Discovery Medicine[JOURNAL]
Sun
200 papers
Nesfatin-1 Suppresses Inflammation in Bronchopulmonary Dysplasia by Regulating HMGB-1/TLR4/p65/NLRP3 Signaling Pathway.
Yang X, Luo G, Lou F
Discov Med · 2025 May · PMID 40415368 · Publisher ↗
BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common respiratory disease in premature infants. Nesfatin-1 is considered for the treatment of BPD. This study aimed to explore the anti-inflammatory effect of nesfatin-1...
BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common respiratory disease in premature infants. Nesfatin-1 is considered for the treatment of BPD. This study aimed to explore the anti-inflammatory effect of nesfatin-1 in the treatment of BPD. METHODS: Hyperoxia-induced newborn rats and transfected primary type II alveolar epithelial cells (AECIIs) were used to evaluate nesfatin-1's efficacy in treating BPD. Lung damage was assessed by means of wet-dry ratio measurement, Hematoxylin and Eosin staining, Masson staining, Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, and Western blotting. Interleukin 6 (), tumor necrosis factor alpha (), and interleukin 1β () levels were measured by Enzyme-linked immunosorbent assay (ELISA) and quantitative polymerase chain reaction (qPCR). Neutrophils in bronchoalveolar lavage fluid were counted. High mobility group box 1 (HMGB-1), Toll-like receptor 4 (TLR4), nuclear factor kappa-light-chain-enhancer of activated B cells p65 subunit (p65), and NOD-like receptor family pyrin domain containing 3 (NLRP3) expressions were analyzed using Western blotting, while NLRP3 expression was detected through immunohistochemistry. AECIIs' viability, apoptosis, and reactive oxygen species (ROS) levels were assessed using cell counting kit-8 (CCK8), flow cytometry, and immunofluorescence, respectively. An immunofluorescence approach was used to detect surfactant protein C and ROS levels. RESULTS: , nesfatin-1 treatment significantly reduced the lung wet-dry ratio, increased the body weight of rats, inhibited apoptosis, alleviated lung damage, decreased inflammation, and lowered neutrophil counts ( < 0.05). , nesfatin-1 enhanced cell viability, inhibited apoptosis, decreased ROS levels ( < 0.01) and decreased mRNA levels of , , and ( < 0.05) while increasing mRNA ( < 0.01). In and scenarios, nesfatin-1 inhibited HMGB-1, TLR4, p65, and NLRP3 protein expression ( < 0.05). In hyperoxia cells, silencing showed similar results to those of nesfatin-1 treatment, while overexpression antagonized the effects of nesfatin-1 treatment. CONCLUSION: This study showed that nesfatin-1 reduces neutrophils and suppresses inflammation via the HMGB-1/TLR4/Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB)/NLRP3 pathway, suggesting its potential clinical application in the treatment of BPD.
Docosahexaenoic Acid Attenuates Endoplasmic Reticulum Stress-Induced Neuron Apoptosis by Targeting Presenilin 2.
Ma B, Ye H, Meng G … +2 more , Hu W, Zhao W
Discov Med · 2025 May · PMID 40415367 · Publisher ↗
BACKGROUND: Traumatic neuronal injury (TNI), a type of traumatic brain injury (TBI), features apoptosis of cortical neurons. Knowing that docosahexaenoic acid (DHA) is enriched in the neuronal cell membranes and related...
BACKGROUND: Traumatic neuronal injury (TNI), a type of traumatic brain injury (TBI), features apoptosis of cortical neurons. Knowing that docosahexaenoic acid (DHA) is enriched in the neuronal cell membranes and related to brain function, we aimed to study the mechanism behind the effect of DHA on TNI model neurons. METHODS: Neurons were derived from Sprague-Dawley rats and a TNI model was established by using a rotating scribe injury device. Four experimental groups were set up based on neuronal injury and DHA concentration, namely the Control, TNI, TNI + DHA-25, and TNI + DHA-50 groups. The cell morphology, toxicity and neuron apoptosis were assessed by means of light microscopy, lactate dehydrogenase (LDH) release assessment, and terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay, respectively. Protein levels of sorcin (SRI), activating transcription factor 6 (ATF6), glucose-regulated protein 78 (GRP78), C/Ebp-homologous protein (CHOP), cleaved-caspase-12 (C-Cas-12) and presenilin 2 (PSEN2) were determined by western blotting. PSEN2 overexpression plasmid and short hairpin RNA against SRI (shSRI) were used for transfection. In the transfection experiment, neurons were assigned into six groups, namely TNI, TNI + DHA-50, short hairpin RNA for negative control (shNC) + Vector, PSEN2, shSRI, and PSEN2 + shSRI groups, and the latter four groups were treated with TNI + DHA. and mRNA levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Cytotoxicity-, apoptosis- and endoplasmic reticulum stress (ERS)-related proteins were examined in the neurons. RESULTS: DHA at a dose of 50 μM attenuated TNI-induced neuronal injury, cell toxicity ( < 0.001), cell apoptosis ( < 0.001), and levels of ERS-related proteins (ATF6, GRP78, CHOP and C-Cas-12) ( < 0.001), PSEN2 and SRI in neurons ( < 0.001). Besides, 50 μM of DHA regulated cell toxicity, cell apoptosis and ERS-related proteins by modulating the interaction between PSEN2 and SRI in neurons ( < 0.05). CONCLUSIONS: DHA mitigates neuron apoptosis induced by SRI-activated ERS via targeting PSEN2.
Investigation of Berberine's Cardioprotective Effects and Its Association With the Notch Signaling Pathway in Rat Myocardial Ischemia-Reperfusion Injury.
