Pub Date : 2024-10-01DOI: 10.1016/j.lfs.2024.123097
Targeted therapies using epidermal growth factor receptor (EGFR) inhibitors have markedly improved survival rates and quality of life for patients with EGFR-mutant lung adenocarcinoma (LUAD). Despite these advancements, resistance to EGFR inhibitors remains a significant challenge, limiting the overall effectiveness of the treatment. This study explored the synergistic effects of combining Paeoniae Radix (PR) with first-generation EGFR-tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, to overcome this resistance. Transcriptomic analysis of EGFR-mutant LUAD cell lines revealed that PR treatment could potentially reverse the gene signatures associated with resistance to EGFR-TKIs, primarily through the suppression of the Aurora B pathway. Experimental validation demonstrated that combining PR with erlotinib and gefitinib enhanced drug responsiveness by inhibiting Aurora kinase activity and inducing apoptosis in LUAD cells. Additionally, gene expression changes confirmed these combined effects, with the suppression of the Aurora B pathway and upregulation of the apoptotic pathway, which was accompanied by increased expression of multiple pro-apoptotic genes. Our findings contribute to the development of natural product-based therapeutic strategies to mitigate drug resistance in LUAD.
使用表皮生长因子受体（EGFR）抑制剂的靶向疗法显著提高了表皮生长因子受体突变肺腺癌（LUAD）患者的生存率和生活质量。尽管取得了这些进展，但表皮生长因子受体抑制剂的耐药性仍然是一个重大挑战，限制了治疗的整体效果。本研究探讨了芍药与第一代表皮生长因子受体酪氨酸激酶抑制剂（TKIs）厄洛替尼和吉非替尼的协同作用，以克服这种耐药性。对表皮生长因子受体突变的 LUAD 细胞系进行的转录组分析表明，PR 治疗有可能逆转与表皮生长因子受体-TKIs 抗性相关的基因特征，主要是通过抑制极光 B 通路。实验验证表明，将 PR 与厄洛替尼和吉非替尼联合使用，可抑制 Aurora 激酶活性并诱导 LUAD 细胞凋亡，从而增强药物反应性。此外，基因表达的变化也证实了这些联合作用，抑制了极光 B 通路，上调了凋亡通路，同时增加了多个促凋亡基因的表达。我们的发现有助于开发基于天然产物的治疗策略，以减轻 LUAD 的耐药性。
{"title":"Paeoniae radix overcomes resistance to EGFR-TKIs via aurora B pathway suppression in lung adenocarcinoma","authors":"","doi":"10.1016/j.lfs.2024.123097","DOIUrl":"10.1016/j.lfs.2024.123097","url":null,"abstract":"<div><div>Targeted therapies using epidermal growth factor receptor (EGFR) inhibitors have markedly improved survival rates and quality of life for patients with EGFR-mutant lung adenocarcinoma (LUAD). Despite these advancements, resistance to EGFR inhibitors remains a significant challenge, limiting the overall effectiveness of the treatment. This study explored the synergistic effects of combining Paeoniae Radix (PR) with first-generation EGFR-tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, to overcome this resistance. Transcriptomic analysis of EGFR-mutant LUAD cell lines revealed that PR treatment could potentially reverse the gene signatures associated with resistance to EGFR-TKIs, primarily through the suppression of the Aurora B pathway. Experimental validation demonstrated that combining PR with erlotinib and gefitinib enhanced drug responsiveness by inhibiting Aurora kinase activity and inducing apoptosis in LUAD cells. Additionally, gene expression changes confirmed these combined effects, with the suppression of the Aurora B pathway and upregulation of the apoptotic pathway, which was accompanied by increased expression of multiple pro-apoptotic genes. Our findings contribute to the development of natural product-based therapeutic strategies to mitigate drug resistance in LUAD.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.lfs.2024.123093
Acute kidney injury (AKI) is a high-burden medical condition, and current diagnostic criteria can only assess AKI after full manifestation. Stress marker growth differentiation factor 15 (GDF15) was reported to have a role in kidney injury of critical patients. Herein, we evaluated dynamic changes in GDF15 across diverse AKI scenarios and explored the underlying mechanisms of its induction. Serum parameters and renal lesions were analyzed in mouse models of unilateral ischemia-reperfusion injury (uni-IRI) and unilateral ureteral obstruction (UUO). The human proximal tubular (HK−2) cell line was stimulated with various conditions, and induction of GDF15 expression was determined. Serum GDF15 levels were rapidly induced within hours after injury in both animal models and declined thereafter. Renal GDF15 expression exhibited a temporary and early increased induction and was mainly located in aquaporin 1-positive proximal tubules in both unilateral AKI model tissues. In cell experiments, rapid GDF15 production was highly induced by t-BHP and CoCl2. Treatment with either an antioxidant or mitogen-activated protein kinase inhibitors abolished t-BHP- and CoCl2-mediated GDF15 expression. In addition, silencing nuclear factor erythroid 2-related factor 2 expression also reduced the basal and t-BHP- or CoCl2-mediated GDF15 expression level in HK-2 cells. Our data showed that elevated serum GDF15 levels could be detected early in unilateral AKI models without notable alterations in kidney function parameters. GDF15 expression was associated with oxidative stress- and hypoxia-mediated proximal tubular cell injury. These data document that elevated serum GDF15 can possibly serve as an early biomarker for proximal tubular cell injury in AKI.
