Antiretroviral therapy (ART) effectively suppresses HIV-1 replication but does not purge the latent HIV-1 reservoir. Strategies aimed at HIV-1 latency reversal and subsequent elimination of infected cells are being explored. Targeting the inhibitor of apoptosis proteins (IAP) and DEAD-box polypeptide 3 (DDX3) RNA helicase reduces the HIV-1 reservoir ex vivo. However, the mechanisms driving apoptosis of HIV-1 infected cells remain unclear. Here, we uncovered the mechanism regarding HIV-1 transcriptional activation and induction of apoptosis specific for HIV-1 infected cells using an acute in vitro infection model. Inhibition of IAP by second mitochondrial-derived activator of caspases mimetic (SMACm; AZD5582) resulted in activation of non-canonical NF-κB pathway (RelB/p52) that induced HIV-1 transcription, confirming previous reports, whereas inhibition of DDX3 sensitized HIV-1 infected cells for apoptosis (DDX3i; FH1321). Transcriptome analysis revealed that HIV-1 actively suppressed apoptosis-related genes in HIV-1 infected cells. SMACm treatment resulted in a broad induction of these genes irrespective of infection. Notably, DDX3 inhibition specifically restored the expression of the majority of HIV-1 suppressed genes, and when combined with SMACm, restored almost all HIV-1 downregulated genes, thereby rendering HIV-1 infected cells sensitive to apoptosis. Thus, our data strongly suggest that inhibition of host factors IAP and DDX3 not only induces activation of HIV-1 transcription but also restores HIV-1 suppressed apoptotic processes in infected cells.
Depression is increasingly linked to microbiota-gut-brain axis dysfunction, yet current monoaminergic antidepressants show limited efficacy. This study investigated the therapeutic potential and underlying mechanisms of GV-971, a marine-derived oligosaccharide, in a chronic restraint stress (CRS) mouse model. We first established that 8 h of daily restraint for 4-8 weeks induces a stable depression-like phenotype characterized by behavioral despair and significant reduction in peripheral monoamine neurotransmitters (5-HT and norepinephrine). GV-971 treatment robustly attenuated CRS-induced depression- and anxiety-like behaviors, restored hippocampal serotonin levels, reduced elevated plasma corticosterone concentrations, and ameliorated CRS-induced adrenal cortical hyperplasia. Mechanistically, GV-971 significantly suppressed neuroinflammation by inhibiting microglial hyperactivation in the prefrontal cortex and hippocampus. Concurrently, it repaired intestinal barrier dysfunction, evidenced by reduced permeability, restored mucosal integrity, and recovered goblet cell numbers. Crucially, integrated shot-gun metagenomics and plasma metabolomics revealed that GV-971 not only reshaped microbial taxonomy but also functionally recalibrated the gut ecosystem. It enriched beneficial taxa (e.g., Bifidobacterium pseudolongum, Bacteroides uniformis) and specific metabolic pathways, leading to increased short-chain fatty acids (valeric and caproic acids) and a significant reduction in plasma levels of tryptophan-kynurenine pathway metabolites, specifically the neurotoxic compounds kynurenine and quinolinic acid. Fecal microbiota transplantation (FMT) from GV-971-treated donors partially recapitulated the antidepressant and gut-protective effects in CRS recipients, confirming a causal role for the remodeled microbiota. Collectively, GV-971 exerts antidepressant effects by coordinately remodeling the gut microbiota, normalizing tryptophan and SCFA metabolism, restoring gut barrier integrity, and dampening central neuroinflammation, supporting its potential as a novel gut-brain axis-targeted therapy for depression.
