeostasis, synchronizing multi-organ physiology across the day-night transition. Pathologically, disruption of this rhythm contributes to metabolic syndromes (e.g., NAFLD (non-alcoholic fatty liver disease), diabetes), neuropsychiatric disorders (e.g., schizophrenia), and age-related dysfunctions, particularly within ocular and immune systems. Despite accumulating correlative and model-based evidence, causal mechanisms remain insufficiently defined, and human data are limited. Future work integrating multi-omics chrono profiling, comparative genomics, and clinical chronotherapeutic trials will be critical to delineate this semidiurnal oscillator's molecular architecture and translational potential, thereby advancing precision chrono medicine and expanding the current paradigm of biological timing.

Nitric oxide (NO) is an important signaling molecule in maintaining normal physiological processes like blood flow, neurotransmission and immune regulation. In cancer, it exhibits a dual role in context-dependent mechanism. At low levels, it activates angiogenesis, migration and tumor promotion; on the other hand, with an increase in concentration, it promotes apoptosis and has an anti-metastatic effect. Hence, regulated levels of NO are required to maintain normal hemostasis. NO has temporal and spatial regulation as its pro- and anti-metastatic effects are decided by the tumor stage, tumor microenvironment, and nitric oxide synthase isoforms expression. NO regulates EMT markers like upregulation of Snail, Twist, and ZEB1 (pro-EMT factors and downregulation of E-cadherin. NO also regulates the crosstalk between signaling factors, such as TGF-β, Wnt/β-catenin and NF-κB; during EMT and hypoxia-induced angiogenesis. NO promotes immunosuppression and metastasis by interacting with tumor-associated macrophages and myeloid-derived suppressor cells, which express iNOS. NO activates cancer promotion pathways like NF-κB, upregulates pro-metastatic genes (MMPs, cytokines), PI3K/Akt/mTOR and p53/Nrf2, along with regulating non-coding RNAs. Thus, NO is a potential target in cancer therapeutics and reviews focus on the new advancements using NO as a potential biomarker and therapeutic agent.

Colon cancer remains a leading global health challenge driven by substantial molecular heterogeneity, complex carcinogenic pathways, and the persistent emergence of therapeutic resistance. This review provides a comprehensive and integrative synthesis of contemporary treatment strategies spanning conventional chemotherapy, molecularly targeted agents, and immunotherapy while contextualizing them within the biological mechanisms that shape therapeutic response. We dissect the mechanistic underpinnings and clinical performance of foundational regimens such as FOLFOX, FOLFIRI, and CAPOX, and analyze how key driver alterations, including RAS/RAF mutations, HER2 amplification, MSI/MMR status, and VEGF-mediated angiogenesis, influence disease progression and therapeutic selection. In addition, we analyze shared resistance pathways and the mechanistic rationale supporting rational combination strategies, including BRAF/EGFR/MEK blockade, HER2-directed dual targeting, and PD-1/PD-L1-based combinations aimed at overcoming immune exclusion in MSS tumors. Emerging advances such as KRAS G12C inhibitors, multi-kinase angiogenesis modulators, antibody-drug conjugates, ribosome biogenesis inhibitors, AI-guided therapeutic algorithms, and ctDNA-based monitoring are also discussed. By integrating mechanistic insights with clinical evidence, this review offers a structured framework to better understand current treatment paradigms and future directions in biomarker-driven precision therapy for colon cancer.

The interaction of cellular organelles is crucial for maintaining intracellular homeostasis, particularly highlighting the impact of the cytoskeleton on mitochondrial dynamics. The aim of our study is to find direct molecular connections between cytoskeletal disturbance and mitochondrial failure which are inadequately characterized particularly in B-ALL. We investigated the effects of cytoskeleton inhibition on mitochondria in B-ALL using Pironetin (an alpha-tubulin inhibitor) and Latrunculin B (an actin inhibitor). Our findings indicate that these inhibitors caused mitochondrial fragmentation, characterized by smaller, rounder mitochondria with disordered cristae, increased Drp1 expression (fission protein), and decreased Mfn 1/2 and OPA 1 (fusion proteins) together with significantly modified the expression of essential mitochondrial transporters, such as VDAC and ANT2. These alterations were linked to increased mitochondrial membrane depolarization & mitochondrial reactive oxygen species and gradual mtDNA depletion, indicative of impaired oxidative phosphorylation (increased non-mitochondrial oxygen consumption, decreased mitochondrial reserve capacity) and diminished mitochondrial functionality. These mitochondrial alterations indicate that communication between the cytoskeleton and mitochondria is essential for preserving mitochondrial homeostasis. This study potentially enhances our understanding of how cancer cells modulate mitochondrial function during progression or therapeutic interventions.