急性肾损伤（AKI）是一种负担沉重的内科疾病，目前的诊断标准只能在急性肾损伤完全显现后才能对其进行评估。据报道，应激标记物生长分化因子 15（GDF15）在危重病人的肾损伤中发挥作用。在此，我们评估了不同 AKI 情景下 GDF15 的动态变化，并探讨了其诱导的内在机制。我们分析了单侧缺血再灌注损伤（uni-IRI）和单侧输尿管梗阻（UUO）小鼠模型的血清参数和肾脏病变。在不同条件下刺激人近曲小管（HK-2）细胞系，并测定诱导 GDF15 的表达。两种动物模型的血清 GDF15 水平在损伤后数小时内迅速诱导，随后下降。在两种单侧 AKI 模型组织中，肾脏 GDF15 的表达都表现出暂时和早期的诱导增加，并且主要位于水肿素 1 阳性的近端肾小管中。在细胞实验中，t-BHP 和 CoCl2 可高度诱导 GDF15 的快速生成。使用抗氧化剂或丝裂原活化蛋白激酶抑制剂可抑制t-BHP和CoCl2介导的GDF15表达。此外，沉默核因子红细胞2相关因子2的表达也会降低HK-2细胞的基础和t-BHP或CoCl2介导的GDF15表达水平。我们的数据显示，在单侧 AKI 模型中，血清 GDF15 水平升高可被早期检测到，而肾功能参数并无明显改变。GDF15 的表达与氧化应激和缺氧介导的近端肾小管细胞损伤有关。这些数据表明，血清GDF15的升高可作为AKI近端肾小管细胞损伤的早期生物标志物。
{"title":"Elevated serum GDF15 level as an early indicator of proximal tubular cell injury in acute kidney injury","authors":"","doi":"10.1016/j.lfs.2024.123093","DOIUrl":"10.1016/j.lfs.2024.123093","url":null,"abstract":"<div><div>Acute kidney injury (AKI) is a high-burden medical condition, and current diagnostic criteria can only assess AKI after full manifestation. Stress marker growth differentiation factor 15 (GDF15) was reported to have a role in kidney injury of critical patients. Herein, we evaluated dynamic changes in GDF15 across diverse AKI scenarios and explored the underlying mechanisms of its induction. Serum parameters and renal lesions were analyzed in mouse models of unilateral ischemia-reperfusion injury (uni-IRI) and unilateral ureteral obstruction (UUO). The human proximal tubular (HK−2) cell line was stimulated with various conditions, and induction of GDF15 expression was determined. Serum GDF15 levels were rapidly induced within hours after injury in both animal models and declined thereafter. Renal GDF15 expression exhibited a temporary and early increased induction and was mainly located in aquaporin 1-positive proximal tubules in both unilateral AKI model tissues. In cell experiments, rapid GDF15 production was highly induced by t-BHP and CoCl<sub>2</sub>. Treatment with either an antioxidant or mitogen-activated protein kinase inhibitors abolished t-BHP- and CoCl<sub>2</sub>-mediated GDF15 expression. In addition, silencing nuclear factor erythroid 2-related factor 2 expression also reduced the basal and t-BHP- or CoCl<sub>2</sub>-mediated GDF15 expression level in HK-2 cells. Our data showed that elevated serum GDF15 levels could be detected early in unilateral AKI models without notable alterations in kidney function parameters. GDF15 expression was associated with oxidative stress- and hypoxia-mediated proximal tubular cell injury. These data document that elevated serum GDF15 can possibly serve as an early biomarker for proximal tubular cell injury in AKI.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.lfs.2024.123094
Aims
Alzheimer's disease is characterized by memory loss and pathological changes in the brain, such as amyloid beta and tau pathology, disruptions in neural circuits and neuronal oscillations are also significant indicators of this disease and potential therapeutic targets. We studied how intranasal insulin impacts memory and neural oscillations in an Alzheimer's disease rat model induced by STZ.