The intestinal barrier-protective efficacy of quercetin (Que) is limited by its poor gastrointestinal stability and insufficient bioaccessibility. To overcome this, we engineered a dual-fibril gel delivery system for Que, termed QTC, through the assembly of tiger-nut protein fibrils and carboxylated cellulose nanofibrils. In the DSS-induced intestinal barrier injury mouse model, QTC outperformed free Que in preserving intestinal mucosal architecture and mitigating epithelial damage. It markedly restored intestinal barrier integrity, reflected by the upregulation of tight-junction proteins and reduced intestinal permeability. Furthermore, QTC effectively suppressed inflammatory responses and oxidative stress, thereby maintaining barrier homeostasis. Notably, QTC intervention positively modulated the gut microbiota, enriching for beneficial genera and boosting short-chain fatty acid production. Collectively, our findings demonstrate that the novel QTC gel significantly amplified the intestinal barrier-protective effects of Que. This study provides an effective food-grade delivery strategy to enhance the efficacy of polyphenols for gut health management.
Metabolic reprogramming within the tumor microenvironment (TME) limits the efficacy of chemo-immunotherapy in triple-negative breast cancer (TNBC). Despite advances in high-resolution profiling, the specific intercellular metabolic crosstalk driving immune evasion remains incompletely understood. Here, we present a comprehensive single-cell metabolic atlas of the TNBC ecosystem to decode spatial and cell-type-specific metabolic vulnerabilities. Our multidimensional analysis reveals a distinct paracrine metabolic communication axis: CXCL9+ macrophages upregulate rate-limiting enzymes (IDO1/2) to become a potential source of local kynurenine, which is subsequently imported by cytotoxic T cells. Through in vitro co-culture and in vivo models, we demonstrate that this kynurenine uptake triggers impaired effector function and phenotypic exhaustion. Crucially, pharmacological blockade of SLC7A5 with the specific inhibitor JPH203 abrogates this metabolic toxicity, restores T cell effector function, and enhances the anti-tumor efficacy of combined cisplatin and anti-PD-1 therapy. Collectively, our findings delineate the Kynurenine-SLC7A5 metabolic axis as a critical driver of immunosuppression, providing a compelling rationale for integrating amino acid transport blockade to overcome resistance to chemo-immunotherapy.
Chronic respiratory diseases (CRDs) represent a significant global mortality burden, largely driven by viral-triggered exacerbations. In the elderly, susceptibility to viral pathogens is critically linked to the "interferon gap"-a kinetic delay in innate antiviral signaling resulting from immunosenescence and Th2-skewed inflammaging. While traditional vaccines provide pathogen-specific protection, their efficacy is often compromised by age-related immune hyporesponsiveness and antigenic drift. This perspective paper proposes a dual-phase, virus-agnostic immunomodulatory platform designed to restore mucosal immune competence and provide a rapid-response intervention for incipient exacerbations. Rather than acting as a pathogen-specific vaccine, the platform serves as a comprehensive host immune-rejuvenation engine and cellular adjuvant platform. The platform consists of two integrated stages: Allopriming and Alloantigen Inhalation Recall (AIR). Allopriming utilizes AlloStim® (activated, allogeneic Th1 cells) to leverage the evolutionarily conserved allo-rejection response, establishing a lung mucosal reservoir of allo-specific Th1 tissue-resident memory cells (Trm). Building on previously published Phase I/II data showing that Allopriming reverses biomarkers of immunosenescence and sustains durable heterologous antiviral responsiveness, the AIR strategy is introduced as a patient-administered rescue mechanism for frail CRD patients. AIR is designed to activate pre-positioned Trm cells at the earliest onset of symptoms, inducing a high-magnitude IFN-γ surge in the lung mucosa. By bridging the senescent "interferon gap" with the rapid effector kinetics of Trm activation, this approach represents a novel paradigm toward reconstituting youthful-like antiviral mucosal immunity to both enhance vaccine efficacy in the elderly and protect against both seasonal pathogens and emerging viral triggers ("Disease X") of CRD. Future randomized studies in long-term care settings are planned to evaluate clinical outcomes in high-risk populations.