Jiang D, Tang X, Yang H … +1 more , Cheng H
Discov Med · 2025 May · PMID 40415366 · Publisher ↗
BACKGROUND: Ischemia-reperfusion injury poses a significant challenge in cardiac pathology, leading to myocardial cell damage and dysfunction. Berberine, a natural compound, has shown potential cardioprotective effects....
BACKGROUND: Ischemia-reperfusion injury poses a significant challenge in cardiac pathology, leading to myocardial cell damage and dysfunction. Berberine, a natural compound, has shown potential cardioprotective effects. This study aims to investigate the protective role of berberine in myocardial cells post-ischemia-reperfusion injury, focusing on its modulation of the Neurogenic locus notch homolog protein (Notch) signaling pathway. METHODS: Male rats were subjected to ischemia-reperfusion injury and treated with berberine. Triphenyltetrazolium chloride (TTC) and hematoxylin and eosin (HE) staining were used to assess myocardial tissue damage and structure. Gene expression of Neurogenic locus notch homolog protein 1 (), Hairy and enhancer of split-1 (), B-cell lymphoma 2 (), and Bcl-2-associated X protein () was analyzed using Quantitative Polymerase Chain Reaction (qPCR). Apoptosis rate in myocardial cells was evaluated using Terminal deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) staining. Protein expression of Bcl-2 and Bax was examined. Molecular docking and Microscale Thermophoresis (MST) validation were performed to investigate the interaction between berberine and Notch1. RESULTS: Berberine treatment was associated with effective protection of myocardial tissue post-ischemia-reperfusion, indicated by reduced infarct area ( < 0.05) and improvements in tissue structure. Coinciding with these observations, berberine also influenced the expression of Notch1, Hes1, Bcl-2, and Bax in myocardial tissue, alongside modulation of Bcl-2 and Bax protein levels ( < 0.05). Additionally, molecular studies revealed that berberine binds to Notch1, suggesting a potential interaction. CONCLUSION: The study suggests an association between berberine's cardioprotective effects and Notch signaling pathway modulation in the context of myocardial ischemia-reperfusion injury. While berberine was found to bind Notch1 and affect gene and protein expression related to apoptosis, further research is necessary to determine whether these effects directly contribute to reduced apoptosis and enhanced cell survival.
Complex Tissue Alterations After Socket Preservation With Demineralized Bone Matrix Binding With Growth Factors: A Study in the Beagle Dogs.
Zhang BH, Zhu JH, Qiu TC … +2 more , Han JM, Guo CB
Discov Med · 2025 May · PMID 40415365 · Publisher ↗
BACKGROUND: To study the hard tissue change after tooth extraction filled with demineralized bone matrix (DBM) collagen scaffold bound with growth factors. METHODS: In 15 Beagle dogs, 90 socket sites were prepared by bil...
BACKGROUND: To study the hard tissue change after tooth extraction filled with demineralized bone matrix (DBM) collagen scaffold bound with growth factors. METHODS: In 15 Beagle dogs, 90 socket sites were prepared by bilateral extraction of the mandibular premolars. Sockets were divided into six groups as follows: Group A: Blank (without any material); Group B: filled with HealiAid® Collagen Wound Dressing (SA001020, Maxigen Biotech Inc.); Group C: DBM; Group D: DBM-collagen-binding domain (CBD)-basic fibroblast growth factor (bFGF) (0.05 μg/mL); Group E: DBM-CBD-bFGF (5 μg/mL); Group F: DBM-CBD-bFGF (5 μg/mL) + bone morphogenetic protein 2 (BMP) (300 μg/mL). The changes in width and height of the buccal and lingual bone plates were determined by Cone-Beam Computed Tomography (CBCT) scan. At the 1st, 2nd, 3rd months after surgery, a total of 15 dogs were euthanized for Micro-computed tomography (Micro-CT) scan and histological examinations. RESULT: At 1 month postoperatively, the differences in buccal bone height (BBH) of Group D [0.34 (0.18, 1.02) mm] and Group F [0.12 (0.04, 1.38) mm] were significantly lower than that of Group E [2.07 (1.03, 2.46) mm] (Group D vs. Group E, p = 0.032; Group F vs. Group E, = 0.047). In the horizontal direction, from 1 to 3 months postoperatively, the median horizontal width changes at 1 mm, 3 mm and 5 mm below the alveolar ridge of both Group D and Group F were generally smaller than those of Group E, but there was no significant difference between the groups ( > 0.05). No significant differences were found among the indices of bone micro-structure measured by Micro-CT scan ( > 0.05). However, the fibers in the new bone zone of Groups E and F exhibited a higher level of maturity, as observed by Masson's trichrome stain. CONCLUSION: Compared with the blank group and the control group, the DBM group with the addition of growth factors showed good alveolar ridge preservation, reduced bone resorption, and promoted the bone maturation of the extraction socket.
Puerarin Inhibits the Development of Thyroid Cancer Through KLF2/NOTCH1 Signaling.
Zhou Y, Li W, Huang H
Discov Med · 2025 May · PMID 40415364 · Publisher ↗
BACKGROUND: Puerarin is the major bioactive ingredient extracted from Pueraria lobata. Puerarin has an antitumor effect on many kinds of cancer. Accordingly, the aim of this study was to investigate the effect and mechan...
