Plant-mediated iron nanoparticles are increasingly utilized in biomedical and health applications due to their biocompatibility and nontoxicity. The therapeutic characteristics of these nanoparticles are extensively diverse.
In this study, iron nanoparticles synthesized from Tribulus terrestris were characterized using various techniques, including Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), UV-visible spectroscopy, vibrating sample magnetometry (VSM), and X-ray diffraction (XRD) analysis. Antioxidant properties were assessed using the hydrogen peroxide (H2O2) and 2, 2-diphenyl-1-picrylhydrazyl (DPPH) assays. Anti-inflammatory activity was evaluated through protein denaturation studies. Antimicrobial activity was tested against wound pathogens. The effects of anticancer and wound healing were investigated using HCT-116 (colon cancer) and MG-63 (osteosarcoma) cells. Molecular docking studies were performed to assess the binding affinity of Tribulus terrestris bioactive compounds with proteins involved in the Adenomatous polyposis coli (APC) pathway of colon cancer.
The Tribulus terrestris-mediated Fe3O4 nanoparticles exhibited a peak at 290 nm using UV-visible spectroscopy. SEM and TEM analyses revealed that the nanoparticles were aggregated with an average size of 29 ± 0.24 nm. XRD analysis indicated a cubic crystalline structure. FTIR spectroscopy identified the biomolecules involved in the synthesis, and VSM confirmed a magnetic saturation of 14.75 emu/g. The antioxidant activity was demonstrated with DPPH (65.5%) and hydrogen peroxide (65.56%) assays at a dosage of 50 μg/mL, demonstrating a significant inhibition. The protein denaturation assay revealed a maximum inhibition of 54.57%. Lactobacillus had the strongest antibacterial activity at a concentration of 100 μg/mL, with an inhibitory zone of 35 mm. The anticancer assays showed IC50 values of 25.95 μg/mL for colon cancer (HCT-116) and 35.36 μg/mL for osteosarcoma (MG-63), indicating significant cytotoxicity, particularly against colon cancer cells. The nanoparticles also demonstrated effective regulation of cell migration at 50 μg/mL. Molecular docking studies revealed strong binding affinities between Tribulus terrestris compounds and APC pathway proteins relevant to colon cancer.
This research underscores the potential of Tribulus terrestris-mediated iron nanoparticles as a sustainable and eco-friendly approach with significant antioxidant and anticancer properties, especially in combating colon cancer. The findings highlight their effectiveness in reducing oxidative stress, inhibiting cancer cell proliferation, and enhancing wound healing.
Brain endothelial cells (BECs) are situated at the interface between the bloodstream and the brain, serving a crucial function in the development and maturation of the brain, particularly in upholding the integrity of the blood-brain barrier (BBB). Consequently, any modifications or gradual breakdown of the endothelium can significantly disrupt brain homeostasis. Ischemic stroke (IS), characterized by the progressive compromise of the BBB and increased BECs mortality, stands as a prominent global cause of mortality and disability. This review will utilize recent research to explore mechanisms underlying death.
Sepsis represents a life-threatening organ dysfunction due to a compromised host response caused by bacterial and viral infections. Although progress has been made to unravel the underlying pathophysiology, sepsis remains a very serious condition. Adiponectin is an adipokine with multiple beneficial activities relevant to glucose and lipid metabolism whose serum levels are low in obesity and metabolic diseases. In addition, several immunoregulatory activities of adiponectin have been described and circulating adiponectin levels have been positively associated with inflammation in autoimmune diseases such as rheumatoid arthritis and type 1 diabetes. Although an understanding of physiological consequences is still limited, blood adiponectin levels are also elevated in chronic kidney disease and liver cirrhosis, possibly due to impaired biliary and renal excretion. Natriuretic peptides, which increase adiponectin synthesis in adipocytes and are induced in autoimmune diseases and cirrhosis and decreased in obesity, appear to contribute to altered systemic adiponectin levels. In patients with sepsis, data on circulating adiponectin levels are not concordant, probably due to the large diversity in cohorts analyzed, often including patients with a higher risk for severe sepsis due to chronic metabolic disease or other comorbidities. This review article summarizes the main physiological activities of adiponectin and describes its role in inflammation and experimental sepsis. Adiponectin levels obtained in observational studies from serum or plasma of patients with critical illness are discussed. From this analysis, we conclude that circulating adiponectin levels are reduced in sepsis and septic shock, suggesting the potential of adiponectin receptor agonists as an option for sepsis therapy.
Akt (v-akt murine thymoma virus oncogene homologue) is a well-known serine-threonine kinase that functions as a central node in various important signal cascades involved in cellular maintenance. Akt has also been implicated in oncogenic malignancies as evidenced by protein overexpression, activation and somatic aberration of components in the phosphoinositide-3 kinase-Akt pathway. As such, Akt is a potential target in cancer therapy. Akt is frequently activated in human cancer tissues not only due to aberrant upstream signaling, but also by genetic mutations in AKT itself. This leads to the aberrant activation of pathways downstream of Akt that regulate cell-cycle progression and metabolism as well as activation of transcription factors that promote oncogenesis. In this review, we summarize previous research on Akt, including the molecular mechanisms underlying Akt signal transduction, as well as its physiologic roles and the pathologic consequences when dysregulated. We also discuss the roles of dysregulated protein overexpression/activation, increases in gene copy number, single nucleotide polymorphisms and the network of non-coding RNAs that regulate this pathway, with a particular focus on lung carcinomas. Finally, we discuss strategies that might lead to more effective targeting of Akt for clinical cancer therapy.