Uveitis is a heterogeneous group of intraocular inflammatory diseases and an important cause of visual impairment worldwide. Although current treatments mainly target inflammation, many patients develop chronic or recurrent disease, suggesting that inflammation control alone may not fully restore intraocular homeostasis. Increasing evidence highlights the blood-ocular barrier (BOB), including the blood-retinal barrier and blood-aqueous barrier, as a key regulator of the intraocular microenvironment. This review aims to summarize the bidirectional interaction between intraocular inflammation and blood-ocular barrier dysfunction in uveitis, and to highlight the clinical significance of barrier dysfunction in disease monitoring and management. In addition, this review discusses the potential value of incorporating barrier assessment into dynamic disease evaluation and relapse-aware management strategies. Recent studies suggest that inflammation and BOB dysfunction are bidirectionally linked. Inflammatory mediators disrupt barrier integrity, while barrier breakdown facilitates immune cell infiltration and further amplifies inflammation, forming a self-reinforcing cycle that may drive disease persistence. Importantly, BOB dysfunction also has clinical implications. Findings such as aqueous flare, macular edema on optical coherence tomography, and vascular leakage on fluorescein angiography reflect barrier status and can serve as dynamic indicators for disease monitoring. Persistent abnormalities despite reduced inflammatory cell activity may indicate incomplete barrier recovery or subclinical inflammation, helping to explain discordant clinical findings and the relapse-prone nature of uveitis. Rather than viewing BOB dysfunction solely as a pathological consequence of inflammation, this review highlights the potential clinical value in disease assessment and management. Barrier-related findings may provide additional information beyond conventional inflammatory evaluation, particularly in cases where inflammatory cell activity appears controlled, but underlying barrier alteration persists. Incorporating barrier assessment into monitoring may help interpret discordant clinical findings, improve evaluation of disease control, and support a more relapse-aware management strategy in uveitis. In addition, therapeutic approaches aimed at restoring barrier integrity may provide a more comprehensive strategy for achieving sustained remission and reducing recurrence risk.
Previous studies conducted in our laboratory have demonstrated that dietary supplementation with Bacillus coagulans BC66 (BC66) can mitigate intestinal, renal, and hepatic injuries induced by Klebsiella pneumoniae in rabbits. However, the potential of Bacillus coagulans BC66 in protecting against Klebsiella pneumoniae- induced acute lung injury remains unexplored. Therefore, the present study aimed to investigate the protective mechanism of Bacillus coagulans BC66 against acute lung injury induced by Klebsiella pneumoniae in rabbits using histological examination (hematoxylin and eosin staining, HE staining), immunofluorescence, immunohistochemistry and Western blotting. Dietary supplementation with Bacillus coagulans BC66 alleviated acute lung injury in rabbits by reducing inflammatory cell infiltration, alleviating alveolar wall thickening, and minimizing alveolar lumen narrowing. Additionally, BC66 enhanced the pulmonary barrier by upregulating proliferating cell nuclear antigen (PCNA) expression and modulating the levels of tight junction proteins, including Occludin, Claudin-1, and ZO-1. Importantly, BC66 restored T helper 17/regulatory T cell (Th17/Treg) immune balance, which was identified as the central mechanism underlying its protective effects. This immune modulation was associated with reduced production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), and contributed to the improvement of pulmonary barrier integrity. Furthermore, the regulation of Th17/Treg balance was accompanied by downstream attenuation of oxidative stress and ferroptosis, as evidenced by increased activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), decreased malondialdehyde (MDA) levels, and modulation of ferroptosis-related proteins, including solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), partly through activation of the Keap1/Nrf2/HO-1 pathway.In conclusion, this study demonstrates that Bacillus coagulans BC66 protects against Klebsiella pneumoniae-induced acute lung injury primarily through restoring Th17/Treg immune balance, with subsequent downstream effects on inflammation, epithelial barrier function, oxidative stress, and ferroptosis. Notably, pretreatment with 1 × 10⁶ colony-forming units per gram (CFU/g) was the most effective. These findings provide a theoretical basis for using Bacillus coagulans BC66 as a preventive agent against acute lung injury induced by Klebsiella pneumoniae in rabbits.
