The purpose of this study was to explore the effect of Semaglutide on intrauterine adhesions and discover new drugs for such adhesions. In this study, the cell model was simulated by TGF-β1-induced human endometrial epithelial cells, and the animal model was established through mechanical curettage and inflammatory stimulation. After co-culturing with TGF-β1 with or without different concentrations of Semaglutide for 48 h, cells were collected for RT-qPCR and Western blotting analyses. Three doses were subcutaneously injected into experimental mice once a day for two weeks, while the control group received sterile ddH2O. The serum and uterine tissues of the mice were collected. HE and Masson staining were used for the uterine histomorphological and pathological analyses. RT-qPCR and Western blotting were used for mRNA and protein expression analyses. Serum indicators were detected using ELISA kits. The results showed that Semaglutide significantly reduced the mRNA levels of fibrosis indicators ACTA2, COL1A1, and FN and inflammatory indicators TNF-α, IL-6, and NF-κB in the two models. Semaglutide improved endometrium morphology, increased the number of endometrial glands, and reduced collagen deposition in IUA mice. The results also showed that Semaglutide could inhibit vimentin, E-Cadherin, and N-Cadherin in the two models. In summary, Semaglutide can ameliorate fibrosis and inflammation of intrauterine adhesions as well as inhibit epithelial–mesenchymal transition in IUA models.
本研究的目的是探讨塞马鲁肽对宫腔内粘连的影响，并发现治疗宫腔内粘连的新药物。本研究以TGF-β1诱导的人子宫内膜上皮细胞模拟细胞模型，通过机械刮宫和炎症刺激建立动物模型。在添加或不添加不同浓度的塞马鲁肽与TGF-β1共同培养48小时后，收集细胞进行RT-qPCR和Western印迹分析。实验组小鼠皮下注射三个剂量的塞马鲁肽，每天一次，连续两周；对照组小鼠注射无菌 ddH2O。收集小鼠血清和子宫组织。采用 HE 和 Masson 染色法进行子宫组织形态学和病理学分析。RT-qPCR和Western印迹法用于mRNA和蛋白质表达分析。使用 ELISA 试剂盒检测血清指标。结果显示，塞马鲁肽能显著降低两种模型中纤维化指标ACTA2、COL1A1和FN以及炎症指标TNF-α、IL-6和NF-κB的mRNA水平。塞马鲁肽改善了IUA小鼠的子宫内膜形态，增加了子宫内膜腺体的数量，并减少了胶原沉积。结果还显示，塞马鲁肽能抑制两种模型中的波形蛋白、E-Cadherin和N-Cadherin。总之，塞马鲁肽可以改善宫腔内粘连的纤维化和炎症，并抑制IUA模型的上皮-间质转化。
{"title":"Semaglutide May Ameliorate Fibrosis and Inhibit Epithelial–Mesenchymal Transition in Intrauterine Adhesion Models","authors":"Luming Wu, Yue Zhan, Yiqing Wang","doi":"10.3390/ijms25116196","DOIUrl":"https://doi.org/10.3390/ijms25116196","url":null,"abstract":"The purpose of this study was to explore the effect of Semaglutide on intrauterine adhesions and discover new drugs for such adhesions. In this study, the cell model was simulated by TGF-β1-induced human endometrial epithelial cells, and the animal model was established through mechanical curettage and inflammatory stimulation. After co-culturing with TGF-β1 with or without different concentrations of Semaglutide for 48 h, cells were collected for RT-qPCR and Western blotting analyses. Three doses were subcutaneously injected into experimental mice once a day for two weeks, while the control group received sterile ddH2O. The serum and uterine tissues of the mice were collected. HE and Masson staining were used for the uterine histomorphological and pathological analyses. RT-qPCR and Western blotting were used for mRNA and protein expression analyses. Serum indicators were detected using ELISA kits. The results showed that Semaglutide significantly reduced the mRNA levels of fibrosis indicators ACTA2, COL1A1, and FN and inflammatory indicators TNF-α, IL-6, and NF-κB in the two models. Semaglutide improved endometrium morphology, increased the number of endometrial glands, and reduced collagen deposition in IUA mice. The results also showed that Semaglutide could inhibit vimentin, E-Cadherin, and N-Cadherin in the two models. In summary, Semaglutide can ameliorate fibrosis and inflammation of intrauterine adhesions as well as inhibit epithelial–mesenchymal transition in IUA models.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"9 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141266399","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}
The mechanical forces exerted by cells on their surrounding microenvironment are known as cellular traction forces. These forces play crucial roles in various biological processes, such as tissue development, wound healing and cell functions. However, it is hard for traditional techniques to measure cellular traction forces accurately because their magnitude (from pN to nN) and the length scales over which they occur (from nm to μm) are extremely small. In order to fully understand mechanotransduction, highly sensitive tools for measuring cellular forces are needed. Current powerful techniques for measuring traction forces include traction force microscopy (TFM) and fluorescent molecular force sensors (FMFS). In this review, we elucidate the force imaging principles of TFM and FMFS. Then we highlight the application of FMFS in a variety of biological processes and offer our perspectives and insights into the potential applications of FMFS.