BACKGROUND: Puerarin is the major bioactive ingredient extracted from Pueraria lobata. Puerarin has an antitumor effect on many kinds of cancer. Accordingly, the aim of this study was to investigate the effect and mechanism of puerarin on thyroid cancer (TC) proliferation and apoptosis. METHODS: TC and normal thyroid cells experienced exposure to puerarin at 0, 10, 50, or 100 μg/mL. Impacts of short hairpin RNA of Kruppel-like factor 2 (sh), overexpression, and notch receptor 1 () overexpression on the malignant biological phenotypes of TC cells were gauged by cell function experiments. Quantification of KLF2, NOTCH1, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X (Bax), and Cleaved caspase 3 was completed using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analyses. and levels in TC were analyzed using the Encyclopedia of RNA Interactomes (ENCORI) project database. Through rescue experiments, whether the anti-tumor effect of puerarin on TC is realized via / axis was dissected. RESULTS: Puerarin inhibited the malignant growth of TC cells by up-regulating , which was reversed by sh. was lowly expressed in TC. Notably, was negatively regulated by and was highly expressed in TC. overexpression abrogated overexpression-inhibited malignant growth of TC cells, which was manifested as increased cell proliferation and Bcl-2 as well as decreased cell apoptosis, Bax and Cleaved caspase 3. CONCLUSION: Puerarin suppresses TC cell proliferation and apoptosis via the / axis.
Spermine Enhances Cholesterol Effluence of Macrophages Through Caspase 2-Mediated Autophagy.
Yuan X, Mao Y, Chen Y … +3 more , Zhuang J, Chen D, Li X
Discov Med · 2025 May · PMID 40415363 · Publisher ↗
BACKGROUND: Spermine (SPM) is known to play a role in regulating cholesterol efflux of macrophages, which is a critical anti-atherosclerotic pathway, but the underlying mechanism remains elusive. The deficiency of caspas...
BACKGROUND: Spermine (SPM) is known to play a role in regulating cholesterol efflux of macrophages, which is a critical anti-atherosclerotic pathway, but the underlying mechanism remains elusive. The deficiency of caspase 2 (), a target of SPM, can induce autophagy, which promotes cholesterol efflux in atherosclerosis. Herein, we aimed to explore whether SPM could regulate -mediated autophagy in the cholesterol efflux of macrophages. METHODS: Human THP-1 monocytes were induced into macrophages. After transfection and treatment with SPM or autophagy inhibitor 3-methyladenine (3-MA), the cholesterol uptake of THP-1 cell-derived macrophages and the lipid accumulation were examined using Dil-oxidized low-density lipoprotein (Dil-oxLDL) uptake assay and Oil Red O staining, respectively. The cholesterol efflux was measured by means of [H]-cholesterol detection. Quantification of CASP2 and factors related to autophagy and apoptosis was completed using Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: SPM treatment boosted cholesterol efflux and prevented lipid accumulation of THP-1 cell-derived macrophages ( < 0.001), without inducing cholesterol uptake of THP-1 cell-derived macrophages ( > 0.05). SPM upregulated the expression of autophagy-related 5 (ATG5), light chain 3 (LC3) II/LC3 I, and B-cell lymphoma-2 (Bcl-2) while downregulating Sequestosome 1 (P62) and CASP2 levels ( < 0.01). Treatment with 3-MA reversed the effects of SPM on cholesterol efflux, lipid accumulation, and autophagy-related protein expression ( < 0.01). Separately, overexpression offset the impacts of SPM on cholesterol efflux, lipid accumulation, and expressions of proteins related to autophagy and apoptosis ( < 0.05). CONCLUSION: SPM promotes autophagy to enhance the cholesterol efflux of THP-1 cell-derived macrophages by downregulating expression.
Investigating the Role of Ferroptosis in Soman-Induced Neurotoxicity: A Pathway to New Potential Therapeutic Targets.
Yang X, Zhao J, Shan Y … +5 more , Wang M, Xu X, Zhuang T, Zhang J, Nie Z
Discov Med · 2025 May · PMID 40415362 · Publisher ↗
BACKGROUND: Soman is a highly toxic organophosphorus nerve agent that can cause persistent neurotoxicity. However, the mechanism of soman-induced neurotoxicity has not been completely clarified. Ferroptosis, a novel type...
BACKGROUND: Soman is a highly toxic organophosphorus nerve agent that can cause persistent neurotoxicity. However, the mechanism of soman-induced neurotoxicity has not been completely clarified. Ferroptosis, a novel type of programmed cell death, has been confirmed to precipitate neurotoxicity caused by organophosphorus flame retardant. Since studies on the relationship between ferroptosis and soman-induced neurotoxicity are lacking, the purpose of this research is to explore the mechanism of soman-induced neurotoxicity from the perspective of ferroptosis. METHODS: Institute of Cancer Research (ICR) mice were injected subcutaneously with low-dose soman (1/2 × median lethal dose (LD)) daily for seven consecutive days to evaluate the neurotoxic injury caused by soman through alterations in body weight, cholinesterase activity, and neuronal counting. The morphologic changes of neurons and levels of ferroptosis-related molecules, including glutamate, glutathione (GSH), system xc (xCT), glutathione peroxidase 4 (GPX4), and malondialdehyde (MDA), were evaluated to confirm the involvement of ferroptosis in soman-induced neurotoxicity. The ferroptosis inhibitor ferrostatin-1 (Fer-1, 5 mg/kg) was administered daily immediately following soman exposure to further explore the role of ferroptosis. RESULTS: Repeated exposure to low-dose soman caused weight loss and neuronal death, and reduced cholinesterase activity. Meanwhile, it induced morphological changes of neurons characteristic of ferroptosis, increased glutamate and MDA levels, decreased GSH, and downregulated xCT and GPX4. Conversely, Fer-1 treatment mitigated neurotoxic injury and reversed the changes in ferroptosis-related molecule levels. CONCLUSION: These findings indicate that ferroptosis engages in the course of neurotoxicity caused by soman and exerts a harmful effect via the glutamate/xCT/GPX4 pathway. This study provides new potential therapeutic targets for countermeasures against soman exposure.
Protective Effect of Resveratrol Against Peri-Implant Inflammation and Oxidative Stress: An Study.