Quadriceps muscle and tendon injuries are a significant cause of impairment of the knee extensor mechanism, ranging from minor muscle strains to complete tendon ruptures and extensive defects following oncologic resections. This narrative review provides a comprehensive analysis of contemporary concepts in anatomy, biomechanics, diagnosis, surgical management, and rehabilitation, with a particular focus on reconstructive techniques and functional outcomes. While most muscle injuries respond well to conservative management, complete quadriceps tendon ruptures typically require surgical repair to restore extensor continuity. Both transosseous suture techniques and suture anchor fixation demonstrate reliable outcomes, with no clear superiority in clinical results. Chronic ruptures present additional challenges due to tendon retraction and poor tissue quality, often necessitating advanced reconstruction methods such as V-Y tendon lengthening and augmentation with autografts, allografts, or synthetic materials. In cases of large defects, especially following soft-tissue sarcoma resection, free functional muscle transfer (FFMT) has emerged as a key reconstructive strategy. Common donor muscles include the latissimus dorsi, gracilis, rectus abdominis, and vastus lateralis, each offering specific biomechanical advantages. Functional recovery is strongly influenced by the extent of quadriceps preservation, with better outcomes observed when at least two muscle heads remain functional. Rehabilitation protocols vary depending on the surgical approach. Early controlled mobilisation is generally recommended after tendon repair, whereas FFMT requires a more cautious and prolonged rehabilitation process to allow for flap integration and reinnervation. Overall, optimal outcomes depend on a multidisciplinary approach combining appropriate surgical technique, individualized rehabilitation, and careful patient selection.
The human facial skin microbiome is a complex and dynamic ecosystem that plays a central role in maintaining skin health, immune regulation, and preventing dermatological skin conditions. Cutibacterium acnes (C. acnes) and Staphylococcus epidermidis (S. epidermidis) are the most prominent bacterial species, with shifts in their relative abundance correlating with skin site, age, skin site, and health status. Exploring the facial microbiome offers exciting opportunities, though it requires careful methodological consideration. Sampling techniques vary in invasiveness and depth, which can influence the accuracy and reproducibility of microbiome profiles. While traditional cultivation methods provide valuable insights, they often miss nonculturable microbes, limiting the view of microbial diversity. Molecular approaches such as amplicon sequencing and metagenomics enable a more comprehensive understanding of microbial communities, even though they currently cannot distinguish between viable and nonviable microbes. Addressing these challenges will help unlock the full potential of facial microbiome research. A balanced facial skin microbiome is associated with healthy skin, whereas a dysbiosis of C. acnes and S. epidermidis is commonly observed in acne-prone skin and more pronounced clinically manifest acne. A comprehensive understanding of the diversity and distribution of C. acnes phylotypes, as well as distinct lineages of S. epidermidis associated with skin disorders, is crucial for developing targeted, microbiome-based cosmetic and medical treatments. Emerging strategies aim to restore microbial balance by leveraging the skin's native microbiota, including probiotic approaches. These strategies represent a promising yet still emerging approach, as current clinical evidence remains limited and further well-controlled studies are required, although they may offer benefits by enhancing microbial diversity and supporting skin barrier function.
The present study was conducted to evaluate the hepatoprotective potential of Strobilanthes callosa using a well-established rat model of experimentally induced liver injury. The investigation assessed biochemical, hematological, oxidative stress, and histopathological parameters to determine the protective efficacy of the plant extract. Body weight was recorded at the beginning and end of the treatment period, while liver weight was measured after sacrifice to evaluate physiological changes associated with hepatic injury. Serum biochemical markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), bilirubin, albumin, and triglycerides, were analyzed using standardized enzymatic assay kits. Treatment with S. callosa significantly reduced serum ALT, AST, and ALP levels respectively, compared with the toxic control group (p < 0.05), indicating improved liver function. Bilirubin levels were significantly decreased, whereas albumin levels were restored toward normal values following treatment. Oxidative stress biomarkers revealed a significant reduction in malondialdehyde (MDA) levels by along with increased antioxidant defense through restoration of catalase and glutathione levels respectively (p < 0.05). Hematological parameters, including hemoglobin (Hb), red blood cell (RBC), white blood cell (WBC) counts, packed cell volume (PCV), and differential leukocyte count, were evaluated to assess systemic toxicity, inflammatory response, and general physiological status. Histopathological examination of liver tissues using hematoxylin and eosin staining demonstrated marked improvement in hepatic architecture, with reduced necrosis, fatty degeneration, inflammatory infiltration, and tissue disorganization in treated groups compared with toxin-treated animals. Statistical analysis was performed using GraphPad Prism 8.0, with results expressed as mean ± SD. Data were analyzed using one-way and two-way ANOVA followed by appropriate post hoc tests, and differences were considered statistically significant at p < 0.05.