{"title":"Molecular Force Sensors for Biological Application","authors":"Huiyan Chen, Shouhan Wang, Yi Cao, Hai Lei","doi":"10.3390/ijms25116198","DOIUrl":"https://doi.org/10.3390/ijms25116198","url":null,"abstract":"The mechanical forces exerted by cells on their surrounding microenvironment are known as cellular traction forces. These forces play crucial roles in various biological processes, such as tissue development, wound healing and cell functions. However, it is hard for traditional techniques to measure cellular traction forces accurately because their magnitude (from pN to nN) and the length scales over which they occur (from nm to μm) are extremely small. In order to fully understand mechanotransduction, highly sensitive tools for measuring cellular forces are needed. Current powerful techniques for measuring traction forces include traction force microscopy (TFM) and fluorescent molecular force sensors (FMFS). In this review, we elucidate the force imaging principles of TFM and FMFS. Then we highlight the application of FMFS in a variety of biological processes and offer our perspectives and insights into the potential applications of FMFS.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"7 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141266144","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}
Aging, marked by a gradual decline in physiological function and heightened vulnerability to age-related diseases, remains a complex biological process with multifaceted regulatory mechanisms. Our study elucidates the critical role of poly(ADP–ribose) glycohydrolase (PARG), responsible for catabolizing poly(ADP–ribose) (pADPr) in the aging process by modulating the expression of age-related genes in Drosophila melanogaster. Specifically, we uncover the regulatory function of the uncharacterized PARG C-terminal domain in controlling PARG activity. Flies lacking this domain exhibit a significantly reduced lifespan compared to wild-type counterparts. Furthermore, we observe progressive dysregulation of age-related gene expression during aging, accelerated in the absence of PARG activity, culminating in a premature aging phenotype. Our findings reveal the critical involvement of the pADPr pathway as a key player in the aging process, highlighting its potential as a therapeutic target for mitigating age-related effects.
衰老以生理功能逐渐衰退和更易患老年相关疾病为特征，它仍然是一个具有多方面调控机制的复杂生物过程。我们的研究阐明了负责分解聚（ADP-核糖）（pADPr）的聚（ADP-核糖）糖水解酶（PARG）通过调节黑腹果蝇中与年龄相关基因的表达在衰老过程中的关键作用。具体来说，我们发现了未表征的 PARG C 端结构域在控制 PARG 活性方面的调控功能。与野生型果蝇相比，缺乏该结构域的果蝇寿命明显缩短。此外，我们还观察到在衰老过程中，与年龄相关的基因表达逐渐失调，在 PARG 活性缺失的情况下会加速，最终形成早衰表型。我们的研究结果揭示了 pADPr 通路在衰老过程中的关键作用，并强调了其作为减轻衰老相关影响的治疗靶点的潜力。
{"title":"PARG Protein Regulation Roles in Drosophila Longevity Control","authors":"Guillaume Bordet, A. Tulin","doi":"10.3390/ijms25116189","DOIUrl":"https://doi.org/10.3390/ijms25116189","url":null,"abstract":"Aging, marked by a gradual decline in physiological function and heightened vulnerability to age-related diseases, remains a complex biological process with multifaceted regulatory mechanisms. Our study elucidates the critical role of poly(ADP–ribose) glycohydrolase (PARG), responsible for catabolizing poly(ADP–ribose) (pADPr) in the aging process by modulating the expression of age-related genes in Drosophila melanogaster. Specifically, we uncover the regulatory function of the uncharacterized PARG C-terminal domain in controlling PARG activity. Flies lacking this domain exhibit a significantly reduced lifespan compared to wild-type counterparts. Furthermore, we observe progressive dysregulation of age-related gene expression during aging, accelerated in the absence of PARG activity, culminating in a premature aging phenotype. Our findings reveal the critical involvement of the pADPr pathway as a key player in the aging process, highlighting its potential as a therapeutic target for mitigating age-related effects.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"8 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141267679","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}
Chan Lee, Yeeun Kwon, Sunmin Park, TaeHee Kim, Min Kim, Eun Kim, Jae Jung, Sangil Min, Kwang-Hyun Park, Jae Jeong, Sun Choi
