Discovery medicine最新文献

{"title":"Idebenone-Loaded Nanocomposite Microspheres for Nasal Administration-A Perspective in the Treatment of Alzheimer's Disease.","authors":"Radka Boyuklieva, Plamen Katsarov, Plamen Zagorchev, Silviya Abarova, Asya Hristozova, Bissera Pilicheva","doi":"10.24976/Discov.Med.202436187.144","DOIUrl":"10.24976/Discov.Med.202436187.144","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease results in neurodegeneration and is characterized by an accumulation of abnormal neuritic lesions and intracellular aggregates of hyperphosphorylated Tau proteins in the cerebrum. That leads to progressive decline in memory, thinking, and learning skills. Oxidative stress has been shown to play a significant role in the pathogenesis of Alzheimer's disease. Antioxidants are identified as part of therapeutic strategy to prevent or reduce the disease. Idebenone is a synthetic analogue of coenzyme Q₁₀ with potent antioxidant properties, originally developed for the treatment of Alzheimer's disease and other cognitive disorders. After oral administration idebenone undergoes excessive first-pass metabolism and has a very low bioavailability of only about 1%. The use of an alternative route of administration such as the nasal and its incorporation into a novel carrier (nanocomposite microspheres) will eliminate the problems associated with reduced absorption, stability, and rapid biotransformation and will increase the opportunity for idebenone to realize its therapeutic potential in Alzheimer's disease.</p><p><strong>Methods: </strong>Idebenone-loaded nanocomposite microspheres were obtained by spray drying. The structures were characterized using laser diffraction, scanning electron microscopy, high-performance liquid chromatography, Fourier-transform infrared spectroscopy, and differential scanning calorimetry. The ability of nanocomposite microspheres to bind human serum albumin was investigated by fluorescence spectroscopy. The mucoadhesive properties of the carrier were also determined.</p><p><strong>Results: </strong>Bioadhesive nanocomposite microparticles with spherical shape, smooth surface, size of 7.37 ± 2.4 μm, and with high production yield, good drug entrapment efficiency, and loading values were obtained. Infrared spectra demonstrated no chemical interactions between idebenone and structure-forming polymers. The ability of particles to bind to human serum albumin depends on their drug loading.</p><p><strong>Conclusions: </strong>Nanocomposite microspheres were developed as the novel delivery system of idebenone for target nose-to-brain delivery. The obtained carrier may increase the therapeutic potential of idebenone by providing higher concentrations in brain tissue and reducing systemic exposure and side effects.</p>","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 187","pages":"1572-1587"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of Nrf2/A20/eEF1A2 Axis by Ginsenoside Rb1: A Key Pathway in Alleviating Cerebral Ischemia-Reperfusion Injury.","authors":"Haijuan He, Yanqing Yang, Xia Zhang, Ying Ying, Bo Zheng","doi":"10.24976/Discov.Med.202436187.160","DOIUrl":"10.24976/Discov.Med.202436187.160","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Cerebral ischemia-reperfusion injury (CIRI) is a prevalent neurological disorder, characterized by the oxidative stress and inflammatory response induced during the ischemia-reperfusion process, leading to significant damage to brain cells. Ginsenoside Rb1, a natural medicinal ingredient, possesses potential neuroprotective effects. This study aims to investigate the mechanism of action of ginsenoside Rb1 in CIRI and its protective effects on brain injury.