Myocardial ischemia-reperfusion (I/R) injury is a frequent complication of acute myocardial infarction (AMI), yet clinical biomarkers and targets remain limited. Although tRNA-derived small RNAs (tsRNAs) are emerging cardiovascular regulators, their roles in I/R injury are not fully elucidated. We identified tsRNA-3025a via sequencing in mouse I/R models and validated its clinical significance. Circulating tsRNA-3025a was significantly upregulated in AMI and unstable angina patients, independently predicting adverse events within 30 days. Functionally, tsRNA-3025a exacerbated apoptosis and mitochondrial dysfunction in vitro, while its in vivo silencing reduced infarct size, improved cardiac function and increased the proportion of Ki67- and pH3-positive cardiomyocytes. Mechanistically, tsRNA-3025a aggravated injury by targeting PIK3C2A, thereby suppressing autophagosome formation and impairing protective autophagic flux during reperfusion. In conclusion, circulating tsRNA-3025a serves as a prognostic biomarker for post-PCI patients. Targeting tsRNA-3025a attenuates myocardial I/R injury and restores myocardial regeneration and repair by regulating PIK3C2A-mediated protective autophagy flux.
Oxidative stress plays a central role in the pathophysiology of type 2 diabetes and contributes to multiorgan dysfunction. Non-pharmacological strategies targeting redox imbalance may provide complementary benefits beyond glycemic control. This study investigated the effects of combined respiratory muscle training (RMT) and photobiomodulation (PBM) on systemic and tissue-specific redox homeostasis in an experimental model of type 2 diabetes. Male rats were allocated into four groups: sedentary Sham (non-diabetic), Sham submitted to RMT combined with PBM, sedentary type 2 diabetes, and type 2 diabetes submitted to the RMT/PBM protocol. Type 2 diabetes was induced by a high-fat diet associated with low-dose streptozotocin. Interventions were performed five days per week for six weeks. Hematological and biochemical parameters were evaluated. Oxidative stress was assessed by lipid peroxidation (thiobarbituric acid reactive substances) and reactive oxygen species production (dichlorofluorescein), while antioxidant defenses were determined by superoxide dismutase activity and non-protein thiol levels in plasma and multiple tissues. In diabetic rats, the combined RMT/PBM protocol increased mean corpuscular hemoglobin concentration, reduced leukocyte and monocyte counts, and restored plasma protein levels. Oxidative damage was attenuated in plasma, diaphragm, lungs, and kidneys, while antioxidant defenses were enhanced, particularly in the diaphragm, heart, and kidneys. In normoglycemic rats, RMT/PBM also enhanced tissue antioxidant capacity, indicating preserved redox responsiveness. Combined RMT and PBM promote systemic and tissue-specific redox adaptations and improve hematological and biochemical parameters in diabetic rats. These findings support the potential of this combined intervention as a non-pharmacological strategy to mitigate oxidative dysfunction associated with type 2 diabetes.