Main methods
Male Wistar rats were intracerebroventricularly injected with STZ, followed by intranasal insulin therapy. Electrophysiological recordings were conducted in the hippocampus and medial prefrontal cortex to assess local field potentials. Memory was assessed using novel object recognition and Y-maze tests. Amyloid and tau pathology and neuronal loss were also evaluated in the hippocampus.
Key finding
Alterations in theta-gamma oscillations following insulin treatment were not significant. However, insulin administration ameliorated hippocampal sharp-wave ripples deficit and augmented hippocampal-prefrontal theta coherence. Concurrently, insulin therapy enhanced spatial memory and object recognition memory performance in behavioral tests. Insulin mitigated tau and amyloid pathology and hippocampal neuronal loss.
Significance
Our findings underscore the potential of intranasal insulin to enhance memory function by modulating hippocampal-prefrontal cortical synchronization and alleviating impairments in hippocampal sharp-wave ripples.
{"title":"Hippocampal sharp-wave ripples and hippocampal-prefrontal synchrony regulate memory-enhancing effects of intranasal insulin in an STZ-induced Alzheimer's model","authors":"","doi":"10.1016/j.lfs.2024.123094","DOIUrl":"10.1016/j.lfs.2024.123094","url":null,"abstract":"<div><h3>Aims</h3><div>Alzheimer's disease is characterized by memory loss and pathological changes in the brain, such as amyloid beta and tau pathology, disruptions in neural circuits and neuronal oscillations are also significant indicators of this disease and potential therapeutic targets. We studied how intranasal insulin impacts memory and neural oscillations in an Alzheimer's disease rat model induced by STZ.</div></div><div><h3>Main methods</h3><div>Male Wistar rats were intracerebroventricularly injected with STZ, followed by intranasal insulin therapy. Electrophysiological recordings were conducted in the hippocampus and medial prefrontal cortex to assess local field potentials. Memory was assessed using novel object recognition and Y-maze tests. Amyloid and tau pathology and neuronal loss were also evaluated in the hippocampus.</div></div><div><h3>Key finding</h3><div>Alterations in theta-gamma oscillations following insulin treatment were not significant. However, insulin administration ameliorated hippocampal sharp-wave ripples deficit and augmented hippocampal-prefrontal theta coherence. Concurrently, insulin therapy enhanced spatial memory and object recognition memory performance in behavioral tests. Insulin mitigated tau and amyloid pathology and hippocampal neuronal loss.</div></div><div><h3>Significance</h3><div>Our findings underscore the potential of intranasal insulin to enhance memory function by modulating hippocampal-prefrontal cortical synchronization and alleviating impairments in hippocampal sharp-wave ripples.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.lfs.2024.123085
Aims
Alzheimer's disease (AD) is characterized by β-amyloid (Aβ) aggregation and neuroinflammation, leading to progressive synaptic loss and cognitive decline. Recent evidence suggests that Galectin-3 (Gal-3) plays a critical role in Aβ pathogenesis. However, strategies to simultaneously target Gal-3 and Aβ are currently insufficient. This study evaluates the therapeutic efficacy of (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one (D30), in reducing Gal-3 and Aβ pathogenesis.