Aging leads to tissue and cellular changes, often driven by oxidative stress and inflammation, which contribute to age-related diseases. Our research focuses on harnessing the potent anti-inflammatory and antioxidant properties of Korean Ulmus macrocarpa Hance, a traditional herbal remedy, to address muscle loss and atrophy. We evaluated the effects of Ulmus extract on various parameters in a muscle atrophy model, including weight, exercise performance, grip strength, body composition, muscle mass, and fiber characteristics. Additionally, we conducted Western blot and RT-PCR analyses to examine muscle protein regulation, apoptosis factors, inflammation, and antioxidants. In a dexamethasone-induced muscle atrophy model, Ulmus extract administration promoted genes related to muscle formation while reducing those associated with muscle atrophy. It also mitigated inflammation and boosted muscle antioxidants, indicating a potential improvement in muscle atrophy. These findings highlight the promise of Ulmus extract for developing pharmaceuticals and supplements to combat muscle loss and atrophy, paving the way for clinical applications.
衰老会导致组织和细胞发生变化，而这些变化往往是由氧化应激和炎症引起的，从而导致与年龄有关的疾病。我们的研究重点是利用传统草药韩国榆树（Ulmus macrocarpa Hance）的强效抗炎和抗氧化特性来解决肌肉流失和萎缩问题。我们评估了榆树提取物对肌肉萎缩模型中各种参数的影响，包括体重、运动表现、握力、身体成分、肌肉质量和纤维特征。此外，我们还进行了 Western 印迹和 RT-PCR 分析，以研究肌肉蛋白调节、凋亡因子、炎症和抗氧化剂。在地塞米松诱导的肌肉萎缩模型中，服用榆叶梅提取物可促进与肌肉形成相关的基因，同时减少与肌肉萎缩相关的基因。榆叶梅提取物还能减轻炎症反应，提高肌肉抗氧化能力，从而改善肌肉萎缩。这些发现凸显了榆树提取物在开发防治肌肉损失和萎缩的药物和补充剂方面的前景，为临床应用铺平了道路。
{"title":"The Impact of Ulmus macrocarpa Extracts on a Model of Sarcopenia-Induced C57BL/6 Mice","authors":"Chan Lee, Yeeun Kwon, Sunmin Park, TaeHee Kim, Min Kim, Eun Kim, Jae Jung, Sangil Min, Kwang-Hyun Park, Jae Jeong, Sun Choi","doi":"10.3390/ijms25116197","DOIUrl":"https://doi.org/10.3390/ijms25116197","url":null,"abstract":"Aging leads to tissue and cellular changes, often driven by oxidative stress and inflammation, which contribute to age-related diseases. Our research focuses on harnessing the potent anti-inflammatory and antioxidant properties of Korean Ulmus macrocarpa Hance, a traditional herbal remedy, to address muscle loss and atrophy. We evaluated the effects of Ulmus extract on various parameters in a muscle atrophy model, including weight, exercise performance, grip strength, body composition, muscle mass, and fiber characteristics. Additionally, we conducted Western blot and RT-PCR analyses to examine muscle protein regulation, apoptosis factors, inflammation, and antioxidants. In a dexamethasone-induced muscle atrophy model, Ulmus extract administration promoted genes related to muscle formation while reducing those associated with muscle atrophy. It also mitigated inflammation and boosted muscle antioxidants, indicating a potential improvement in muscle atrophy. These findings highlight the promise of Ulmus extract for developing pharmaceuticals and supplements to combat muscle loss and atrophy, paving the way for clinical applications.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"74 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141268383","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}
Michael Haug, Mena Michael, P. Ritter, Larisa Kovbasyuk, Maria Eleni Vazakidou, O. Friedrich
Levosimendan’s calcium sensitizing effects in heart muscle cells are well established; yet, its potential impact on skeletal muscle cells has not been evidently determined. Despite controversial results, levosimendan is still expected to interact with skeletal muscle through off-target sites (further than troponin C). Adding to this debate, we investigated levosimendan’s acute impact on fast-twitch skeletal muscle biomechanics in a length-dependent activation study by submersing single muscle fibres in a levosimendan-supplemented solution. We employed our MyoRobot technology to investigate the calcium sensitivity of skinned single muscle fibres alongside their stress–strain response in the presence or absence of levosimendan (100 µM). While control data are in agreement with the theory of length-dependent activation, levosimendan appears to shift the onset of the ‘descending limb’ of active force generation to longer sarcomere lengths without notably improving myofibrillar calcium sensitivity. Passive stretches in the presence of levosimendan yielded over twice the amount of enlarged restoration stress and Young’s modulus in comparison to control single fibres. Both effects have not been described before and may point towards potential off-target sites of levosimendan.