The continuous expression of HPV oncogenes E6 and E7 contributes to the maintenance of the cervical cancer (CC) phenotype by altering gene expression programs involved in tumor progression and aggressiveness. MicroRNAs (miRNAs) have emerged as critical regulators of gene expression in CC, including miR-218-5p, which has been described as a tumor suppressor. In this study, we investigated the impact of HPV-16 oncoproteins E6 and E7 on the regulation of miR-218-5p expression and its target gene PIK3C2A, as well as their functional and clinical relevance in CC. We found that miR-218-5p expression is significantly reduced in HPV-16-positive CC cell lines, while PIK3C2A expression is increased. Silencing the expression of the E6/E7 oncogenes in Ca Ski cells restored miR-218-5p levels and reduced PIK3C2A expression. Conversely, overexpression of the E6 and E7 oncogenes in C-33 A cells significantly decreased miR-218-5p expression and increased PIK3C2A expression. Functional assays performed on C-33 A cells expressing E6 and E7 revealed that ectopic expression of miR-218-5p suppresses cell proliferation and migration, effects that are partially mediated by PIK3C2A. Bioinformatics analysis showed that low miR-218-5p expression and high PIK3C2A expression are associated with reduced overall survival in patients with cervical cancer. Our findings identify the miR-218-5p/PIK3C2A axis as a novel regulatory pathway modulated by HPV-16 oncoproteins E6 and E7 that contributes to CC cell proliferation and migration. Furthermore, miR-218-5p and PIK3C2A emerge as potential prognostic biomarkers in CC.
Brain dysfunction is a primary symptom of Gulf War illness (GWI). The present study investigated the effects of an amorphous formula of curcumin (CUR) and α-glycosyl isoquercitrin (AGIQ) on neurobehaviors and adult neurogenesis and following synaptic plasticity of produced neurons in the hippocampal dentate gyrus (DG) in a rat GWI model. Ten-week-old rats received GWI-related chemicals and restraint stress for 28 days; thereafter, animals were fed either a diet without supplement or mixed with 0.1% CUR or 0.5% AGIQ for 126 days. GWI treatment adversely affected behavioral endpoints, including novel object recognition, sucrose preference, novelty-suppressed feeding, and contextual fear conditioning. CUR ameliorated all these effects, while AGIQ caused anxiety-like behavior and improved fear extinction learning. GWI treatment downregulated NRF2-KEAP1 pathway-related genes in the DG; both phytochemicals reversed most of these changes. GWI treatment increased CD68+ and CD163+ microglia populations in the DG hilus; both phytochemicals reversed the increase of CD68+ microglia. In the neurogenic niche, GWI treatment decreased GFAP+ neural stem cells but increased DCX+ and PCNA+ cells, decreased hilar SST+ and GAD67+ GABAergic interneurons, and downregulated Pvalb. CUR reversed decreases in GFAP+ cell and SST+ interneuron numbers. Both phytochemicals increased VGLUT1 immunoreactivity, restored the VGLUT1/VGAT ratio, and upregulated Bdnf, Gria1, Gria2, Gria3, Slc17a7, Ptgs2, and Mapk1. AGIQ further increased COX2+ cell numbers and upregulated Grin2a, Grin2b, and Mapk3. In summary, both phytochemicals may have exerted antioxidant effects and modulated excitatory/inhibitory balance via glutamatergic signaling in GWI animals; CUR was superior to AGIQ at normalizing aberrant neurobehaviors and neurogenesis.
Food-grade titanium dioxide (E171) is widely used as a food additive and has raised concerns about its potential systemic toxicity. However, its impact on cardiac cellular metabolism and mitochondrial function remains incompletely understood. In the present study, we investigated the effects of E171 on intracellular labile iron, oxidative stress, mitochondrial ultrastructure, and mitochondrial bioenergetics in H9c2 cardiomyoblasts. Exposure to E171 leads to a significant increase in intracellular labile iron (Fe2+) levels. This alteration was accompanied by elevated reactive oxygen species (ROS) production and reduced intracellular glutathione levels, consistent with enhanced oxidative stress following E171 exposure. Ultrastructural analysis by transmission electron microscopy (TEM) revealed marked mitochondrial alterations, including reduced cristae density and structural damage. Functional assessment of mitochondrial bioenergetics demonstrated impaired oxidative phosphorylation and reduced maximal respiratory capacity in E171-treated cells. The potential protective role of quercetin (a powerful antioxidant and iron chelator) was explored in mitochondrial respiration assays; however, at the concentration and exposure conditions tested, quercetin treatment did not fully restore the bioenergetic parameters induced by E171. Collectively, these findings indicate that E171 increases intracellular labile iron levels and promotes oxidative stress, associated with alterations in mitochondrial ultrastructure and impaired bioenergetic function in H9c2 cardiomyoblasts, suggesting a potential mechanism by which food additives may affect cardiac cellular metabolism.