Inhibitors of DNA-binding (Id) proteins constitute a family of repressor factors that modulate a multitude of cellular processes and have been linked to tumor aggressiveness, resistance to chemotherapy, angiogenesis, and worse prognosis in numerous malignancies. This review explores the role of Id proteins in the pathogenesis of neuroendocrine neoplasms (NENs). The findings revealed that this family of proteins shows significant overexpression in tumors such as small cell lung carcinoma (SCLC), neuroendocrine prostate carcinoma (NEPC), and medullary thyroid carcinoma (MTC), although the role of epigenetics in regulating Id proteins within NENs remains poorly understood, with most evidence limited to NEPC. These results underscore the potential of Id proteins not only as diagnostic biomarkers and promising therapeutic targets for the management of NENs, but also highlight the need for further research to better understand their epigenetic regulation and broader role in these tumors.
Metabolic syndrome (MetS) is a widespread multi-component pathological condition characterized by meta-inflammation and cellular dysfunction. MetS and other metabolic diseases (metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular-kidney-metabolic syndrome (CKMS)) stem from the disorder of energy metabolism and changes in the structure and function of specialized organelles such as lipid droplets, endoplasmic reticula, mitochondria, and nuclei. The discovery of lipid droplets within the nucleus and the investigation of their functions across various cell types in both health and disease provide a foundation for discussing their role in the development and progression of metabolic syndrome. This review examines studies on lipid droplets in the nucleus, focusing on pathways of formation, structure, and function. The importance of (nuclear) lipid droplets in liver and brain is emphasized in the context of inflammation associated with obesity, MetS, and liver disease. This suggests that these structures are promising targets for the development of effective drugs against diseases associated with dysregulation of energy metabolism.
Fatty acid binding proteins (FABPs) transport lipids in the brain and may be involved in the course of various neuropsychiatric syndromes, e.g., major depressive disorder (MDD), anxiety, schizophrenia, neurodegenerative disorders, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and substance use disorders (SUDs). However, the nature of this link is not sufficiently elucidated. To that end, we performed a comprehensive literature search on the role of FABPs in neuropsychiatric disorders. Literature searches were conducted from Medline/PubMed electronic databases utilizing the search terms (“fatty acid binding protein” OR “FABP”) AND (“psychiatry” OR “ADHD” OR “autism” OR “schizophrenia” OR “substance abuse” OR “substance use disorder” OR “addiction” OR “cocaine” OR “ethanol” OR “tetrahydrocannabinol (THC)” OR “nicotine” OR “anxiety” OR “depression” OR “major depressive disorder”, OR “neurodegenerative” OR “Alzheimer” OR “Parkinson” OR “dementia”). Of the 1281 publications found, 90 met the inclusion criteria. FABP alterations were found to be involved in pathology and/or associated with the severity of all conditions examined. Elevated levels of FABP2 and FABP7 were found in patients with MDD and ASD, while FABP3 is implicated in dopamine receptor regulation linked to ADHD and SUDs. Moreover, FABPs’ involvement in neuroinflammation and lipid metabolism could shed light on new therapeutic strategies. Alterations in FABP expression may contribute to the increased prevalence and severity of certain neuropsychiatric conditions. Our findings, albeit pending further validation via prospective clinical trials, call for further research into the mechanisms by which FABPs affect neurophysiopathology and highlight the therapeutic potential of FABP inhibitors in mitigating such illnesses.
Nasopharyngeal carcinoma (NPC) is a kind of malignant tumour originating from the mucosal epithelium of the nasopharynx, which has apparent regional distribution characteristics, and its incidence is increasing yearly. At present, the primary treatment method for nasopharyngeal carcinoma is radiotherapy, but radioresistance has become a complex problem to overcome to improve the therapeutic effect. Recently, ferroptosis has been proposed as a new type of iron-dependent programmed cell death, distinct from apoptosis, cell necrosis and autophagy. Many studies have shown that ferroptosis is involved in the occurrence, development, invasion and metastasis of nasopharyngeal carcinoma cells, and promoting the occurrence of ferroptosis of the same cells is a promising treatment method that should be written in the prospect. Therefore, this paper summarizes the mechanism of action of ferroptosis and its role in treating the same as above.
The ocular surface microbiota plays a fundamental role in maintaining ocular health, offering protection against pathogens, modulating immune responses, and supporting tear film stability. Dysbiosis, or disruption of this microbial balance, is increasingly recognized as a contributing factor to various ocular surface and anterior segment pathologies, including dry eye disease, blepharitis, conjunctivitis, and keratitis. This review explores the critical functions of the ocular microbiota and the consequences of its alteration in disease progression, particularly through mechanisms such as inflammation, biofilm formation, and epithelial damage. Current therapeutic approaches, including antibiotics and probiotics, face significant limitations in restoring microbial balance. A key challenge in these therapies is the delivery of beneficial bacteria in suspension, where they are rapidly cleared from the ocular surface, limiting their ability to establish a stable, protective population. To address this issue, a novel approach is proposed: the use of bioprinting technology to deliver beneficial bacteria in a solid, structured form. This bioprinted approach offers several advantages, including improved retention of bacteria on the ocular surface and a controlled release over time, increasing the likelihood of successful repopulation with beneficial microbial species. By overcoming the rapid clearance observed with conventional suspensions, this method holds the potential to restore ocular microbial balance more effectively, providing long-term therapeutic benefits for chronic ocular surface diseases. Future research will require preclinical and clinical studies to validate the safety and efficacy of this innovative approach. This bioprinted bacterial therapy represents a significant advancement in the management of ocular surface and anterior segment pathologies, offering a novel, targeted strategy for microbiota restoration.