Materials and methods
We applied exogenous oligomeric Aβ and used 5 × FAD mice to assess the impact of Aβ on Gal-3 deposition, microglial activation, and cognitive function. Thy1-EGFP mice were employed to observe dendritic spines. Comprehensive evaluations of D30's effects included behavioral studies, transcriptomic analysis, Western blotting, and immunofluorescent staining. The interaction between D30 and Gal-3 was examined using fluorescence resonance energy transfer (FRET) and microscale thermophoresis (MST).
Key findings
D30 effectively reduced Aβ monomer production by inhibiting Amyloid Precursor Protein (APP) and presenilin 1 (PS1) expression, and decreased Aβ aggregation. Treatment with D30 improved cognitive functions, reversed dendritic spine loss, and increased PSD95 expression in 5 × FAD mice. Additionally, D30 significantly lowered Gal-3 levels in both plasma and hippocampal tissues. D30 binds to Gal-3 and disrupts the interaction between Gal-3 and TREM2, as confirmed by FRET and MST.
Significance
Our findings underscore the interaction between Gal-3 and Aβ in AD and its role in systemic inflammation using the 5 × FAD mouse model. Being able to target and regulate Gal-3 together with Aβ is crucial for preventing neuroinflammation and protecting synapses, D30 emerged as a novel compound with promising potential for AD treatment.
{"title":"Compound (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one downregulation of Galectin-3 ameliorates Aβ pathogenesis-induced neuroinflammation in 5 × FAD mice","authors":"","doi":"10.1016/j.lfs.2024.123085","DOIUrl":"10.1016/j.lfs.2024.123085","url":null,"abstract":"<div><h3>Aims</h3><div>Alzheimer's disease (AD) is characterized by β-amyloid (Aβ) aggregation and neuroinflammation, leading to progressive synaptic loss and cognitive decline. Recent evidence suggests that Galectin-3 (Gal-3) plays a critical role in Aβ pathogenesis. However, strategies to simultaneously target Gal-3 and Aβ are currently insufficient. This study evaluates the therapeutic efficacy of (<em>E</em>)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one (D30), in reducing Gal-3 and Aβ pathogenesis.</div></div><div><h3>Materials and methods</h3><div>We applied exogenous oligomeric Aβ and used 5 × FAD mice to assess the impact of Aβ on Gal-3 deposition, microglial activation, and cognitive function. Thy1-EGFP mice were employed to observe dendritic spines. Comprehensive evaluations of D30's effects included behavioral studies, transcriptomic analysis, Western blotting, and immunofluorescent staining. The interaction between D30 and Gal-3 was examined using fluorescence resonance energy transfer (FRET) and microscale thermophoresis (MST).</div></div><div><h3>Key findings</h3><div>D30 effectively reduced Aβ monomer production by inhibiting Amyloid Precursor Protein (APP) and presenilin 1 (PS1) expression, and decreased Aβ aggregation. Treatment with D30 improved cognitive functions, reversed dendritic spine loss, and increased PSD95 expression in 5 × FAD mice. Additionally, D30 significantly lowered Gal-3 levels in both plasma and hippocampal tissues. D30 binds to Gal-3 and disrupts the interaction between Gal-3 and TREM2, as confirmed by FRET and MST.</div></div><div><h3>Significance</h3><div>Our findings underscore the interaction between Gal-3 and Aβ in AD and its role in systemic inflammation using the 5 × FAD mouse model. Being able to target and regulate Gal-3 together with Aβ is crucial for preventing neuroinflammation and protecting synapses, D30 emerged as a novel compound with promising potential for AD treatment.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.lfs.2024.123103
Aims
Ficolin 3 (FCN3) has the highest complement-activating capacity through the lectin pathway and is synthesized mainly in the liver and lung. Yet, its potential molecular mechanism in hepatocarcinogenesis is not fully understood.
Materials and methods
The expression of FCN3 in hepatocellular carcinoma (HCC) tumor and non-tumor tissues was analyzed by RT-qPCR, Western blotting and immunofluorescence staining assays. Lentivector-mediated ectopic overexpression was performed to explore the role of FCN3 in vitro and in vivo. Whether FCN3 inhibited HCC cell growth and survival via complement pathway was determined with immunocytochemical staining for C3b, membrane attack complex (MAC) formation and complement killing assay using recombinant FCN3 (rFCN3) in combination with human serum with or without heat inactivation, and with C6 blocking antibody.