Zhang C, Jiao B, Qian D
Discov Med · 2025 May · PMID 40415361 · Publisher ↗
BACKGROUND: Implants are commonly used to repair teeth. However, with their widespread use, the incidence of peri-implantitis has also increased. The Mitogen activated protein kinase/Protein kinase B/Nuclear factor kappa...
BACKGROUND: Implants are commonly used to repair teeth. However, with their widespread use, the incidence of peri-implantitis has also increased. The Mitogen activated protein kinase/Protein kinase B/Nuclear factor kappa-B (MAPK/AKT/NF-κB) signaling pathway is associated with various inflammatory responses. This study aims to evaluate the role of resveratrol in managing peri-implant inflammation and its regulatory effect on the MAPK/AKT/NF-κB signaling pathway. METHODS: Peri-implant bone loss was measured by micro-computed tomography, and gingival cell apoptosis was detected by the TdT-mediated dUTP-biotin nick end labeling (TUNEL) method. The levels of apoptosis-related proteins (caspase-3, B-cell lymphoma-2 (Bcl-2)), inflammation-related proteins (caspase-1, phospho-p65 (p-p65)/p65), and MAPK/AKT/NF-κB signaling pathway-related proteins (p38 MAPK, AKT, and NF-κB) in inflammatory tissue were determined by western blotting. Enzyme-linked immunosorbent assay was used to measure the levels of tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), IL-1β, IL-4, and IL-10 in the serum of mice. Biochemical kits were used to measure the levels of malondialdehyde (MDA), nitric oxide (NO), and superoxide dismutase (SOD) in inflammatory tissue. The intercellular reactive oxygen species (ROS) content was detected by ROS staining, and the morphology of inflammatory tissue was observed by hematoxylin-eosin (HE) and tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: The administration of resveratrol significantly reduced bone loss around the implant and prevented the apoptosis of gingival cells ( < 0.001). Additionally, resveratrol effectively reduced the concentration of serum inflammatory factors and inflammation-related proteins, namely caspase-1 and p-p65/p65 ( < 0.001). Additionally, in the resveratrol intervention group, the contents of MDA and NO, and the level of ROS decreased, while the content of SOD increased ( < 0.05). The HE, immunofluorescence, and TRAP staining results confirmed that resveratrol effectively reduced the number of total inflammatory cells in gingival tissue ( < 0.05). CONCLUSION: Resveratrol has the potential to alleviate peri-implant inflammation and regulate the MAPK/AKT/NF-κB signaling pathway. This offers a novel approach for drug-based clinical interventions in peri-implant inflammation.
Mechanism Underlying Hyperbaric Oxygen's Effect on Nitric Oxide in an Model of Traumatic Brain Injury.
Zhou Q, Wu S, Zhu H
Discov Med · 2025 May · PMID 40415360 · Publisher ↗
BACKGROUND: Hyperbaric oxygen (HBO) therapy functions as a possible therapeutic option for traumatic brain injury (TBI). The aim of this study is to detect the mechanism of HBO on TBI. METHODS: Neurons and astrocytes iso...
BACKGROUND: Hyperbaric oxygen (HBO) therapy functions as a possible therapeutic option for traumatic brain injury (TBI). The aim of this study is to detect the mechanism of HBO on TBI. METHODS: Neurons and astrocytes isolated from healthy neonatal rat cortices were co-cultured, a TBI model was established, and cells were cultured under HBO conditions. Neuron/astrocyte viability and glutamate transporter-1 (GLT-1) expression in neuron/astrocyte co-cultures were assessed by immunofluorescence. Tumor necrosis factor (TNF)-α/tumor necrosis factor receptor 1 (TNFR1)/nitric oxide (NO)/neuronal nitric oxide synthase (nNOS)/interleukin (IL)-1β/inducible nitric oxide synthase (iNOS)/GLT-1 levels in neuron/astrocyte co-cultures were detected using quantitative real-time polymerase chain reaction (qRT-PCR), colorimetry, and western blotting. To identify the key role of the target gene TNF receptor 1 () in HBO therapy, was silenced or overexpressed. After transfection, the cellular functions and the levels of related factors were re-examined. RESULTS: HBO (2 atmospheric absolute (ATA) for 30/60 min) attenuated the effect of TBI-induced on decrease of neuronal viability, increase of astrocyte viability, up-regulation of TNF-α, IL-1β, NO, nNOS, iNOS, and TNFR1 levels, down-regulation of GLT-1 levels, and reduce of GLT-1-positive astrocytes in neuron/astrocyte co-cultures ( < 0.05). TNFR1 knockdown and HBO (2 ATA for 60 min) enhanced neuronal viability, decreased astrocyte viability, and down-regulated TNF-α, IL-1β, NO, nNOS, iNOS, and TNFR1 levels in TBI-induced neuron/astrocyte co-cultures ( < 0.01). overexpression reversed the above role of HBO in TBI-induced neuron/astrocyte co-cultures. HBO (2 ATA for 60 min) up-regulated GLT-1 levels in TBI-induced neuron/astrocyte co-cultures ( < 0.05). CONCLUSIONS: HBO inhibits TNFR1 expression to down-regulate NO content in TBI in an model.
Glycyrrhizic Acid Ameliorates Sepsis-Induced Acute Lung Injury Through Suppression of Endoplasmic Reticulum Stress.
Fang L, Wang X, Guan W
Discov Med · 2025 May · PMID 40415359 · Publisher ↗
BACKGROUND: Sepsis-mediated acute lung injury (ALI) has a high mortality rate, and glycyrrhizic acid (GA) possesses diverse pharmacologic activities. Herein, we investigated the role of GA in attenuating sepsis-triggered...