Sodium-dependent glucose transporter-2 inhibitors (SGLT-2i) have potential hypotensive effects, enhancing the hypotensive effect of renal denervation (RDN). Spontaneously hypertensive rats (SHRs) were used to verify this hypothesis and explore the associated underlying pathways.
Seven Wistar-Kyoto (WKY) rats and 35 SHRs were divided into 6 groups. The blank WKY control (W) group consisted of all 7 WKY rats, whereas the SHRs were divided into the following groups, each containing 7 rats: sham operation (Sham), renal denervation (RDN), SGLT-2 inhibitor treatment (SGLT-2i), and the combination of renal denervation with SGLT-2 inhibitor treatment (RDN+SGLT-2i). The rats in the RDN+SGLT-2i and SGLT-2i groups were gavaged with dapagliflozin (DAPA) before RDN. The sham group was subjected to a sham operation. One-week post-operation, rat tail manometry, and echocardiography were subsequently performed, and peripheral blood inflammatory cells were detected via flow cytometry before sample collection. Following sample collection, the serum, including interleukin-6, angiotensin-II, renin, and norepinephrine, was tested via enzyme-linked immunosorbent assay. Pathological testing included Masson staining of the myocardial tissue, tyrosine hydroxylase (TH) immunohistochemistry, and Fos protooncogene (C-Fos) immunofluorescence staining of the hypothalamus tissue.
Compared with RDN alone, RDN following intragastric DAPA administration reduced systolic blood pressure (SBP) in SHRs, independent of its hypoglycemic effect. Compared with the RDN group, the pathological results of the RDN+SGLT-2i group revealed a greater improvement in the intensity of TH staining in the hypothalamus tissue, closer to the normal level of the cross-sectional area in myocardial cells. Furthermore, we observed enhanced sympathetic inhibition in the brain and a reduction in the fibrotic area within myocardial cells. Additionally, the proportions of inflammatory mononuclear cell subsets and the levels of inflammatory factors improved. Although DAPA reduced inflammation and sympathetic nerve overexcitation alone, it could not completely reverse blood pressure (BP) or cardiac function. Similarly, the alleviation of inflammation and BP reduction in RDN-treated rats were inferior to those in rats treated with RDN combined with DAPA.
Compared with RDN alone, DAPA addition before RDN can considerably reduce the BP of SHRs. The enhancement of the hypotensive effect may be attributed to the inhibition of sympathetic activity and the reduction in inflammatory reactions.
As the global population ages, the risks associated with primary sarcopenia, including falls, fractures, functional decline, and frailty, are becoming increasingly apparent, all of which significantly impair the quality of life in older adults. Emerging evidence suggests that the gut microbiota plays a pivotal role in maintaining muscle physiology. Specific gut bacteria promote intramuscular protein synthesis through the production of certain amino acids (e.g., leucine, tryptophan), short-chain fatty acids (SCFAs), and hydrogen sulfide. Notably, Escherichia coli expressing the enzyme nicotinamidase (PncA) has been shown to enhance nicotinamide adenine dinucleotide (NAD+) synthesis, potentially improving mitochondrial function in muscle tissue. Furthermore, secondary bile acids and lactate influence the levels of fibroblast growth factor 15/19 and unacylated ghrelin in circulation by binding to receptors that are highly expressed in gut endocrine cells, thereby affecting muscle physiology. This review examines the characteristic composition of the gut microbiota in patients with sarcopenia, its role in primary sarcopenia, and potential therapeutic targets.
Lysine tyrosylquinone (LTQ), the cofactor formed through copper-assisted tyrosine oxidation and subsequent intramolecular cross-linking, is inherent in all members of the lysyl oxidase family. Lysyl oxidases are unique among amine oxidases in that they maintain the LTQ coenzyme in a relatively surface-exposed position, making it accessible for the oxidative deamination of lysine side chains in various proteins, especially in the extracellular matrix. This process facilitates the formation of intramolecular cross-links, which are vital for the normal development of skin, bones, aorta, and other tissues. Unfortunately, in accordance with the antagonistic pleiotropy theory of aging, the enzyme activity that is essential in youth may become non-optimal throughout the lifespan. One consequence of excessive lysyl oxidase and its ectopic activity in the nucleus is the promotion of stiffness in solid tumors and increased survival of metastasizing cells. Therefore, LTQ-dependent oxidative deamination, especially at the stage of LTQ formation, is a promising druggable target for future combination therapies aimed at treating the most lethal cancers.