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We utilized a mouse CIRI model and randomly divided the mice into control group, CIRI group, and ginsenoside Rb1 treatment group. The effects of Rb1 on brain tissue damage, apoptosis, expression of inflammatory factors, and pyroptotic cell numbers in CIRI mice were observed through triphenyl tetrazolium chloride (TTC) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, real-time reverse transcription polymerase chain reaction (qRT-PCR), and electron microscopy. In a cell model, the regulatory effect of Rb1 on oxygen-glucose deprivation/reperfusion (OGD/R)-induced HT22 cell pyroptosis via the nuclear respiratoty factor 2/tumor necrosis factor-α (TNF-α)-induced Protein 3 (TNFAIP3, aka A20)/eukaryotic translation elongation factor 1A2 (Nrf2/A20/eEF1A2) axis was detected using Western blot and TUNEL staining. Additionally, the impact of Nrf2 inhibitor ML385 and eEF1A2 overexpression on the neuroprotective effect of Rb1 was assessed. Using the comprehensive experimental methods mentioned above, the neuroprotective mechanism of Rb1 in CIRI was thoroughly evaluated.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Our findings demonstrate that treatment with ginsenoside Rb1 alleviated behavioral deficits induced by CIRI and reduced pathological damage in brain tissue. Furthermore, ginsenoside Rb1 treatment notably decreased oxidative stress and the inflammatory response induced by CIRI, leading to lower levels of inflammatory factors (&lt;i&gt;p&lt;/i&gt; &lt; 0.05). Further experimental results indicated that ginsenoside Rb1 promoted antioxidant and anti-inflammatory responses by regulating the activity of the Nrf2/A20/eEF1A2 axis. Additionally, ginsenoside Rb1 inhibited the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, thereby reducing the release of inflammatory factors and the occurrence of cell apoptosis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Our study results suggest that ginsenoside Rb1 exerts neuroprotective effects and alleviates brain injury induced by CIRI by regulating the Nrf2/A20/eEF1A2 axis and inhibiting the activation of the NLRP3 inflammasome. These findings provide new treatment insights for CIRI and support ginsenoside Rb1's development as a therapeutic drug. However, despite the promising nature of our findings, further research is required to validate these discoveries and explore the feasibility and safety of ginsenoside Rb1 in clinical applications. We hope ","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 187","pages":"1743-1757"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PAR1 Activation, via LMBR1/BMP Axis, Promotes the Osteogenesis of Periodontal Ligament Stem Cells (PDLSCs) and Alleviates the Inhibitory Effect of Sodium Butyrate on PDLSCs Osteogenesis.","authors":"Lin Xia, Ziliang Yang, Chao Hu","doi":"10.24976/Discov.Med.202436187.152","DOIUrl":"10.24976/Discov.Med.202436187.152","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Periodontitis is the leading cause of tooth loss and can exacerbate various systemic inflammatory conditions. Periodontal ligament stem cells (PDLSCs) stand out as prominent and favorable candidates for promoting periodontal tissue regeneration. This study aimed to investigate whether the protease-activated receptor type 1 (PAR1) can mitigate the sodium butyrate (NaB)-induced PDLSCs osteogenesis inhibition and unravel the underlying mechanism.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Public datasets from the Gene Expression Omnibus (GEO) were utilized to analyze differentially expressed genes (DEGs) in periodontitis and subsequent Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. PDLSCs were cultured normally in control medium (CM) as the negative control or in osteogenic medium (OM) to induce osteogenesis. PAR1 was either activated or suppressed using a selective agonist or antagonist (OM+agonist and OM+antagonist). The evaluation of PDLSCs osteogenesis was based on the levels of osteogenesis-related markers, including runt-related transcription factor 2 (RUNX2), osterix (OSX), osteocalcin (OCN), and osteopontin (OPN), alkaline phosphatase (ALP) activity, and calcium concentration. Additionally, cell proliferation and osteogenic differentiation were measured through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Alizarin Red Staining. To determine the PAR1 targeting the limb development membrane protein 1 (LMBR1)/bone morphogenetic protein (BMP) pathway, LMBR1 was upregulated through cell transfection and BMP2 was inhibited using the selective inhibitor Noggin protein. Finally, NaB was introduced into PDLSCs to investigate the effect on NaB-induced inhibition of PDLSCs osteogenesis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;PAR1, RUNX2, OSX, OCN, OPN, proliferation, ALP