BACKGROUND: Sepsis-mediated acute lung injury (ALI) has a high mortality rate, and glycyrrhizic acid (GA) possesses diverse pharmacologic activities. Herein, we investigated the role of GA in attenuating sepsis-triggered ALI. METHODS: Septic ALI was induced by cecal ligation and puncture (CLP). Mice were assigned into 5 groups with varied treatments. Their time of death was recorded every 6 hours after surgery. The wet/dry (W/D) weight ratio of the lung was measured. Observation of lung tissues was conducted by hematoxylin and eosin (HE) staining. Protein concentration in bronchoalveolar lavage fluid (BALF), levels of inflammatory cytokines, and production of reactive oxygen species (ROS) were detected by bicinchoninic acid (BCA), enzyme-linked immunosorbent assay, and dihydroethidium (DHE) staining, respectively. Endoplasmic reticulum (ER) stress-related genes, heme oxygenase-1 (HO-1), Janus kinase 2 (JAK2), and signal transducer and activator of transcription 3 (STAT3) levels were quantified by western blot. RESULTS: GA remarkably elevated survival rate and mitigated lung injury ( < 0.05). CLP markedly increased the W/D weight ratio and BALF protein concentration, while GA did the opposite ( < 0.05). CLP promoted interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), phosphorylation of eIF2α (p-eIF2α), activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), the phosphorylation level of JAK/STAT3, along with DHE intensity, while GA showed opposite effects ( < 0.01). Additionally, GA markedly enhanced the HO-1 level ( < 0.05). CONCLUSION: GA holds promise for future improvements in treating sepsis-induced ALI.
The Roles of CBX4 in Gastrointestinal Cancer.
Zheng X, Ding J, Chen Y … +1 more , Li Z
Discov Med · 2025 May · PMID 40415358 · Publisher ↗
Chromobox 4 (CBX4) is a polycomb group protein involved in epigenetic regulation via the polycomb repressive complex 1 (PRC1) and its small ubiquitin-like modifier (SUMO) ligase activity. It has been reported that CBX4 p...
Chromobox 4 (CBX4) is a polycomb group protein involved in epigenetic regulation via the polycomb repressive complex 1 (PRC1) and its small ubiquitin-like modifier (SUMO) ligase activity. It has been reported that CBX4 plays several oncogenic functions, contributing to tumor growth, metastasis, and therapeutic resistance. Elevated CBX4 expression is also correlated with poor patient prognosis and advanced tumor stages in multiple gastrointestinal cancers. Preclinical studies demonstrate that targeting CBX4 using small-molecule inhibitors, RNA interference, and monoclonal antibodies mitigates tumor progression and enhances treatment efficacy. Additionally, CBX4 exhibits potential as a diagnostic biomarker, with its high expression levels serving as an indicator of early-stage disease. Despite these advances, further research is needed to elucidate molecular mechanisms behind CBX4's involvement in carcinogenesis to accelerate the translation of tools and approaches targeting CBX4 to clinical settings. The aim of this paper is to review the role of CBX4 in gastrointestinal cancers, including gastric, liver, colorectal, and esophageal cancers, offering invaluable insights for developing novel diagnostic tools and targeted therapies to improve patient outcomes.
Targeting Ferroptosis via Mitochondria Dynamics in Myocardial Ischemia/Reperfusion Injury.
Cruz-Gregorio A
Discov Med · 2025 May · PMID 40415357 · Publisher ↗
Myocardial infarction remains a significant worldwide public health issue, primarily owing to its mortality and morbidity rates. This condition is due to myocardial ischemia, appearing once the heart's blood flow is obst...
Myocardial infarction remains a significant worldwide public health issue, primarily owing to its mortality and morbidity rates. This condition is due to myocardial ischemia, appearing once the heart's blood flow is obstructed or significantly reduced, causing the death of heart muscle cells. Reperfusion prevents further death of cardiomyocytes, restoring coronary flow. However, the initial lack of coronary blood flow and the subsequent restoration induce ischemia/reperfusion injury (IRI) due to abrupt metabolic and biochemical changes, such as calcium overload, activation of inflammatory cells, and oxidative stress (OS). OS is associated with damage to cellular biomolecules such as proteins, lipids, DNA, or carbohydrates and with organelles such as mitochondria, activating mitochondrial dynamics. These oxidative conditions may also trigger ferroptosis, cell death linked to cellular oxidation. While ferroptosis induction is desirable in certain diseases like cancer, it is not beneficial in situations such as myocardial IRI. Although considerable research has been conducted on ferroptosis in myocardial IRI, the potential impact of reducing ferroptosis via mitochondrial dynamics in IRI remains to be reviewed. Consequently, this review concentrates on mitochondrial dynamics during myocardial ferroptosis in IRI and explores the potential therapy to inhibit myocardial ferroptosis by targeting mitochondrial dynamics to mitigate IRI.
Adjuvant Immunotherapy in Microsatellite Instability-High Colon Cancer: A Literature Review on Efficacy, Challenges, and Future Directions.
Karri V, Nimkar S, Dalia SM
Discov Med · 2025 May · PMID 40415356 · Publisher ↗
Colon cancer accounts for nearly 10% of all cancer diagnoses annually. Microsatellite instability-high (MSI-H) colon cancer is a particularly aggressive subtype of colon cancer that is known to have a significant number...