Extracellular vesicles (EVs) are nanoscale, membrane-enclosed structures that are secreted by nearly all cell types. EVs include small EVs (exosomes), large EVs (microvesicles), and apoptotic bodies, which are distinguished by their biogenesis and size. EV biogenesis involves endosomal pathways or direct budding from the plasma membrane, influenced by cellular states and external stimuli. The complex composition of EVs, proteins, lipids, RNA, DNA, and metabolites reflects their cell of origin, enabling EVs to mediate intercellular communication. EV uptake by recipient cells occurs via endocytosis, membrane fusion, or receptor–ligand interactions, influencing diverse physiological and pathological processes. Indeed, the biological roles of EVs range from immune modulation to tissue repair and contributions to cancer, neurodegeneration, musculoskeletal pathologies, and other disorders. Advances in isolation methods, including ultracentrifugation, size exclusion chromatography, and immunoaffinity techniques, have improved the purity and yield of EVs. Characterization technologies, such as nanoparticle tracking analysis, electron microscopy, and omics approaches, provide insights into their heterogeneity and functional cargo. Thus, EVs hold promise as non-invasive biomarkers for disease diagnosis and prognosis, offering high specificity and stability. Furthermore, the natural biocompatibility, ability to cross biological barriers, and capacity for functional cargo delivery of EVs position them as therapeutic tools and drug-delivery vehicles. Some of the most promising fields of application for EVs include cancer, neurodegeneration, and joint diseases; however, challenges remain in scaling production, achieving targeted delivery, and ensuring regulatory compliance. This review highlights recent advances in EV biology, isolation, and applications, emphasizing their crucial potential in precision medicine while identifying knowledge gaps and future research directions.
Aldo-keto reductase 1B10 (AKR1B10) is expressed in various malignant tissues. Several studies have highlighted the essential function of AKR1B10 in lipid metabolism and in the detoxification of lipid peroxides. The aim of this research was to explore the role of AKR1B10 in the susceptibility of MDA-MB-231 cells to ferroptosis. These cells serve as a model for triple-negative breast cancer (TNBC).
Lentiviral transfection was used to establish stable cell lines with high or low expression of AKR1B10. Our model of ferroptosis used the ferroptosis activator RSL3, and the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) to rescue cell death. Stable cell lines were treated with the specific inhibitor OSU-T315 directed against phosphorylation of Ser473 in protein kinase B (AKT) and Ser9 in glycogen synthase kinase 3 beta (GSK3β), either alone or in combination with RSL3. A fatty acid stress model was established using palmitic acid (PA) or arachidonic acid (AA), either in the presence or absence of serum starvation and with or without co-treatment with RSL3. Cell viability was evaluated with the cell counting kit-8 (CCK8) assay and lipid peroxidation levels by flow cytometry after staining with C11 BODIPY 581/591. Exploration of the underlying mechanisms was conducted through RNA sequencing and bioinformatics analysis. Western blotting was performed to evaluate protein levels, and quantitative real-time polymerase chain reaction (qPCR) was used to evaluate transcript levels.
Western blot and qPCR analyses validated the successful establishment of stable MDA-MB-231 cell lines with and without AKR1B10 overexpression. Cell viability and lipid reactive oxygen species (ROS) assays showed that AKR1B10 suppressed ferroptosis in the RSL3-induced cell death model. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) analyses indicated the phosphatidylinositol 3-kinase (PI3K)-AKT pathway was likely to play a role in the underlying mechanisms. AKR1B10 increased the expression of glutathione peroxidase 4 (GPX4), thus potentially implicating the AKT/GSK3β/nuclear factor erythroid 2-related factor 2 (NRF2)/GPX4 pathway in the mechanism. These changes in protein levels were also observed by Western blot analysis after 6 h of RSL3 treatment. Under the influence of RSL3, the transcript levels of NRF2-related genes including GPX4, ferritin heavy chain 1 (FTH1), heme oxygenase 1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO-1) were significantly elevated in the AKR1B10 overexpression cell line, whereas that of prostaglandin-endoperoxide synthase 2 (PTGS2) was significantly reduced. Similar changes were observed after treatment with OSU-T315. AKR1B10 was found to suppress the sensitivity to ferroptosis induced by treatment with OSU-T315, PA, or AA. These phenomena were rescued by the ferroptosis inhibitor Fer-1.
AKR1B10 appears to be an important mechanism protecting MDA-MB-231 cells from ferroptosis, possibly through the AKT Ser473/GSK3β Ser9/NRF2/GPX4 pathway. AKR1B10 may be a key factor underlying the therapeutic effect of RSL3 under different exogenous fatty acid microenvironments.
Heart failure (HF) continues to represent a significant global public health concern. Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a calcium-permeable channel that has been linked to cardiac disease and function. However, its significance in HF and underlying processes is unknown. This study aims to determine the regulatory role of TRPV1 in mitochondrial autophagy in HF.
AC16 cardiomyocytes were exposed to angiotensin II (Ang II) to simulate pathological conditions, and changes in oxidative stress were assessed. Transverse aortic constriction (TAC) was used to create a pressure overload-induced HF mouse model, and cardiac-specific TRPV1 overexpression was achieved by Adeno-associated virus 9 (AAV9). RNA sequencing and bioinformatics analysis were performed to identify TRPV1-related mitochondrial genes. Finally, the effects of TRPV1 overexpression and sideroflexin 2 (SFXN2) knockdown on markers related to mitophagy and ferroptosis were analyzed.