activity, calcium concentration, osteogenic differentiation, BMP2, and BMP4 exhibited significant increases in PDLSCs cultured in OM (&lt;i&gt;p&lt;/i&gt; &lt; 0.01). These parameters were further elevated by PAR1 agonist and conversely reduced by PAR1 antagonist (&lt;i&gt;p&lt;/i&gt; &lt; 0.01). Conversely, LMBR1 was decreased in PDLSCs cultured in OM (&lt;i&gt;p&lt;/i&gt; &lt; 0.001), with further reduction induced by PAR1 agonist and a reverse increase observed with PAR1 antagonist (&lt;i&gt;p&lt;/i&gt; &lt; 0.001). OE-LMBR1 transfection successfully elevated LMBR1 levels, subsequently inhibiting BMP2 and BMP4 (&lt;i&gt;p&lt;/i&gt; &lt; 0.001). Meanwhile, the Noggin protein effectively suppressed BMP2 and BMP4 (&lt;i&gt;p&lt;/i&gt; &lt; 0.001). All observed osteogenesis-related changes were reversed by the increased LMBR1 or inhibition of the BMP pathway (&lt;i&gt;p&lt;/i&gt; &lt; 0.001). Furthermore, NaB suppressed osteogenesis-related changes in OM-cultured PDLSCs (&lt;i&gt;p&lt;/i&gt; &lt; 0.001), and these effects were entirely reversed by PAR1 agonist (&lt;i&gt;p&lt;/i&gt; &lt; 0.001). Conversely, the increased LMBR1 or inhibited BMP pathway disrupted the osteogenesis reversion induced by PAR1 agonist (&lt;i&gt;p&lt;/i&gt; &lt; 0.001).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclu","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 187","pages":"1657-1671"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pediatric Life Support in Prehospital Emergency Medicine: An Empirical Investigation in the Context of Taiwan's Critical Shortage of Pediatric Emergency Specialists.","authors":"Wen-Fan Chen, Yung-Kuan Chan, Wei-Hsi Chang, Ming Yuan Hsieh","doi":"10.24976/Discov.Med.202436187.156","DOIUrl":"10.24976/Discov.Med.202436187.156","url":null,"abstract":"<p><strong>Background: </strong>This study aims to facilitate parental identification of designated emergency facilities for expeditious pediatric care within the framework of Taiwan's newly implemented \"regional joint defense\" approach to pediatric emergency services. The research seeks to elucidate the mechanisms by which this novel system can enhance timely access to appropriate emergency care for children, potentially improving health outcomes and resource utilization in acute pediatric situations.</p><p><strong>Methods: </strong>Factor analysis (FA) and triangular entropy matrix (TEM) analyzed the appearance, breathing and skin of pediatric assessment triangle (ABC of PAT), three types of prehospital pediatric emergence condition (PPEC), five levels of Taiwan's pediatric emergency triage (TPET), and applied the social learning theory (SLT) in educational doctrine, using experts' weighted questionnaires.</p><p><strong>Results: </strong>Firstly, to address deficiencies in Taiwan's pediatric prehospital emergency medicine (PEM) system, integrating emergency medical knowledge (EMK) and pediatric life support (PLS) into medical education, staff training, and the national handbook for new parents is crucial. This equips parents to manage children's illnesses and prevent emergencies. Then, in life-threatening situations, immediate emergency room (ER) transport is vital for symptoms like whitish or purple lips, cold limbs, mottled skin, cold sweat, convulsions, dyspnea, chest dimples, weak consciousness, and oxygen saturation below 94%. Finally, for non-life-threatening emergencies, seek medical evaluation if symptoms include wheezing, chest tightness, chest pain, persistent high fever over 39 degrees with convulsions, chills, cold sweats, not eating or urinating for over 12 hours, or fever lasting more than 48 hours.</p><p><strong>Conclusion: </strong>Parents must remain calm and provide their baby with a sense of security while observing the development of physical symptoms. This approach enables them to effectively determine the most appropriate time to take their children to the emergency room, thereby avoiding life-threatening emergencies. Prompt and proper measures and treatments not only alleviate various discomforts caused by illness or medical emergencies but also reduce systemic distress, life-threatening situations, and unfortunate incidents before hospitalization.