Autism is a multifactorial neurodevelopmental disorder characterized by social deficits, stereotypical behaviour, and neurotransmitter imbalance. This study evaluated the neuroprotective potential of Puerarin (PUN) and Magnesium Acetyl Taurate (MGAT) in a propionic acid (PPNA)-induced rat model of autism. PPNA was administered intracerebroventricularly for 11 consecutive days to induce autism-like features, followed by a 44-day treatment period with PUN (300 mg/kg, i.p.) and MGAT (500 mg/kg, p.o.). A comprehensive assessment was conducted, including behavioural analysis, biochemical and molecular evaluations, cerebrospinal fluid and plasma profiling, and histopathology. Treatment with PUN and MGAT, particularly in combination, improved behavioural outcomes, restored neurotransmitter balance, reduced neuroinflammation and apoptotic signaling, and attenuated activation of the glutaminase-glutamate/NMDAR and MAPK pathways (C-JNK, ERK1/2, P38 MAPK). Additionally, treatment increased magnesium levels and PSD-95 expression, indicating significant neuroprotection. These findings support the potential of PUN and MGAT as a multitarget therapeutic strategy for autism and warrant further translational investigation.
Osteoarthritis (OA) is a chronic degenerative joint disease characterized by persistent low-grade inflammation and progressive cartilage destruction. Macrophage-driven inflammatory responses contribute to extracellular matrix (ECM) degradation and accelerate disease progression. Here, we investigated the therapeutic potential of a DHA-derived lipid mediator mixture (LM), generated via soybean lipoxygenase and composed of 17S-hydroxydocosahexaenoic acid, resolvin D5, and protectin DX (3:47:50), in regulating macrophage-chondrocyte crosstalk and OA progression. LM significantly reduced IL-6, IL-1β, and TNF-α production in lipopolysaccharide-induced THP-1 macrophages. Conditioned medium from LM-treated macrophages attenuated ECM degradation in primary chondrocytes by suppressing MMP13 and ADAMTS5 while restoring COL2A1 and ACAN expression, indicating that LM may indirectly protects ECM by modulating the inflammatory microenvironment. In parallel, LM directly protected chondrocytes against IL-1β-induced inflammatory and catabolic responses, and restored ECM homeostasis. Mechanistically, LM significantly increased SIRT1 expression and deacetylation activity, as demonstrated by reduced NF-κB p65 acetylation. Both pharmacological inhibition by EX527 and siRNA-mediated SIRT1 knockdown abolished the protective effects of LM on ECM preservation. In vivo, LM oral administration alleviated cartilage destruction, improved joint structure and suppressed OA progression in a monosodium iodoacetate-induced OA model. Notably, micro-CT studies have demonstrated that LM significantly improved subchondral bone architecture, as evidenced by increased bone volume fraction and improved trabecular parameters. Histological analyses confirmed that LM attenuated inflammation and maintained cartilage integrity. Consistently, immunohistochemical findings showed reduced MMP13 expression, restoration of collagen II and aggrecan, and upregulation of SIRT1 in the LM-treated group compared to OA rats. Collectively, these findings suggest that LM mitigates OA progression by reducing inflammation, preserving ECM homeostasis, and attenuating subchondral bone deterioration.