In vitro, TRPV1 overexpression drastically decreased intracellular Ca2+ levels, lessened oxidative stress, and reduced Ang II-induced cell death (p < 0.05). Bioinformatics analysis identified seven mitochondrial genes associated with TRPV1, among which SFXN2 showed a strong correlation with TRPV1 (p < 0.05). Overexpressing cardiac-specific TRPV1 in the TAC model led to improved cardiac function, higher fractional shortening and ejection fraction, and reduced levels of mitophagy markers (p < 0.05). Mechanistically, TRPV1 activated SFXN2, increasing glutathione peroxidase 4 (GPX4) expression and antioxidant capacity (glutathione (GSH), superoxide dismutase (SOD)) while decreasing malondialdehyde (MDA) and ferrous iron (Fe2+) levels (p < 0.05). These protective effects were removed by SFXN2 knockdown. Furthermore, the TRPV1-SFXN2 axis suppressed mitophagy by modulating the PTEN-induced kinase 1 (PINK1)-Parkin-sequestosome 1 (SQSTM1) axis.
Our results show that TRPV1 overexpression alleviates Ang II-induced myocardial injury in HF. This protective effect is mediated through SFXN2-dependent mitophagy and ferroptosis, highlighting TRPV1 as a potential therapeutic target for HF.
Type 2 immunity is represented by T helper 2 (Th2) lymphocytes and the cytokines produced downstream (Interleukin (IL)-4, IL-13, IL-31). They are increasingly recognized as pivotal mediators in the pathogenesis of immune-mediated dermatological conditions such as atopic dermatitis (AD) and psoriasis (Pso). In these disorders, they initiate and amplify immunological signaling cascades, promote cutaneous inflammation, and contribute to the induction of pruritus. In this context, IL-33 and IL-31 would be believed to be intrinsically linked and related to the acuity of the disease. The presence of an interleukin could in fact trigger the other, amplifying the inflammatory process of itchy skin disorders and therefore the extent of the symptoms. High levels of IL-31 may support the maintenance of a microenvironment that promotes both the growth and spread of solid tumors, as well as the development of cancer-associated pruritus. Given these premises, non-histaminergic mediators such as IL-31 and IL-33 could be explored as novel therapeutic targets for the treatment of pruritus in immune-mediated skin diseases and cancer, improving the QoL of patients. Finally, we briefly discussed the recent innovations in the field of monoclonal anti-IL-31 therapies.
The ossification of the posterior longitudinal ligament (OPLL) is a progressive spinal disorder predominantly observed in Asian populations. Unfortunately, there is a limited availability of conservative therapies to impede the progression of OPLL. This study investigates the effects of cobalt chloride (CoCl2), which simulates an in vitro hypoxic microenvironment, on OPLL and explores its potential mechanisms, aiming to enhance our understanding of the pathogenesis of OPLL.
Ligament cells were extracted from patients with OPLL and normal posterior longitudinal ligament (PLL) tissues, confirming their mesenchymal stem cell (MSC)-like properties. To simulate hypoxia, cells were treated with varying concentrations of CoCl2, and the effects on hypoxia-inducible factor 1-alpha (HIF1A) expression and osteogenic differentiation were assessed. Real-time quantitative reverse transcription–polymerase chain reaction (qRT-PCR) and Western blotting were used to quantify HIF1A and bone morphogenetic protein 4 (BMP4) expression. Immunohistochemistry was performed to visualize HIF1A in tissue samples. Osteogenic differentiation was evaluated through Alizarin Red S staining and alkaline phosphatase (ALP) assays, with optical density (OD) values measured using a microplate reader. Transcriptome sequencing was conducted to identify differentially expressed genes following CoCl2 treatment.
We found that HIF1A was differentially expressed in the OPLL. Both PLL cells and OPLL cells exhibited mesenchymal stem cell properties; however, OPLL cells demonstrated a greater capacity for osteogenic differentiation (p < 0.05). Following stimulation with cobalt chloride, the expression of HIF1A increased, which correlated with an enhanced osteogenic differentiation ability in PLL cells. Biosignature analysis revealed that HIF1A plays a regulatory role in BMP4 expression. Notably, BMP4 was downregulated, and the degree of osteogenic differentiation decreased upon inhibition of HIF1A with siRNA in OPLL cells.
Primary cells derived from normal PLL and OPLL exhibited MSC-like properties and demonstrated the capacity for osteogenic, adipogenic, and chondrogenic differentiation, with OPLL cells showing a greater propensity for osteogenic differentiation. This study reports the potential involvement of HIF1A in the development of OPLL and investigates the regulatory role of the HIF1A-BMP4 axis in this process.
The study aims to investigate the potential of aptamers as diagnostic and targeted therapeutic tools for gastric cancer (GC) and other cancer types through the cell-systematic evolution of ligands by exponential enrichment (cell-SELEX) process. GC is associated with high global incidence rates and a substantial lack of effective targeted therapies. Aptamers have emerged as a promising innovation for both the diagnosis and targeted treatment of various cancers.
Cell-SELEX process was employed to screen for aptamers specific to GC cells, utilizing the GC cell lines HGC-27, MKN-45, SNU-638, and NUGC-3 as target cells. Aptamer affinity, specificity, and biological properties were evaluated through flow cytometry, and mass spectrometry was utilized to identify potential target proteins.
Aptamer-gastric cancer (APT-GC) is efficiently internalized by GC cell lines (HGC-27, MKN-45, SNU-638, NUGC-3) through receptor-mediated endocytosis at concentrations up to 300 nM, with intracellular stability for at least 2 hours and stability in serum for up to 6 hours. Furthermore, APT-GC is internalized by various cancer cell types, suggesting its potential for broad application in pan-cancer diagnosis and treatment.