</p>","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 187","pages":"1703-1714"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tailored-Biomaterials Based Potential Strategies for Cardiovascular Disease.","authors":"Sukhwinder K Bhullar, Haimanti Mondal, John Thomas, Duygu Gazioglu Ruzgar, Natarajan Chandrasekaran, Amitava Mukherjee, Martin B G Jun, Stephanie M Willerth","doi":"10.24976/Discov.Med.202436187.142","DOIUrl":"10.24976/Discov.Med.202436187.142","url":null,"abstract":"<p><p>Cardiovascular disease is a significant health concern worldwide, and varied effective treatment and prevention methods have been developed. Among these, tailored biomaterials-based strategies such as stents, scaffolds, patches, and drug delivery systems have emerged as a promising avenue. These devices are designed to match the mechanical and biological mechanisms of the cardiovascular system, ensuring optimal performance and compatibility. By effectively treating or preventing cardiovascular diseases, these devices have the potential to improve patient health outcomes significantly. They can restore blood flow by addressing blocked arteries and regenerate damaged cardiac tissue by delivering bioactive agents or cells directly to the affected area in a targeted, sustained, and controllable manner. Therefore, the objective of this article is to summarize the available evidence on these tailored biomaterial-based tunable cardiovascular devices. This knowledge can help to transform cardiovascular medicine for the treatment or prevention of cardiovascular disease and restore cardiac function to improve patients' quality of life.</p>","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 187","pages":"1544-1554"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effect of Riboflavin on Neurological Rehabilitation after Traumatic Brain Injury in Children.","authors":"Qiao Cai, Bei Zhao, Yuanxiang Ke","doi":"10.24976/Discov.Med.202436187.145","DOIUrl":"10.24976/Discov.Med.202436187.145","url":null,"abstract":"<p><strong>Background: </strong>Traumatic brain injury (TBI), which is the brain impairment and lesion caused by the external force injuring the head and the underlying brain, can cause pediatric death, disability, neurological disorders, and even lifelong disability. This study was to explore the effect of riboflavin (RF) on neurological rehabilitation and functional recovery after TBI.</p><p><strong>Methods: </strong>The rat models of TBI were constructed by treating rats with controlled cortical impact (CCI). By treating TBI rats with RF, we investigated whether the administration of RF would affect the sensorimotor function and cognitive ability recovery through adhesive removal test, modified neurological severity score (mNSS), corner test, wire-grip test and the Morris water maze. The effects of RF on lesion volume and water content were investigated using hematoxylin and eosin (H&E) staining and wet-dry method. The Nissl staining and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining were used to demonstrate the effect of RF on neural apoptosis. Inflammation-related cytokines of interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1 were measured by enzyme-linked immunosorbent assay (ELISA) to evaluate the effect of RF on neuroinflammation. The impact of RF on oxidative stress was assessed by measuring malondialdehyde (MDA) content and superoxide dismutase (SOD) activity, and the platelet endothelial cell adhesion molecule-1 (CD31) staining for observing vessel density, the reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) for measuring vascular endothelial growth factor (<i>VEGF</i>) mRNA expression and western blot for VEGF protein expression were used for evaluated angiogenesis.</p><p><strong>Results: </strong>The administration of RF could facilitate the recovery of neurological function by promoting the recovery of sensorimotor function and cognitive ability (<i>p</i> < 0.05). Furthermore, RF could reduce the lesion volume and water content after TBI and ameliorate neural apoptosis, neuroinflammation, and oxidative stress (<i>p</i> < 0.05). Finally, RF increased vessel density (<i>p</i> < 0.01) and <i>VEGF</i> levels (<i>p</i> < 0.01) in brain tissues after TBI, promoting angiogenesis.