左西孟旦在心肌细胞中的钙敏化作用已得到证实，但其对骨骼肌细胞的潜在影响尚未得到明确确定。尽管结果存在争议，但人们仍然认为左西孟旦会通过非靶点（肌钙蛋白 C 以外）与骨骼肌相互作用。为了补充这一争论，我们在一项长度依赖性激活研究中，通过将单个肌纤维浸没在添加了左西孟旦的溶液中，调查了左西孟旦对快肌骨骼肌生物力学的急性影响。我们利用 MyoRobot 技术研究了带皮单肌纤维的钙敏感性，以及它们在左西孟旦（100 µM）存在或不存在时的应力-应变反应。虽然对照组数据与长度依赖性激活理论一致，但左西孟旦似乎将主动发力 "下降肢 "的起始点转移到了更长的肌节长度上，而没有明显改善肌纤维的钙敏感性。与对照组单纤维相比，左西孟旦存在时的被动拉伸产生的恢复应力和杨氏模量扩大了两倍多。这两种效应以前从未描述过，可能指向左西孟旦的潜在脱靶位点。
{"title":"Levosimendan’s Effects on Length-Dependent Activation in Murine Fast-Twitch Skeletal Muscle","authors":"Michael Haug, Mena Michael, P. Ritter, Larisa Kovbasyuk, Maria Eleni Vazakidou, O. Friedrich","doi":"10.3390/ijms25116191","DOIUrl":"https://doi.org/10.3390/ijms25116191","url":null,"abstract":"Levosimendan’s calcium sensitizing effects in heart muscle cells are well established; yet, its potential impact on skeletal muscle cells has not been evidently determined. Despite controversial results, levosimendan is still expected to interact with skeletal muscle through off-target sites (further than troponin C). Adding to this debate, we investigated levosimendan’s acute impact on fast-twitch skeletal muscle biomechanics in a length-dependent activation study by submersing single muscle fibres in a levosimendan-supplemented solution. We employed our MyoRobot technology to investigate the calcium sensitivity of skinned single muscle fibres alongside their stress–strain response in the presence or absence of levosimendan (100 µM). While control data are in agreement with the theory of length-dependent activation, levosimendan appears to shift the onset of the ‘descending limb’ of active force generation to longer sarcomere lengths without notably improving myofibrillar calcium sensitivity. Passive stretches in the presence of levosimendan yielded over twice the amount of enlarged restoration stress and Young’s modulus in comparison to control single fibres. Both effects have not been described before and may point towards potential off-target sites of levosimendan.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"3 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141267421","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}
The skin–brain axis has been suggested to play a role in several pathophysiological conditions, including opioid addiction, Parkinson’s disease and many others. Recent evidence suggests that pathways regulating skin pigmentation may directly and indirectly regulate behaviour. Conversely, CNS-driven neural and hormonal responses have been demonstrated to regulate pigmentation, e.g., under stress. Additionally, due to the shared neuroectodermal origins of the melanocytes and neurons in the CNS, certain CNS diseases may be linked to pigmentation-related changes due to common regulators, e.g., MC1R variations. Furthermore, the HPA analogue of the skin connects skin pigmentation to the endocrine system, thereby allowing the skin to index possible hormonal abnormalities visibly. In this review, insight is provided into skin pigment production and neuromelanin synthesis in the brain and recent findings are summarised on how signalling pathways in the skin, with a particular focus on pigmentation, are interconnected with the central nervous system. Thus, this review may supply a better understanding of the mechanism of several skin–brain associations in health and disease.