APT-GC exhibits high affinity for GC cells and can also be internalized by diverse cancer cell types, positioning it as a versatile diagnostic and therapeutic agent for a wide range of cancers.
Intervertebral disc degeneration (IDD) is a major cause of chronic lower back pain, with current treatment options offering limited efficacy. Exosome-loaded hydrogels have emerged as a promising therapeutic approach due to their biocompatibility and regenerative potential, making them a focus of research for IDD treatment. This study systematically evaluates and performs a meta-analysis of the effectiveness of exosome-loaded hydrogels in preclinical models of IDD.
A comprehensive literature search was conducted across four major databases (PubMed, Embase, Cochrane, Web of Science), including animal studies that met predefined criteria. Data extraction and quality assessment were independently performed by two authors. Treatment effects were quantified using standardized mean differences (SMD) with 95% confidence intervals (CI). Outcome measures included disc height index (DHI), magnetic resonance imaging (MRI) grade, histological grade, IDD-related immunohistochemical (IHC) markers (e.g., collagen type II (COL2), matrix metalloproteinase 13 (MMP13)), and aging-related markers (e.g., p16Ink4a-positive cells, p21CIP1A-positive cells).
Treatment with exosome-loaded hydrogels significantly enhanced DHI scores at 4 (p = 0.002) and 8 weeks (p < 0.0001), and decreased MRI scores at 8 (p < 0.00001) and 12 weeks (p < 0.0001), and histological assessments. Furthermore, the treatment group exhibited increased COL2 expression at 8 (p = 0.0002) and 12 weeks (p = 0.002), decreased MMP13 levels at 8 (p = 0.0001) and 12 weeks (p = 0.0009), and a reduction in aging markers (p16Ink4a, p21CIP1A, all p < 0.05), suggesting that exosome-loaded hydrogels facilitate intervertebral disc repair through the modulation of molecular pathways. Sensitivity analysis confirmed the robustness of the findings.
Exosome-loaded hydrogels show potential for improving the structure and function of intervertebral discs in IDD treatment, potentially slowing degeneration by inhibiting matrix degradation and cellular aging. Further investigation is required to elucidate the underlying mechanisms and to assess the safety and efficacy of these hydrogels for clinical application.
CRD420250649970 (https://www.crd.york.ac.uk/PROSPERO/view/CRD420250649970).
Keratoconus (KC) is a corneal disease that causes changes in corneal topography, leading to central/paracentral cone formation, which affects visual acuity.
We studied in vivo optical coherence tomography (OCT) images of normal and KC corneas images. The relative cellular and collagen content in the control and KC human corneas was measured by collecting OCT images and then dividing the images into low (green), medium (blue), and high pixel intensity (red) subchannel images. The green image was used to evaluate the cellular content in the cornea, the blue image presented information on the collagen content, and the red image provided information on both the cellular and collagen contents.
These results suggest that the cellular and collagen contents decrease with increased corneal depth in KC, while the collagen content appears to reduce as changes in the keratocyte content occur.
This study proposes that using the green, blue, and red subchannel OCT images may be an effective method for detecting KC and other corneal diseases earlier, before observing changes in corneal topography, and that these images can be collected remotely using telemedicine.
Pancreatic carcinoma (PC), a severely malignant neoplasm of the digestive system, is characterized by an unfavorable prognosis. Neutrophil extracellular trap (NETosis) is a neutrophilic inflammatory form of cell death. However, it is still unknown how they relate to one another. This study aims to explore the part NETosis plays in the onset and progression of pancreatic cancer.
Expression and clinical data for patients with pancreatic carcinoma were obtained from publicly accessible databases. Multigene features were constructed using the least absolute shrinkage and selection operator (LASSO). Bioinformatics analysis was combined with in vitro experiments to determine the relevant mechanism.
Seventeen NETosis-related genes were identified. LASSO analysis finally led to the generation of six gene characteristics, which were divided into two clusters according to the expression level. The survival outcomes of the high- and low-risk groups differ significantly, and their predictive performance is good (p < 0.05). Drug sensitivity analysis confirmed that the high-risk cohort could benefit more from 5-fluorouracil, gemcitabine, and epirubicin (p < 0.01). Using survival analysis and single-cell binding quantitative real-time polymerase chain reaction (RT-qPCR), the crucial gene LGALS3 was identified (p < 0.0001). In vitro experiments demonstrated that inhibiting LGALS3 expression may significantly decrease the proliferation and movement of PANC-1 and SW1990 cells (p < 0.05).
We established a 6-gene risk scoring model and confirmed the effect of LGALS3 on the development of PC.
Breast cancer is currently the most prevalent malignancy among females, representing a substantial threat to both physical and psychological health. Moreover, its incidence rate continues to rise annually. Therefore, screening potential therapeutic targets and developing candidate drugs for breast cancer treatment holds significant clinical implications.
In this study, in silico methods were used to identify potential therapeutic targets of fatty acid metabolism-related genes in breast cancer and to screen potential drugs using molecular docking. In addition, Cell Counting Kit-8 (CCK-8) and Transwell assays were utilized to analyze the effect of atorvastatin calcium (AC) on the malignant phenotype of breast cancer cells. Furthermore, the effects of AC-induced ferroptosis in tumor cells were evaluated using transmission electron microscopy, ROS, Fe2+, and Liperfluo probes, and the potential molecular mechanisms were explored through real-time qPCRand western blotting.