</p><p><strong>Conclusion: </strong>RF benefits neurological rehabilitation after TBI by promoting neurological function recovery, ameliorating the pathogenesis after TBI, and facilitating brain vascular remodeling. These findings provide a novel mechanism for RF treating pediatric TBI.</p>","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 187","pages":"1588-1599"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simvastatin Inhibits the Formation of NETs by the Mac-1 Pathway to Reduce Hepatic Ischemia-Reperfusion Injury under High-Fat Conditions.","authors":"Shikai Wang, Zhipeng Li, Yunxiang Chang, Kai Dong, Di He, Xinsheng Cheng","doi":"10.24976/Discov.Med.202436187.158","DOIUrl":"10.24976/Discov.Med.202436187.158","url":null,"abstract":"<p><strong>Background: </strong>Hyperlipidemia is one of the main causes of aggravated hepatic ischemia-reperfusion injury (IRI). Simvastatin (SIM), a lipid-lowering drug, has been shown to effectively alleviate IRI caused by hyperlipidemia. However, the regulatory mechanism by which SIM alleviates hyperlipidemia-induced hepatic IRI is still not clear. This study aims to explore the potential mechanisms of SIM in inhibiting hyperlipidemia-induced hepatic IRI, providing new therapeutic strategies for the alleviation of hepatic IRI.</p><p><strong>Methods: </strong>An animal model of hyperlipidemia was induced by feeding mice a high-fat diet for 8 weeks. Subsequently, a hepatic IRI animal model of hyperlipidemia was established by occluding the hepatic artery and portal vein for one hour, followed by reperfusion for 6 or 12 h. Enzyme linked immunosorbent assay, Western blotting, hematoxylin-eosin (H&E) staining, immunohistochemistry, immunofluorescence, and Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling assay, were used to evaluate liver injury, neutrophil extracellular traps (NETs) formation, and related molecular mechanisms.</p><p><strong>Results: </strong>Hepatic IRI was accelerated by hyperlipidemia, which enhanced the expression of oxidized low-density lipoprotein (oxLDL) and Macrophage-1antigen (Mac-1), leading to the promotion of NETs formation and apoptosis of liver cells. The administration of simvastatin reduced the levels of oxLDL and Mac-1, decreased the formation of NETs, and alleviated hepatic IRI induced by hyperlipidemia.</p><p><strong>Conclusions: </strong>Simvastatin reduced hyperlipidemia-induced hepatic IRI by inhibiting the formation of NETs through the regulation of the oxLDL/Mac-1 pathway.</p>","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 187","pages":"1721-1731"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"\"<i>Matters Arising</i>\" on a Recent Biologic (Ab-IPL-IL-17™) for IL-17-Mediated Diseases.","authors":"Anella Saviano, Adel Abo Mansour, Paolo Grieco, Asif Jilani Iqbal, Francesco Maione","doi":"10.24976/Discov.Med.202436187.161","DOIUrl":"10.24976/Discov.Med.202436187.161","url":null,"abstract":"","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 187","pages":"1758-1760"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Remimazolam Alleviates Ventilator-Induced Lung Injury by Activating TSPO to Inhibit Macrophage Pyroptosis.","authors":"Lei Zhang, Dong Zhao, Huayan Lv, Xiaofeng Jiang","doi":"10.24976/Discov.Med.202436187.146","DOIUrl":"10.24976/Discov.Med.202436187.146","url":null,"abstract":"<p><strong>Background: </strong>Macrophages are activated in ventilator-induced lung injury (VILI), accompanied by macrophage pyroptosis. Remimazolam (Re) plays a role in inhibiting macrophage activation. In this study, we aimed to investigate the mechanism of Re in VILI.</p><p><strong>Methods: </strong>A VILI model (20 mL/kg mechanical ventilation) was created using C57BL/6 mice. Alveolar macrophages were isolated from bronchoalveolar lavage fluid (BALF) and received mechanical stretching to simulate the mechanical ventilation <i>in vitro</i>. VILI model mice were treated with Re (16 mg/kg) to assess the alveolar structure, wet/dry (W/D) weight ratio, endothelial barrier antigen (EBA) permeability index, BALF protein content, inflammatory factors, macrophage pyroptosis, pyroptosis-related factors, and translocator protein (TSPO) level using a series of biological experiments. Whether Re alleviated macrophage pyroptosis by regulating TSPO was determined by rescue experiments.