Key findings
The transcript and protein of FCN3 were found to be remarkably down-regulated in HCC tumor tissues. FCN3 expression was found to be associated with better survival of HCC patients. Restoration of FCN3 expression significantly inhibited proliferation, migration and anchorage independent growth of HCC cell lines, and xenograft tumor growth. FCN3 expression induced apoptosis of HCC cells. C3 and MAC formation was stimulated by FCN3 overexpression or rFCN3 treatment. rFCN3 enhanced human serum-induced complement activation and cell death. C6 blocking antibody significantly attenuated complement-mediated cell death and restored the growth of FCN3-overexpressing HCC cells.
Significance
FCN3 has a malignant suppressor role in HCC cells. Our study provides new insights into the molecular mechanisms that drive HCC progression and potential therapeutic targets for treating HCC.
{"title":"Ficolin-3 induces apoptosis and suppresses malignant property of hepatocellular carcinoma cells via the complement pathway","authors":"","doi":"10.1016/j.lfs.2024.123103","DOIUrl":"10.1016/j.lfs.2024.123103","url":null,"abstract":"<div><h3>Aims</h3><div>Ficolin 3 (FCN3) has the highest complement-activating capacity through the lectin pathway and is synthesized mainly in the liver and lung. Yet, its potential molecular mechanism in hepatocarcinogenesis is not fully understood.</div></div><div><h3>Materials and methods</h3><div>The expression of FCN3 in hepatocellular carcinoma (HCC) tumor and non-tumor tissues was analyzed by RT-qPCR, Western blotting and immunofluorescence staining assays. Lentivector-mediated ectopic overexpression was performed to explore the role of FCN3 in vitro and in vivo. Whether FCN3 inhibited HCC cell growth and survival via complement pathway was determined with immunocytochemical staining for C3b, membrane attack complex (MAC) formation and complement killing assay using recombinant FCN3 (rFCN3) in combination with human serum with or without heat inactivation, and with C6 blocking antibody.</div></div><div><h3>Key findings</h3><div>The transcript and protein of FCN3 were found to be remarkably down-regulated in HCC tumor tissues. <em>FCN3</em> expression was found to be associated with better survival of HCC patients. Restoration of FCN3 expression significantly inhibited proliferation, migration and anchorage independent growth of HCC cell lines, and xenograft tumor growth. FCN3 expression induced apoptosis of HCC cells. C3 and MAC formation was stimulated by FCN3 overexpression or rFCN3 treatment. rFCN3 enhanced human serum-induced complement activation and cell death. C6 blocking antibody significantly attenuated complement-mediated cell death and restored the growth of FCN3-overexpressing HCC cells.</div></div><div><h3>Significance</h3><div>FCN3 has a malignant suppressor role in HCC cells. Our study provides new insights into the molecular mechanisms that drive HCC progression and potential therapeutic targets for treating HCC.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.lfs.2024.123100
Long COVID is estimated to have affected 6.9 % of US adults, 17.8 million people in the US alone, as of early 2023. While SARS-CoV-2 is primarily considered a respiratory virus, gastrointestinal (GI) symptoms are also frequent in patients with coronavirus disease 2019 (COVID-19) and in patients with Long COVID. The risk of developing GI symptoms is increased with increasing severity of COVID-19, the presence of GI symptoms in the acute infection, and psychological distress both before and after COVID-19. Persistence of the virus in the GI tract, ensuing inflammation, and alteration of the microbiome are all likely mediators of the effects of SARS Co-V-2 virus on the gut. These factors may all increase intestinal permeability and systemic inflammation. GI inflammation and dysbiosis can change the absorption and metabolism of tryptophan, an important neurotransmitter. Long COVID GI symptoms resemble a Disorder of Gut Brain Interaction (DGBI) such as post infection Irritable Bowel Syndrome (IBS). Current standards of treatment for IBS can guide our treatment of Long COVID patients. Dysautonomia, a frequent Long COVID condition affecting the autonomic nervous system, can also affect the GI tract, and must be considered in Long COVID patients with GI symptoms. Long COVID symptoms fall within the broader category of Infection Associated Chronic Conditions (IACCs). Research into the GI symptoms of Long COVID may further our understanding of other post infection chronic GI conditions, and elucidate the roles of therapeutic options including antivirals, probiotics, neuromodulators, and treatments of dysautonomia.