2,4-Dienoyl-CoA Reductase 1 (DECR1) overexpression was related to a dismal prognostic outcome in breast cancer patients. AC interfered with breast cancer cell proliferation and invasion, potentially through its effects in DECR1 expression, while suppressing tumor growth in vivo. In addition, AC demonstrated antitumor effects, possibly through the downregulation of DECR1 and the upregulation of Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4), which may contribute to the induction of ferroptosis in tumor cells.
DECR1 is associated with breast cancer progression and may serve as a potential therapeutic indicator, and AC plays an antitumor role by modulating DECR1 expression and promoting ACSL4-mediated ferroptosis. Therefore, AC may be considered a potential candidate drug for treating breast cancer.
Cultivated peanut (Arachis hypogaea L.) is a major oil and economic crop. Pod size is one of the important agronomic traits of peanut variety, with a direct impact on peanut yield.
In a previous study, AhRUVBL2 was identified by map-based cloning technology as a candidate gene that regulates peanut pod size.
Overexpression of AhRUVBL2 in transgenic Arabidopsis significantly increased plant height, branch number, leaf size, silique size, seed size, and thousand-seed weight. Further examination revealed an increase in the area of silique exocarp cells, and the number and area of endocarp lignified cells. A total of 337 differentially expressed genes, including PRX (Periaxin) , SAUR (Small Auxin-up RNA), and PYL (Pyrabactin Resistance 1-like), were identified by transcriptome analysis of transgenic Arabidopsis silique. proAhRUVBL2-GUS was found to be expressed explicitly in seeds, and the expression activity of proAhRUVBL2-D893 was significantly greater than that of proAhRUVBL2-79266. Exogenous ABA (abscisic acid) and IAA (indole acetic acid) treatment of proAhRUVBL2-GUS-transformed tobacco leaves revealed that the AhRUVBL2 promoter was hormone-responsive.
This study sheds light on the function of AhRUVBL2 in regulating plant growth and development. Moreover, characterization of the AhRUVBL2 promoter provides a valuable genetic resource for enhancing peanut yield.
Sepsis is a prevalent disease with high mortality involving severe systemic inflammatory responses. Although the mechanisms underlying sepsis have been widely explored, the occurrence and exacerbation of sepsis remain unclear, with limited therapeutic options. Inflammation and mitochondrial oxidative stress have been proposed as primary factors in the development of sepsis.
In the present research, normal and sepsis samples were obtained from the Gene Expression Omnibus (GEO) database (GSE54514, GSE65682, and GSE95233). To identify the key mitochondrial oxidative stress-related gene (MOSRG) signature associated with sepsis, both weighted gene co-expression network analysis (WGCNA) and differential expression analysis were conducted. Least Absolute Shrinkage and Selection Operator (LASSO) analysis and univariate and multivariate Cox analysis were used to construct the prognostic risk model for sepsis. Immune infiltration characteristics were analyzed using the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) and single-sample Gene Set Enrichment Analysis (ssGSEA) algorithms. Single-cell RNA sequencing and in vitro experiments provided additional evidence for the pivotal role of RNA-binding protein, ribonuclease 2 (RNASE2) in the regulation of mitochondrial oxidative stress in sepsis.
Three MOSRGs RNASE2, CX3C chemokine receptor 1 (CX3CR1), and epoxide hydrolase 2 (EPHX2) were recognized as potential diagnostic indicators for sepsis in this study. The immune infiltration analysis provides strong evidence that three biomarkers were linked to immune-related mechanisms involved in the pathogenesis of sepsis. The pivotal role of RNASE2 in regulating mitochondrial oxidative stress during sepsis was confirmed using single-cell RNA-seq analysis and validated by in vitro molecular biology experiments. Inhibition of RNASE2 was found to significantly mitigate mitochondrial oxidative stress injury in sepsis.
This research underscores the significant impact of mitochondrial oxidative stress-related genes on immune regulation in sepsis and highlights the potential therapeutic implications of candidate biomarkers.
Acute pancreatitis (AP) is a common gastrointestinal emergency and critical condition worldwide. Given the absence of specific therapeutic targets, managing the progression of AP to severe phases and the accompanying systemic inflammatory response remains challenging. We detected an abnormally elevated expression of norcholic acid (NorCA) in the serum of patients with various types of AP and found that this bile acid is closely associated with the Wnt/β-catenin signaling pathway in the context of AP. This study was designed to investigate NorCA’s dual role as a novel diagnostic biomarker and molecular therapeutic target in AP, with particular emphasis on elucidating its mechanistic regulation of M1 macrophage polarization in RAW 264.7 murine macrophages during AP pathogenesis.
Serum samples from AP patients were collected and screened to identify the levels of NorCA and the extent of metabolic abnormalities using bile acid targeting detection. Transcriptome sequencing and bioinformatics analyses were conducted to investigate the role of the Wnt/β-catenin pathway. To evaluate NorCA’s regulatory effect on M1 macrophage polarization through the Wnt/β-catenin signaling pathway in AP development, we employed flow cytometry, western blotting, and qRT-PCR analyses.
NorCA demonstrated a significant elevation in the peripheral blood across different AP subtypes, showing promising diagnostic potential with high sensitivity and specificity. NorCA promotes the polarization of M1 macrophages by activating the Wnt/β-catenin pathway, leading to further inflammation. Treatment with JW74, a specific Wnt/β-catenin inhibitor, significantly reduced the degree of NorCA-induced M1 macrophage polarization.