</p><p><strong>Results: </strong>Re alleviated VILI, as evidenced by improvement of abnormal morphology of lung tissues during VILI and decreases in the lung W/D weight ratio, lung EBA permeability index, and BALF protein content. Re attenuated pulmonary inflammation and macrophage pyroptosis during VILI via down-regulation of inflammatory factors (myeloperoxidase, malondialchehyche, 8-hydroxy-2 deoxyguanosine, interleukin-6, tumor necrosis factor-α, macrophage inflammatory protein-2, interleukin-1β, and interleukin-18), and pyroptosis factors (cleaved gasdermin D (GSDMD)/GSDMD value, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), and caspase-1). Re activated TSPO in macrophages. TSPO overexpression rescued the cell stretch-inhibited macrophage viability and cell stretch-induced macrophage pyroptosis.</p><p><strong>Conclusion: </strong>Re alleviates VILI by activating TSPO to inhibit macrophage pyroptosis.</p>","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 187","pages":"1600-1609"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP7 Promotes TGF-β1 Signaling by De-Ubiquitinating Smad2/Smad3 in Pulmonary Fibrosis.","authors":"Fang Tang, Hongyan Gong, Tiantian Ke, Wenming Yang, Yuxuan Yang, Zhiyi Liu","doi":"10.24976/Discov.Med.202436187.148","DOIUrl":"10.24976/Discov.Med.202436187.148","url":null,"abstract":"<p><strong>Background: </strong>Idiopathic pulmonary fibrosis (IPF) is a long-term, progressive, and irreversible pulmonary interstitial disease. The activation of Smad family member 2 (Smad2) and Smad3 transcription factors by transforming growth factor β-1 (TGF-β1) is a critical event in the pathogenesis of IPF. However, there is still a lack of understanding regarding the molecular mechanisms governing Smad2 and Smad3 proteins. Ubiquitin-specific protease 7 (USP7) is a deubiquitinase that plays a vital role in regulating protein stability within cells. However, its regulation of the TGF-β signaling pathway and its significance in IPF remain undiscovered. This study aims to clarify the function of USP7 in the TGF-β signaling pathway, while simultaneously exploring the specific molecular mechanisms involved. Additionally, this study seeks to evaluate the therapeutic potential of targeted USP7 inhibitors in IPF, thereby providing novel insights for the diagnosis and management of IPF.</p><p><strong>Methods: </strong>We first detected the expression of USP7 in lung tissues of mice with Bleomycin (BLM)-induced pulmonary fibrosis and in Beas-2B cells treated with or without TGF-β1 through Western blot analysis. Subsequently, we explored the influence of USP7 on fibrotic processes and the TGF-β1 signaling pathway, utilizing <i>in vitro</i> and <i>in vivo</i> studies. Finally, we assessed the effectiveness of USP7-specific inhibitors in an IPF murine model.</p><p><strong>Results: </strong>In the present study, USP7 was found to de-ubiquitinate Smad2 and Smad3, consequently increasing their stability and promoting the TGF-β1-induced production of profibrotic proteins including α-smooth muscle actin (α-SMA) and fibronectin 1 (FN-1). Inhibition or knockdown of USP7 resulted in decreased levels of Smad2 and Smad3 proteins, leading to reduced expression of FN-1, Collagen Type I Alpha 1 Chain (Col1A1), and α-SMA induced by TGF-β1 in human pulmonary epithelial cells. These findings demonstrate that overexpression of USP7 reduces Smad2/3 ubiquitination, whereas inhibition or knockdown of USP7 enhances their ubiquitination. USP7 is abundantly expressed in IPF lungs. The expressions of USP7, Smad2, and Smad3 were upregulated in bleomycin-induced lung injury. The USP7 inhibitor P22077 reduced the expression of FN-1 and type I collagen as well as Smad2/3 and collagen deposition in lung tissue in a model of pulmonary fibrosis induced by bleomycin.</p><p><strong>Conclusions: </strong>This study demonstrates that USP7 promotes TGF-β1 signaling by stabilizing Smad2 and Smad3. The contribution of USP7 to the progression of IPF indicates it may be a viable treatment target.</p>","PeriodicalId":93980,"journal":{"name":"Discovery medicine","volume":"36 187","pages":"1616-1626"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}