Colon cancer accounts for nearly 10% of all cancer diagnoses annually. Microsatellite instability-high (MSI-H) colon cancer is a particularly aggressive subtype of colon cancer that is known to have a significant number of genetic mutations. Microsatellite instability (MSI) refers to genetic hypermutability caused by the dysfunction of the DNA mismatch repair () system, which leads to errors in repetitive DNA sequences and is a hallmark of certain cancers, including MSI-H colon cancer. MSI-H colon cancer acts on the DNA mismatch repair system causing an accumulation of mutations in microsatellite regions of the DNA. These mutations have been linked with increased tumorigenesis and decreased response to conventional forms of chemotherapy for colon cancer. However, this increased tumor burden results in significant production of neoantigens which makes these tumors immunogenic and therefore perfect candidates for pairing with immunotherapy. As a result, adjuvant immunotherapy in MSI-H colon cancer has become a burgeoning field of research, and synthesizing information regarding the efficacy of these immunotherapies is the goal of this literature review. Pembrolizumab, a monoclonal antibody targeting programmed cell death protein 1 (), was among the first to receive approval for the treatment of MSI-H colon cancer and was observed to have significant efficacy versus traditional chemotherapy with statistically significant improvements in metrics such as progression-free survival (PFS), overall response (OR), and disease-free survival (DFS). Similarly, Nivolumab, another inhibitor, and the combination of nivolumab and ipilimumab (a cytotoxic T-lymphocyte-associated protein 4 () inhibitor) were granted Food and Drug Administration (FDA) approval for the treatment of MSI-H colon cancer and have also shown the ability to outperform traditional chemotherapy with a higher overall response rate (ORR), mean PFS, and overall survival rates. Off-label uses of existing adjuvant immunotherapies such as Atezolizumab (a programmed death-ligand 1 () inhibitor) and Durvalumab (a inhibitor) have shown promise with preliminary results showing higher DFS and recurrence-free survival but need further data collection. Emerging immunotherapy targets such as lymphocyte activation gene 3 () and T-cell immunoreceptor with immunoglobin and Immunoreceptor Tyrosine-based Inhibitory Motif domains () inhibitors show preliminary promise and may one day become a part of the approach to the treatment of MSI-H colon cancer. This review highlights current advancements, challenges, and emerging trends in the application of immunotherapy for MSI-H colon cancer, with a focus on improving patient outcomes.
Is SARS-CoV-2 Spike Evolution Being Retargeted at the N-Terminal Domain?
Focosi D, Alfonsi T, Bernasconi A
Discov Med · 2025 May · PMID 40415355 · Publisher ↗
Since 2020, most of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) evolution has been focused on the receptor-binding domain (RBD) of the Spike protein. Nevertheless, the N-terminal domain (NTD) of Spike ha...
Since 2020, most of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) evolution has been focused on the receptor-binding domain (RBD) of the Spike protein. Nevertheless, the N-terminal domain (NTD) of Spike has been shown to represent the target for neutralizing antibodies, and accordingly, NTD mutations are relevant for immune escape. In 2024, after the introduction of the BA.2.86 saltation variant (heavily mutated at the NTD antigenic supersite), its descendant JN.1 has further explored NTD evolution in its progeny, largely focused on positions 22, 31, 59 and 60. In this review, we explore such convergent evolution in detail and hypothesize the underlying mechanisms.
The Cerebellum as a Predictor: Recent Insights Into Cognitive Control and Extension of Kalman Filter Theory to Cognition.
Kakei S, Tanaka H, Mitoma H … +1 more , Manto M
Discov Med · 2025 May · PMID 40415354 · Publisher ↗
Traditionally viewed as a motor control center, the cerebellum is increasingly recognized as a crucial component of a neural network that enables adaptive behavior across various domains, including cognition, affect, emo...
Traditionally viewed as a motor control center, the cerebellum is increasingly recognized as a crucial component of a neural network that enables adaptive behavior across various domains, including cognition, affect, emotion, and social interactions. Recent clinical studies have linked cerebellar dysfunction to impairments in mentalizing and narrative coherence in autism spectrum disorder (ASD). Given that narratives involve the temporal sequencing of causally related events and actions, these findings imply the potential role of the cerebellum in predictive sequence. The aim of this review is to dissect the neural circuitry and computational mechanisms underlying cerebellar predictive cognitive control. We propose that the Kalman filter model, which has been applied successfully to the motor cerebrocerebellum, can be extended to the non-motor (cognitive/affective/social) regions. In sharp contrast, the cerebral cortex employs a recurrent network architecture, as evidenced by intracortical connections, which underlies hierarchical processing in areas such as the visual and motor cortices. Surprisingly, the computational principles of the cerebrocerebellar loop have received relatively little attention in computational and theoretical neuroscience. We stress the need for a comprehensive theory on cerebrocerebellar connectivity that integrates the distinct neural mechanisms of the cerebrum and cerebellum, to help understand the role of this network in cognitive, affective, and social functions. Our theory provides a theoretical framework that explains how the cerebellum deals with motor and non-motor operations. The Kalman filter theory fits with two major requirements: sequencing and predictions. We propose a core operational mechanism for motor, cognitive, affective and social operations handled by the cerebellar circuitry.
The Relationship of Gene Polymorphism With P-Wave Peak Time and P-Wave Dispersion in Elderly Patients With Paroxysmal Atrial Fibrillation.
Wang W, Liang G, Bian A … +3 more , Luo D, Cai L, Wang X
Discov Med · 2025 Apr · PMID 40287813 · Publisher ↗
BACKGROUND: The incidence of atrial fibrillation (AF) presents a markedly increasing trend with advancing age. Thus, with the growing population of elderly individuals, AF has emerged as a significant medical and socioec...