Posthemorrhagic hydrocephalus is a severe complication to intraventricular hemorrhage. The condition results in enlarged brain ventricles and increased intracranial pressure due to accumulation of cerebrospinal fluid (CSF). In this study, two mouse models of intraventricular hemorrhage were investigated: injection of lysed red blood cells (LRBC) and injection of autologous full blood. CSF secretion and ventricular volume were assessed using ventriculo-cisternal perfusion and magnetic resonance imaging (MRI), while molecular and biochemical responses were analyzed by immunoblotting, RT-qPCR, flame photometry, and blood-gas measurements. LRBC injection induced a transient change in choroid plexus bicarbonate transporter expression, as the protein-abundance of Ncbe, a basolateral sodium-bicarbonate transporter, was reduced by 23% after 24 h but increased by 17% after 48 h. Injection with full blood transiently increased mRNA levels of the basolateral sodium-bicarbonate transporter NBCn1 and Ncbe without altering protein expression. The luminal electrogenic sodium: bicarbonate transporter, NBCe2, was unaffected both at the RNA and protein level. Both models were validated using ventriculo-cisternal perfusion demonstrating an increase in CSF volume by 70% in the IVH model after 24 h and 73% in the LRBC model after 3 days. No effect on secretion rate of CSF was detected. Additionally, in the LRBC model MRI was used to assess the time-course of brain ventricle size following hemorrhage. Here, an overall volume increase of 30% was found in the hemorrhage-induced mice compared to the control. These results demonstrate that both LRBC and full-blood injections can induce ventricular enlargement in mice, but through different molecular responses. Neither model reproduced sustained CSF hypersecretion, underscoring that murine models of intraventricular hemorrhage display a milder form of pathophysiology compared to e.g. rats.

This study aimed to investigate the effects of amitriptyline administration on the salivary glands and saliva of rats. Twenty-eight male Wistar rats (60 days old) were divided into two groups (n = 14 per group): control and amitriptyline-treated (10 mg/kg/day for 30 days). After the treatment period, saliva samples induced by pilocarpine were collected to analyze total protein concentration, amylase activity, and antioxidant capacity, while salivary glands were harvested for assessments of oxidative stress markers and morphological changes. Amitriptyline increased total protein and decreased amylase activity in saliva, with no change in the Trolox-equivalent antioxidant capacity (TEAC). The drug triggered oxidative stress in both glands by the decrease in TEAC concentration and increased lipid peroxidation. Morphometric analysis showed that amitriptyline increased the total area of stroma and decreased the ductal area in both glands. In the submandibular gland, acinar area was reduced as well. These findings suggest that amitriptyline-salivary gland dysfunction is associated with oxidative imbalance, morphometric, and alterations in saliva composition, contributing to a broader understanding of amitriptyline's adverse effects.

The development and progression of cardiovascular diseases (CVDs) are closely linked to an imbalance in endoplasmic reticulum homeostasis. UFMylation, a recently identified ubiquitin-like post-translational modification, plays a crucial role in maintaining cellular homeostasis by regulating substrate protein functions through a unique enzymatic cascade. Accumulating evidence has demonstrated that UFMylation exerts complex regulatory effects on the pathogenesis of atherosclerosis, primarily by modulating endothelial function, macrophage foam cell formation, and inflammasome activation. Furthermore, UFMylation of the calcium-regulating protein SPCA1 disrupts calcium homeostasis in hypertrophic cardiomyopathy. Conversely, UFMylation also exhibits protective roles; for instance, it prevents pathological cardiac remodeling in heart failure by maintaining endoplasmic reticulum function via its E3 ligase, UFL1. Accordingly, this review systematically summarizes these multifaceted protective mechanisms of UFMylation in CVDs. We also explore potential therapeutic strategies targeting UFMylation, discussing its promise as a CVD biomarker and the opportunities and challenges in developing UFMylation agonists. In-depth research in this field is expected to provide novel theoretical foundations and precise intervention targets for the prevention and treatment of CVDs.