{"title":"The Skin–Brain Axis: From UV and Pigmentation to Behaviour Modulation","authors":"Anna A. Ascsillán, L. Kemény","doi":"10.3390/ijms25116199","DOIUrl":"https://doi.org/10.3390/ijms25116199","url":null,"abstract":"The skin–brain axis has been suggested to play a role in several pathophysiological conditions, including opioid addiction, Parkinson’s disease and many others. Recent evidence suggests that pathways regulating skin pigmentation may directly and indirectly regulate behaviour. Conversely, CNS-driven neural and hormonal responses have been demonstrated to regulate pigmentation, e.g., under stress. Additionally, due to the shared neuroectodermal origins of the melanocytes and neurons in the CNS, certain CNS diseases may be linked to pigmentation-related changes due to common regulators, e.g., MC1R variations. Furthermore, the HPA analogue of the skin connects skin pigmentation to the endocrine system, thereby allowing the skin to index possible hormonal abnormalities visibly. In this review, insight is provided into skin pigment production and neuromelanin synthesis in the brain and recent findings are summarised on how signalling pathways in the skin, with a particular focus on pigmentation, are interconnected with the central nervous system. Thus, this review may supply a better understanding of the mechanism of several skin–brain associations in health and disease.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"8 40","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141267958","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}
Cartilage, a flexible and smooth connective tissue that envelops the surfaces of synovial joints, relies on chondrocytes for extracellular matrix (ECM) production and the maintenance of its structural and functional integrity. Melatonin (MT), renowned for its anti-inflammatory and antioxidant properties, holds the potential to modulate cartilage regeneration and degradation. Therefore, the present study was devoted to elucidating the mechanism of MT on chondrocytes. The in vivo experiment consisted of three groups: Sham (only the skin tissue was incised), Model (using the anterior cruciate ligament transection (ACLT) method), and MT (30 mg/kg), with sample extraction following 12 weeks of administration. Pathological alterations in articular cartilage, synovium, and subchondral bone were evaluated using Safranin O-fast green staining. Immunohistochemistry (ICH) analysis was employed to assess the expression of matrix degradation-related markers. The levels of serum cytokines were quantified via Enzyme-linked immunosorbent assay (ELISA) assays. In in vitro experiments, primary chondrocytes were divided into Control, Model, MT, negative control, and inhibitor groups. Western blotting (WB) and Quantitative RT-PCR (q-PCR) were used to detect Silent information regulator transcript-1 (SIRT1)/Nuclear factor kappa-B (NF-κB)/Nuclear factor erythroid-2-related factor 2 (Nrf2)/Transforming growth factor-beta (TGF-β)/Bone morphogenetic proteins (BMPs)-related indicators. Immunofluorescence (IF) analysis was employed to examine the status of type II collagen (COL2A1), SIRT1, phosphorylated NF-κB p65 (p-p65), and phosphorylated mothers against decapentaplegic homolog 2 (p-Smad2). In vivo results revealed that the MT group exhibited a relatively smooth cartilage surface, modest chondrocyte loss, mild synovial hyperplasia, and increased subchondral bone thickness. ICH results showed that MT downregulated the expression of components related to matrix degradation. ELISA results showed that MT reduced serum inflammatory cytokine levels. In vitro experiments confirmed that MT upregulated the expression of SIRT1/Nrf2/TGF-β/BMPs while inhibiting the NF-κB pathway and matrix degradation-related components. The introduction of the SIRT1 inhibitor Selisistat (EX527) reversed the effects of MT. Together, these findings suggest that MT has the potential to ameliorate inflammation, inhibit the release of matrix-degrading enzymes, and improve the cartilage condition. This study provides a new theoretical basis for understanding the role of MT in decelerating cartilage degradation and promoting chondrocyte repair in in vivo and in vitro cultured chondrocytes.