BACKGROUND: The incidence of atrial fibrillation (AF) presents a markedly increasing trend with advancing age. Thus, with the growing population of elderly individuals, AF has emerged as a significant medical and socioeconomic problem. The objective of this study was to investigate the correlation of mitogen-activated protein kinase 10P () gene polymorphism with P-wave peak time (Pwd) and P-wave dispersion (Pmax) among elderly individuals with paroxysmal AF. METHODS: From January 2021 to October 2022, 125 elderly patients with essential hypertension were recruited for research in our Cardiology Department. According to the European Society of Cardiology (ESC) Atrial Fibrillation Management Guidelines, 53 patients with ≥2 documented paroxysmal AF episodes in the previous year were classified as the observation group, while 72 patients without AF formed the control group. Patient data were collected, and a 12-lead electrocardiogram was used to measure Pwd and Pmax. genotype was identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The association between genotype and AF risk, as well as the impact of different genotypes on Pwd and Pmax parameters, were evaluated. RESULTS: The baseline characteristics did not show any significant difference between the two groups ( > 0.05). The values of Pwd and Pmax in the observation group were significantly greater than those in the control group ( < 0.05). The occurrence rate of the genotype was lower in the observation group than in the control group ( < 0.05), while the occurrence rates of the and genotypes were higher in the observation group than in the control group ( < 0.05). Additionally, the frequency of the allele was higher in the observation group than in the control group ( < 0.05). AF patients with the + genotype exhibited higher Pwd and Pmax values compared to those with the genotype ( < 0.05). Patients without AF who had the + genotype had higher Pwd and Pmax values compared to those with the genotype ( < 0.05). CONCLUSION: In elderly patients, the presence of the allele in the gene polymorphism is linked to an increased risk of AF, as well as Pwd and Pmax. This study provides valuable insights into the potential role of gene variations in influencing P-wave characteristics during the development of paroxysmal AF in elderly patients.
Curcumin Attenuates PD-L1-Positive Neutrophil-Induced T-Lymphocyte Apoptosis and Alleviates Lung Injury During Sepsis in Rats.
Zou J, Guo J, Hu G … +1 more , Qian Y
Discov Med · 2025 Apr · PMID 40287812 · Publisher ↗
OBJECTIVE: This study aimed to investigate the effects of curcumin (Cur) on programmed cell death 1 ligand 1 (PD-L1) expression in neutrophils from septic rats and its regulatory influence on T-lymphocyte apoptosis and l...
OBJECTIVE: This study aimed to investigate the effects of curcumin (Cur) on programmed cell death 1 ligand 1 (PD-L1) expression in neutrophils from septic rats and its regulatory influence on T-lymphocyte apoptosis and lung injury in a rat sepsis model. METHODS: Cecum ligation and puncture (CLP) experiments were conducted to establish a rat sepsis model, with the subsequent grouping of rats based on curcumin administration. Rats were monitored for 7 days to assess the 7-day survival rate. Serum, lung tissues, and thymus tissues were collected. Flow cytometry and immunohistochemistry were utilized to assess the number of PD-L1-positive neutrophils and PD-L1 positivity in both blood and lung tissues. Hematoxylin and eosin (HE) staining and Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) histochemistry were employed to examine pathological changes and cell apoptosis in lung and thymus tissues. Furthermore, a kit was employed to measure the activity of myeloperoxidase (MPO), a marker of neutrophil activation, in lung tissues. Enzyme-linked immunosorbent assay (ELISA) was utilized to determine plasma levels of inflammatory factors. Neutrophils were extracted and co-cultured with normal T lymphocytes. TUNEL assays were used to evaluate T-lymphocyte apoptosis, and Western blotting was performed to analyze the expression of PD-L1 and programmed cell death 1 (PD-1). RESULTS: In experiments, septic rats exhibited a markedly low 7-day survival rate of 12.5%, significantly elevated PD-L1 expression and positivity in blood and lung tissues, severe lung and thymus tissue damage, and significant cell apoptosis. Additionally, they had increased plasma concentrations of tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6), and decreased plasma concentration of interleukin 10 (IL-10) compared to normal and sham-operated rats ( < 0.05). Curcumin-treated septic rats demonstrated significantly improved 7-day survival, reduced PD-L1 expression and positivity in blood and lung tissues, mitigated lung and thymus tissue injury and cell apoptosis, lower plasma concentrations of TNF-α and IL-6, and higher plasma concentrations of IL-10 ( < 0.05). experiments showed that co-culture of T lymphocytes with neutrophils from septic rats resulted in a significantly higher rate of T cell apoptosis and increased expression of PD-L1 and PD-1 compared to co-culture with neutrophils from sham-operated rats ( < 0.05). Neutrophils from curcumin-treated rats exhibited a significantly lower rate of apoptosis in co-cultured T lymphocytes and decreased expression of PD-L1 and PD-1 ( < 0.05). The addition of PD-L1 antibodies to co-cultured neutrophils and T lymphocytes in septic rats significantly reduced T lymphocyte mortality ( < 0.05). CONCLUSION: Curcumin effectively mitigates lung and thymus injury during sepsis and attenuates the apoptosis of rat T lymphocytes by down-regulating PD-L1 expression in centrocytes, both and .
Effects of Aerobic Exercise and Intermittent Fasting on Fecal Microbiome Diversity in Obese Mice.
Yuan L, Luan Y, Hong W … +2 more , Zhang B, Xiong Y
Discov Med · 2025 Apr · PMID 40287811 · Publisher ↗
BACKGROUND: Obesity threatens human health, and interventions to reduce obesity may have important effects on the gut microbiota. This study investigated alterations in gut microbial composition in response to aerobic ex...