Objectives: Circadian rhythms regulate key physiological processes, including metabolism and energy balance. Emerging evidence suggests that the timing of physical activity may influence metabolic outcomes. However, how the timing of endurance exercise impacts long-term metabolic health and the role of the circadian clock in this process remain unclear. This study aimed to investigate whether time-dependent endurance exercise improves metabolic health via circadian rhythm regulation. Methods: A 12-week endurance exercise protocol was established using wild-type (WT) and circadian-disrupted ClockΔ19 mice. Mice were assigned to exercise at Zeitgeber time 0 (ZT0) or Zeitgeber time 0 (ZT12), or to sedentary controls. Assessments included rotarod fatigue test, body weight, epididymal fat ratio, fasting blood glucose, serum triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-esterified fatty acids (NEFA), intraperitoneal glucose tolerance test (IPGTT), and insulin tolerance test (ITT). Results: ClockΔ19 mice exhibited circadian phase-dependent fatigue susceptibility on the rotarod, particularly at ZT0. Both exercised ClockΔ19 groups (ZT0 and ZT12) showed significant weight reduction compared to sedentary controls, indicating that endurance exercise may counteracts circadian disruption-induced weight gain independent of timing. In WT mice, evening exercise (ZT12) led to enhanced lipid regulation and better glucose tolerance. These time-dependent benefits were absent in ClockΔ19 mutants, demonstrating that the full metabolic advantages of exercise require a functional circadian clock. Notably, endurance training also partially restored serum HDL-C levels in ClockΔ19 mice, suggesting compensatory metabolic responses. Conclusions: Aligning endurance exercise with the body's internal clock provides greater metabolic benefits than untimed exercise. The circadian clock is essential for time-dependent improvements in glucose and lipid metabolism, although some beneficial effects occur independently of a functional clock.
Despite its critical role in disease diagnosis as a radiopharmaceutical, Fluorine-18 generates medical wastewater that necessitates efficient treatment, for which membrane adsorption stands out as a potent method, albeit one that demands high-performance membranes with exceptional permeability and adsorption capacity. This study presents a novel cerium-loaded amyloid fibril hybrid membrane designed for efficient removal of fluorine-18 from such wastewater. The membrane is fabricated through a facile process involving oxidation-precipitation of cerium species onto amyloid fibrils, followed by vacuum filtration, with further compositional tuning via incorporation of porous silica or activated carbon dopants. The resulting membrane retains the characteristic amyloid fibril structure and exhibits high water permeability with a flux of up to 803.3 L/(m2·h·bar), superior to most of the other membrane materials. It effectively removes fluoride ions (F-) from both low and high-concentration solutions, achieving a removal efficiency of up to 99% and a maximum adsorption capacity of 580 mg/g, outperforming many existing membrane materials. The hybrid membrane also demonstrates notable resistance to ionic interference, enabling selective F- adsorption from solutions containing high concentrations of Cl-, NO3- and SO42-, with a distribution coefficient (Kd) as high as 4.1 × 104 mL/g; furthermore, it maintains a fluoride removal rate above 51% after ten consecutive adsorption cycles. The membrane retains 51% of its initial fluoride removal efficiency after 10 cycles, indicating potential for repeated use, although further optimization or regeneration strategies would be required to fully restore performance. Mechanistic investigations reveal that F- adsorption occurs mainly through ion exchange with hydroxyl groups on CeO2. This work introduces a promising novel material with significant potential for the efficient treatment of medical radioactive wastewater containing fluorine-18.
As a cornerstone of modern science, cell lines are the foundational platforms for key medical advances. They enable vaccinology (through viral propagation and attenuation), gene therapy (via vector development), and biopharmaceutical production (via recombinant protein expression). Designer mammalian, avian, and insect expression systems, including Vero, MDCK, HEK293, BHK21, CHO, PER.C6, EB66, and Sf21/Sf9, have become indispensable cellular platforms, delivering enhanced biologic yields, superior genetic stability, and validated end-product biosafety. Simultaneous advances in cell culture media optimization have enabled a critical shift from serum-dependent media to serum-free, chemically defined, and xeno-free alternatives, which aim to restore compositional traceability of culture media components, reduce potential residual xenogeneic proteins in serum-supplemented media, and promote reproducibility even at the molecular level. This review emphasizes the far-reaching influence of cell culture systems as the expression powerhouse that sustains modern virology, whilst focusing on recent cell-engineering methods and optimization strategies in culture media that have facilitated this shift.