{"title":"Melatonin Delays Arthritis Inflammation and Reduces Cartilage Matrix Degradation through the SIRT1-Mediated NF-κB/Nrf2/TGF-β/BMPs Pathway","authors":"Mingchao Zhao, Di Qiu, Xue Miao, Wenyue Yang, Siyao Li, Xin Cheng, Jilang Tang, Hong Chen, Hongri Ruan, Ying Liu, Chengwei Wei, Jianhua Xiao","doi":"10.3390/ijms25116202","DOIUrl":"https://doi.org/10.3390/ijms25116202","url":null,"abstract":"Cartilage, a flexible and smooth connective tissue that envelops the surfaces of synovial joints, relies on chondrocytes for extracellular matrix (ECM) production and the maintenance of its structural and functional integrity. Melatonin (MT), renowned for its anti-inflammatory and antioxidant properties, holds the potential to modulate cartilage regeneration and degradation. Therefore, the present study was devoted to elucidating the mechanism of MT on chondrocytes. The in vivo experiment consisted of three groups: Sham (only the skin tissue was incised), Model (using the anterior cruciate ligament transection (ACLT) method), and MT (30 mg/kg), with sample extraction following 12 weeks of administration. Pathological alterations in articular cartilage, synovium, and subchondral bone were evaluated using Safranin O-fast green staining. Immunohistochemistry (ICH) analysis was employed to assess the expression of matrix degradation-related markers. The levels of serum cytokines were quantified via Enzyme-linked immunosorbent assay (ELISA) assays. In in vitro experiments, primary chondrocytes were divided into Control, Model, MT, negative control, and inhibitor groups. Western blotting (WB) and Quantitative RT-PCR (q-PCR) were used to detect Silent information regulator transcript-1 (SIRT1)/Nuclear factor kappa-B (NF-κB)/Nuclear factor erythroid-2-related factor 2 (Nrf2)/Transforming growth factor-beta (TGF-β)/Bone morphogenetic proteins (BMPs)-related indicators. Immunofluorescence (IF) analysis was employed to examine the status of type II collagen (COL2A1), SIRT1, phosphorylated NF-κB p65 (p-p65), and phosphorylated mothers against decapentaplegic homolog 2 (p-Smad2). In vivo results revealed that the MT group exhibited a relatively smooth cartilage surface, modest chondrocyte loss, mild synovial hyperplasia, and increased subchondral bone thickness. ICH results showed that MT downregulated the expression of components related to matrix degradation. ELISA results showed that MT reduced serum inflammatory cytokine levels. In vitro experiments confirmed that MT upregulated the expression of SIRT1/Nrf2/TGF-β/BMPs while inhibiting the NF-κB pathway and matrix degradation-related components. The introduction of the SIRT1 inhibitor Selisistat (EX527) reversed the effects of MT. Together, these findings suggest that MT has the potential to ameliorate inflammation, inhibit the release of matrix-degrading enzymes, and improve the cartilage condition. This study provides a new theoretical basis for understanding the role of MT in decelerating cartilage degradation and promoting chondrocyte repair in in vivo and in vitro cultured chondrocytes.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"15 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141266237","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}
Z. Afghah, Nabab Khan, Gaurav Datta, P. Halcrow, Jonathan D. Geiger, Xuesong Chen
Aurora kinase A (AURKA) is a serine/threonine-protein kinase that regulates microtubule organization during neuron migration and neurite formation. Decreased activity of AURKA was found in Alzheimer’s disease (AD) brain samples, but little is known about the role of AURKA in AD pathogenesis. Here, we demonstrate that AURKA is expressed in primary cultured rat neurons, neurons from adult mouse brains, and neurons in postmortem human AD brains. AURKA phosphorylation, which positively correlates with its activity, is reduced in human AD brains. In SH-SY5Y cells, pharmacological activation of AURKA increased AURKA phosphorylation, acidified endolysosomes, decreased the activity of amyloid beta protein (Aβ) generating enzyme β-site amyloid precursor protein cleaving enzyme (BACE-1), increased the activity of the Aβ degrading enzyme cathepsin D, and decreased the intracellular and secreted levels of Aβ. Conversely, pharmacological inhibition of AURKA decreased AURKA phosphorylation, de-acidified endolysosomes, decreased the activity of cathepsin D, and increased intracellular and secreted levels of Aβ. Thus, reduced AURKA activity in AD may contribute to the development of intraneuronal accumulations of Aβ and extracellular amyloid plaque formation.