BACKGROUND: Obesity threatens human health, and interventions to reduce obesity may have important effects on the gut microbiota. This study investigated alterations in gut microbial composition in response to aerobic exercise (AE) and intermittent fasting (IF). METHODS: We randomly divided mice into four groups of seven mice each: normal, obesity, exercise, and fasting. The normal group was fed a Chow Diet, whereas the other three groups were fed a High Fat Diet (HFD). After 13 weeks, the exercise group was subjected to aerobic treadmill running, and the fasting group started IF for 8 weeks. We then analyzed the composition of the fecal microbiome in all mice at the end of 21 weeks. RESULTS: Our investigation revealed that the HFD significantly influenced , , and . AE predominantly affected and , indicating its impact on enhancing microbial taxa associated with improved metabolic health profiles. On the other hand, IF prominently altered the abundance of and , which are known for their roles in enhancing glucolipid metabolism and anti-inflammatory activity. Furthermore, the exercise group displayed increased diversity within , potentially associated with anti-inflammatory benefits. The IF intervention was particularly effective in enriching , suggesting its pivotal role in regulating metabolic responses influenced by fasting. CONCLUSION: The results demonstrated significant beneficial alterations in microbial composition following AE and IF interventions, which supports the use of personalized approaches for obesity management and overall health.
SPAG4 Regulates Glycolytic Metabolism in HT29 Cells as a Target via the c-MYC/SULT2B1 Pathway.
He H, Zhang X, Zhong L … +3 more , Li T, Ding J, Wen S
Discov Med · 2025 Apr · PMID 40287810 · Publisher ↗
BACKGROUND: Glycolytic metabolism has been identified as a facilitator of tumor cell proliferation. Therefore, this study aims to investigate the mechanisms by which the sperm-associated antigen 4 (SPAG4)/cellular myeloc...
BACKGROUND: Glycolytic metabolism has been identified as a facilitator of tumor cell proliferation. Therefore, this study aims to investigate the mechanisms by which the sperm-associated antigen 4 (SPAG4)/cellular myelocytomatosis oncogene (c-Myc)/sulfotransferase 2B1 (SULT2B1) axis regulates glycolytic metabolism and influences the viability of HT29 cells. METHODS: SPAG4, c-Myc, and SULT2B1 levels were assessed in HT29 cells using Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western blot analyses. Moreover, overexpression and knockdown in HT29 cell models were successfully established. Furthermore, cell viability and proliferation were evaluated using Cell Counting Kit-8 (CCK-8) and colony formation assays. Various key parameters such as glucose uptake, lactate production, Adenosine Triphosphate (ATP)/Adenosine Diphosphate (ADP) ratio, and the expression levels of Glucose transporter 1 (GLUT1) and Lactate dehydrogenase A (LDHA) were determined to examine glycolytic metabolism. Additionally, the relationship between SPAG4, c-Myc, SULT2B1, and glycolysis was assessed using the immunofluorescence staining approach and 2-Deoxy-D-glucose (2-DG) therapy. RESULTS: The expression levels of SPAG4, c-Myc, and SULT2B1 were significantly elevated in HT29 cells ( < 0.05). Moreover, silencing SPAG4 and c-Myc substantially reduced glycolytic metabolism and suppressed HT29 cell viability and colony formation capability ( < 0.05). Additionally, elevated SULT2B1 expression effectively counteracted the glycolytic reduction induced by silencing SPAG4 and c-Myc, enhancing cellular viability and colony formation capability ( < 0.05). CONCLUSIONS: In summary, SPAG4 knockdown effectively suppresses HT29 cell proliferation and colony formation ability by decreasing SULT2B1 expression through the downregulation of c-Myc, leading to the reduction of glycolytic metabolism.
A Potential Link Between Early Onset Reactive Astrogliosis and Adult-Onset Dysfunction of Leptin Signaling in Polyubiquitin Gene Knockout Mice.
Bae JS, Yoon S, Kim TY … +1 more , Ryu KY
Discov Med · 2025 Apr · PMID 40287809 · Publisher ↗
BACKGROUND: Polyubiquitin gene knockout (KO) mice exhibit early onset reactive astrogliosis and adult-onset hypothalamic neurodegeneration with obesity. However, it remains unknown why the obesity phenotype only manifes...
BACKGROUND: Polyubiquitin gene knockout (KO) mice exhibit early onset reactive astrogliosis and adult-onset hypothalamic neurodegeneration with obesity. However, it remains unknown why the obesity phenotype only manifests in adulthood and why mice are smaller at an early age. Therefore, this study aimed to identify the link between neuroinflammation at an early age and adult-onset leptin signaling dysfunction in KO mice. METHODS: To investigate neuroinflammatory marker expression in the hypothalamus of KO mice, RNA-seq analysis and quantitative reverse transcription-polymerase chain reaction were used. Moreover, astrocytes isolated from postnatal brains were cultured and pure astrocytes were obtained by magnetic-activated cell sorting. Furthermore, mice were challenged with lipopolysaccharide (LPS) to induce upregulation of neuroinflammatory markers, including lipocalin-2 (LCN2). Leptin signaling was examined through the administration of leptin via intraperitoneal or intracerebroventricular injection, followed by monitoring of relevant proteins using immunofluorescence and western blot analyses. RESULTS: In KO mice, reactive astrogliosis occurred at an early age and increased the expression of and other neuroinflammatory markers. Upon exposure to LPS, these levels showed upward trends; however, they were comparable with those in wild-type mice, suggesting that KO mice were under intrinsic inflammatory stress. In adulthood, leptin signaling dysfunction was observed owing to elevated levels of negative regulators, such as suppressor of cytokine signaling-3 (SOCS3) and forkhead box protein O1 (FOXO1), possibly as a result of chronic neuroinflammation. CONCLUSION: This study demonstrates that expression is increased in young KO mice. Although leptin signaling is intact at an early age, high LCN2 levels may contribute to reduced daily food intake and lower body weight. Chronic neuroinflammation resulting from reactive astrogliosis persists into adulthood, leading to leptin signaling dysfunction. This is most likely a result of elevated levels of SOCS3 and FOXO1, both of which are negative regulators of leptin signaling.
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