NorCA demonstrates dual clinical utility as both a novel diagnostic biomarker for AP and a promising molecular target for therapeutic intervention in severe AP and its concomitant systemic inflammatory response syndrome (SIRS).
Sepsis-induced myocardial injury (SIMI) represents a major contributor to prolonged hospitalization in intensive care units (ICUs) and is associated with increased mortality rates. Mitochondria serve as the primary energy source for cardiomyocytes and are also essential for various other cell functions. The essential voltage-dependent anion channel 3 (VDAC3) protein located in the outer mitochondrial membrane plays a crucial role in preserving mitochondrial homeostasis by controlling metabolite transport and the shape of cristae. However, the precise mechanism by which VDAC3 is involved in SIMI remains unclear. This study aimed to explore the function and mechanism of VDAC3 in SIMI pathogenesis, with a particular emphasis on its regulatory role in ferroptosis.
Lipopolysaccharide (LPS)-treated HL-1 cardiomyocytes (a murine cardiomyocyte cell line) were used to construct an in vitro myocardial injury model, and mice were used to establish a cecal ligation and puncture (CLP)-induced in vivo myocardial injury model. Transmission electron microscopy (TEM) was employed to evaluate the mitochondrial ultrastructure in cardiac tissues, while hematoxylin-eosin (H&E) staining was used to assess histopathological alterations. Echocardiography was used to evaluate the structural and functional characteristics of the heart. Integrated transcriptome and proteomic studies were performed to identify differentially expressed genes. VDAC3 expression levels, inflammatory responses, cellular proliferation, and ferroptosis were assessed using colorimetric assays, flow cytometry, enzyme-linked immunosorbent assay (ELISA), Cell Counting Kit-8 (CCK-8) proliferation assay, western blotting, and quantitative reverse transcription PCR (qRT-PCR). The relationship between VDAC3 and ferroptosis was investigated in vitro by transfecting cells with VDAC3 overexpression plasmids.
The injury model group in both the in vitro and in vivo experiments showed a decreased level of the antioxidant glutathione (GSH) and an elevated level of the lipid peroxidation product malondialdehyde (MDA). Moreover, ferroptosis regulation occurred through the modulation of glutathione peroxidase 4 (GPX4), solute carrier family 7 members 11 (SLC7A11), ferritin, prostaglandin-endoperoxide synthase 2 (PTGS2), lipocalin 2 (LCN2), and acyl-coenzyme A (CoA)-synthetase long-chain family member 4 (ACSL4) expression. Administration of ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, markedly reduced the cardiac injury caused by CLP. Additionally, VDAC3 expression was significantly downregulated in experimental models and septic children. In contrast, Fer-1 treatment increased the expression of both VDAC3 and dihydroorotate dehydrogenase (DHODH) and significantly ameliorated cardiac damage. Overexpression of VDAC3 reduced mitochondrial oxidative stress, increased the expression of DHODH, and altered the progression of ferroptosis.
Collectively, this research provides insights into the molecular mechanism behind the VDAC3/DHODH axis in SIMI. This axis mitigates cardiac injury by regulating ferroptosis, thereby suggesting novel therapies for SIMI.
Insomnia, the most prevalent sleep disorder, is clinically defined as difficulty initiating or maintaining sleep. Although many medications are effective for insomnia treatment, they carry risks of drug dependence and abuse. The microbiota-gut-brain axis (MGBA) facilitates bidirectional signaling between the gastrointestinal tract and the central nervous system via gut microbes. Probiotics that provide mental and behavioral benefits through MGBA (psychobiotics) offer broad therapeutic potential.
A non-toxic, drug-resistant strain of Lactobacillus reuteri E9 was isolated and characterized. Its effects were evaluated in a pentylenetetrazol (PTZ)-induced zebrafish model of sleep disorder. Neurotransmitter levels (glycine, serine, taurine, γ-aminobutyric acid (GABA)) and gene expression of GABA/melatonin receptors were analyzed.
E9 significantly upregulated inhibitory neurotransmitters, including GABA, taurine, glycine, and serine (p < 0.05). In PTZ-induced zebrafish, E9 exerted sedative effects by reducing seizures and hyperactivity. Concurrently, E9 upregulated the expression of GABA receptor genes and melatonin receptor (Mtnr1aa) genes in zebrafish neural tissue.
Lactobacillus reuteri E9 demonstrates potential as a psychobiotic for sleep disorder management by modulating key inhibitory neurotransmitters and sleep-related receptor expression via the MGBA pathway, offering a non-pharmacological alternative to conventional treatments.
Mitochondria, ubiquitous in eukaryotic cells, evolved from an ancestral aerobic alpha-proteobacterium that had been phagocytosed by a primordial archaeal cell. Numerous factors link mitochondria to current-day bacteria, notably the facultative pathogens that are phagocytosed and survive within the host as a chronic infection. Despite these parallels, we typically refer to mitochondria as “symbionts” and rarely consider them as perhaps the most successful example of long-term chronic infection. Here, we will explore critical aspects of mitochondrial structure and function and consider what we might learn by refocusing our attention on mitochondria as bacteria that are uniquely adapted to their host cell, i.e., as a chronic infection tolerated by its eukaryotic host.