极光激酶 A（AURKA）是一种丝氨酸/苏氨酸蛋白激酶，在神经元迁移和神经元形成过程中调节微管组织。阿尔茨海默病（AD）脑样本中发现 AURKA 活性降低，但人们对 AURKA 在 AD 发病机制中的作用知之甚少。在这里，我们证明了 AURKA 在原代培养的大鼠神经元、成年小鼠大脑的神经元和人类 AD 死后大脑的神经元中均有表达。AURKA的磷酸化与其活性呈正相关，而在人类AD大脑中，AURKA的磷酸化降低。在 SH-SY5Y 细胞中，药物激活 AURKA 可增加 AURKA 磷酸化，酸化内溶酶体，降低淀粉样 beta 蛋白（Aβ）生成酶 β 位点淀粉样前体蛋白裂解酶（BACE-1）的活性，增加 Aβ 降解酶 cathepsin D 的活性，降低 Aβ 的胞内和分泌水平。相反，药物抑制 AURKA 可减少 AURKA 磷酸化，使内溶酶体脱酸，降低酪蛋白酶 D 的活性，增加细胞内和分泌的 Aβ 水平。因此，AD 中 AURKA 活性的降低可能有助于 Aβ 在神经元内的积聚和细胞外淀粉样斑块的形成。
{"title":"Involvement of Endolysosomes and Aurora Kinase A in the Regulation of Amyloid β Protein Levels in Neurons","authors":"Z. Afghah, Nabab Khan, Gaurav Datta, P. Halcrow, Jonathan D. Geiger, Xuesong Chen","doi":"10.3390/ijms25116200","DOIUrl":"https://doi.org/10.3390/ijms25116200","url":null,"abstract":"Aurora kinase A (AURKA) is a serine/threonine-protein kinase that regulates microtubule organization during neuron migration and neurite formation. Decreased activity of AURKA was found in Alzheimer’s disease (AD) brain samples, but little is known about the role of AURKA in AD pathogenesis. Here, we demonstrate that AURKA is expressed in primary cultured rat neurons, neurons from adult mouse brains, and neurons in postmortem human AD brains. AURKA phosphorylation, which positively correlates with its activity, is reduced in human AD brains. In SH-SY5Y cells, pharmacological activation of AURKA increased AURKA phosphorylation, acidified endolysosomes, decreased the activity of amyloid beta protein (Aβ) generating enzyme β-site amyloid precursor protein cleaving enzyme (BACE-1), increased the activity of the Aβ degrading enzyme cathepsin D, and decreased the intracellular and secreted levels of Aβ. Conversely, pharmacological inhibition of AURKA decreased AURKA phosphorylation, de-acidified endolysosomes, decreased the activity of cathepsin D, and increased intracellular and secreted levels of Aβ. Thus, reduced AURKA activity in AD may contribute to the development of intraneuronal accumulations of Aβ and extracellular amyloid plaque formation.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"68 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141268493","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}
Cindy Hsin-Ti Lin, Muhammad Junaid Tariq, F. Ullah, Aishwarya Sannareddy, Farhan Khalid, Hasan Abbas, Abbas Bader, C. Samaras, Jason Valent, J. Khouri, F. Anwer, Shahzad Raza, D. Dima
Multiple myeloma (MM) is a hematologic malignancy caused by the clonal expansion of immunoglobulin-producing plasma cells in the bone marrow and/or extramedullary sites. Common manifestations of MM include anemia, renal dysfunction, infection, bone pain, hypercalcemia, and fatigue. Despite numerous recent advancements in the MM treatment paradigm, current therapies demonstrate limited long-term effectiveness and eventual disease relapse remains exceedingly common. Myeloma cells often develop drug resistance through clonal evolution and alterations of cellular signaling pathways. Therefore, continued research of new targets in MM is crucial to circumvent cumulative drug resistance, overcome treatment-limiting toxicities, and improve outcomes in this incurable disease. This article provides a comprehensive overview of the landscape of novel treatments and emerging therapies for MM grouped by molecular target. Molecular targets outlined include BCMA, GPRC5D, FcRH5, CD38, SLAMF7, BCL-2, kinesin spindle protein, protein disulfide isomerase 1, peptidylprolyl isomerase A, Sec61 translocon, and cyclin-dependent kinase 6. Immunomodulatory drugs, NK cell therapy, and proteolysis-targeting chimera are described as well.
多发性骨髓瘤（MM）是由骨髓和/或髓外部位产生免疫球蛋白的浆细胞克隆性扩增引起的血液系统恶性肿瘤。骨髓瘤的常见表现包括贫血、肾功能障碍、感染、骨痛、高钙血症和疲劳。尽管近来骨髓瘤治疗模式取得了许多进展，但目前的疗法显示出的长期疗效有限，疾病最终复发的情况仍然极为常见。骨髓瘤细胞往往通过克隆进化和细胞信号通路的改变产生耐药性。因此，继续研究骨髓瘤的新靶点对于规避累积性耐药性、克服治疗限制性毒性以及改善这种不治之症的治疗效果至关重要。本文按分子靶点全面概述了 MM 的新型疗法和新兴疗法。概述的分子靶点包括 BCMA、GPRC5D、FcRH5、CD38、SLAMF7、BCL-2、驱动蛋白纺锤体蛋白、蛋白二硫异构酶 1、肽基脯氨酰异构酶 A、Sec61 转座子和细胞周期蛋白依赖性激酶 6。此外还介绍了免疫调节药物、NK 细胞疗法和蛋白水解靶向嵌合体。
{"title":"Current Novel Targeted Therapeutic Strategies in Multiple Myeloma","authors":"Cindy Hsin-Ti Lin, Muhammad Junaid Tariq, F. Ullah, Aishwarya Sannareddy, Farhan Khalid, Hasan Abbas, Abbas Bader, C. Samaras, Jason Valent, J. Khouri, F. Anwer, Shahzad Raza, D. Dima","doi":"10.3390/ijms25116192","DOIUrl":"https://doi.org/10.3390/ijms25116192","url":null,"abstract":"Multiple myeloma (MM) is a hematologic malignancy caused by the clonal expansion of immunoglobulin-producing plasma cells in the bone marrow and/or extramedullary sites. Common manifestations of MM include anemia, renal dysfunction, infection, bone pain, hypercalcemia, and fatigue. Despite numerous recent advancements in the MM treatment paradigm, current therapies demonstrate limited long-term effectiveness and eventual disease relapse remains exceedingly common. Myeloma cells often develop drug resistance through clonal evolution and alterations of cellular signaling pathways. Therefore, continued research of new targets in MM is crucial to circumvent cumulative drug resistance, overcome treatment-limiting toxicities, and improve outcomes in this incurable disease. This article provides a comprehensive overview of the landscape of novel treatments and emerging therapies for MM grouped by molecular target. Molecular targets outlined include BCMA, GPRC5D, FcRH5, CD38, SLAMF7, BCL-2, kinesin spindle protein, protein disulfide isomerase 1, peptidylprolyl isomerase A, Sec61 translocon, and cyclin-dependent kinase 6. Immunomodulatory drugs, NK cell therapy, and proteolysis-targeting chimera are described as well.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"5 15","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141266185","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}
Jung-min Kim, Woo Ryung Kim, Eun Gyung Park, Duhyung Lee, Yun Ju Lee, Hae Jin Shin, Hyeon-su Jeong, Hyun-Young Roh, Heui-Soo Kim
Dementia, a multifaceted neurological syndrome characterized by cognitive decline, poses significant challenges to daily functioning. The main causes of dementia, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), and vascular dementia (VD), have different symptoms and etiologies. Genetic regulators, specifically non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are known to play important roles in dementia pathogenesis. MiRNAs, small non-coding RNAs, regulate gene expression by binding to the 3′ untranslated regions of target messenger RNAs (mRNAs), while lncRNAs and circRNAs act as molecular sponges for miRNAs, thereby regulating gene expression. The emerging concept of competing endogenous RNA (ceRNA) interactions, involving lncRNAs and circRNAs as competitors for miRNA binding, has gained attention as potential biomarkers and therapeutic targets in dementia-related disorders. This review explores the regulatory roles of ncRNAs, particularly miRNAs, and the intricate dynamics of ceRNA interactions, providing insights into dementia pathogenesis and potential therapeutic avenues.
{"title":"Exploring the Regulatory Landscape of Dementia: Insights from Non-Coding RNAs","authors":"Jung-min Kim, Woo Ryung Kim, Eun Gyung Park, Duhyung Lee, Yun Ju Lee, Hae Jin Shin, Hyeon-su Jeong, Hyun-Young Roh, Heui-Soo Kim","doi":"10.3390/ijms25116190","DOIUrl":"https://doi.org/10.3390/ijms25116190","url":null,"abstract":"Dementia, a multifaceted neurological syndrome characterized by cognitive decline, poses significant challenges to daily functioning. The main causes of dementia, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), and vascular dementia (VD), have different symptoms and etiologies. Genetic regulators, specifically non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are known to play important roles in dementia pathogenesis. MiRNAs, small non-coding RNAs, regulate gene expression by binding to the 3′ untranslated regions of target messenger RNAs (mRNAs), while lncRNAs and circRNAs act as molecular sponges for miRNAs, thereby regulating gene expression. The emerging concept of competing endogenous RNA (ceRNA) interactions, involving lncRNAs and circRNAs as competitors for miRNA binding, has gained attention as potential biomarkers and therapeutic targets in dementia-related disorders. This review explores the regulatory roles of ncRNAs, particularly miRNAs, and the intricate dynamics of ceRNA interactions, providing insights into dementia pathogenesis and potential therapeutic avenues.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"6 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141265872","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}
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