据估计，截至 2023 年初，长 COVID 已影响到 6.9 % 的美国成年人，仅美国就有 1780 万人。虽然 SARS-CoV-2 主要被认为是一种呼吸道病毒，但在冠状病毒病 2019（COVID-19）和长 COVID 患者中，胃肠道 (GI) 症状也很常见。出现消化道症状的风险会随着 COVID-19 的严重程度、急性感染时出现的消化道症状以及 COVID-19 前后的心理困扰而增加。病毒在消化道的持续存在、随之而来的炎症和微生物群的改变都可能是 SARS Co-V-2 病毒对肠道产生影响的介质。这些因素都可能增加肠道渗透性和全身炎症。肠道炎症和菌群失调会改变色氨酸（一种重要的神经递质）的吸收和代谢。长期的 COVID 胃肠道症状类似于感染后肠易激综合症（IBS）等肠道与大脑相互作用紊乱的症状。目前治疗肠易激综合征的标准可以指导我们对 Long COVID 患者的治疗。自律神经失调症是一种常见的影响自律神经系统的 Long COVID 病症，也会影响消化道，有消化道症状的 Long COVID 患者必须考虑到这一点。长COVID症状属于更广泛的感染相关慢性疾病范畴。对 Long COVID 消化道症状的研究可进一步加深我们对其他感染后慢性消化道疾病的了解，并阐明抗病毒药物、益生菌、神经调节剂和自律神经失调治疗等治疗方案的作用。
{"title":"Gastrointestinal manifestations of long COVID","authors":"","doi":"10.1016/j.lfs.2024.123100","DOIUrl":"10.1016/j.lfs.2024.123100","url":null,"abstract":"<div><div>Long COVID is estimated to have affected 6.9 % of US adults, 17.8 million people in the US alone, as of early 2023. While SARS-CoV-2 is primarily considered a respiratory virus, gastrointestinal (GI) symptoms are also frequent in patients with coronavirus disease 2019 (COVID-19) and in patients with Long COVID. The risk of developing GI symptoms is increased with increasing severity of COVID-19, the presence of GI symptoms in the acute infection, and psychological distress both before and after COVID-19. Persistence of the virus in the GI tract, ensuing inflammation, and alteration of the microbiome are all likely mediators of the effects of SARS Co-V-2 virus on the gut. These factors may all increase intestinal permeability and systemic inflammation. GI inflammation and dysbiosis can change the absorption and metabolism of tryptophan, an important neurotransmitter. Long COVID GI symptoms resemble a Disorder of Gut Brain Interaction (DGBI) such as post infection Irritable Bowel Syndrome (IBS). Current standards of treatment for IBS can guide our treatment of Long COVID patients. Dysautonomia, a frequent Long COVID condition affecting the autonomic nervous system, can also affect the GI tract, and must be considered in Long COVID patients with GI symptoms. Long COVID symptoms fall within the broader category of Infection Associated Chronic Conditions (IACCs). Research into the GI symptoms of Long COVID may further our understanding of other post infection chronic GI conditions, and elucidate the roles of therapeutic options including antivirals, probiotics, neuromodulators, and treatments of dysautonomia.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.lfs.2024.123088
Parkinson's disease (PD), a neurodegenerative disorder characterized by impaired motor function, is typically treated with medications and surgery. However, recent studies have validated physical exercise as an effective adjunct therapy, significantly improving both motor and non-motor symptoms in PD patients. Irisin, a myokine, has garnered increasing attention for its beneficial effects on the nervous system. Research has shown that irisin plays a crucial role in regulating metabolic balance, optimizing autophagy, maintaining mitochondrial quality, alleviating oxidative stress and neuroinflammation, and regulating cell death—all processes intricately linked to the pathogenesis of PD. This review examines the mechanisms through which irisin may counteract PD, provides insights into its biological effects, and considers its potential as a target for therapeutic strategies.
{"title":"Irisin's emerging role in Parkinson's disease research: A review from molecular mechanisms to therapeutic prospects","authors":"","doi":"10.1016/j.lfs.2024.123088","DOIUrl":"10.1016/j.lfs.2024.123088","url":null,"abstract":"<div><div>Parkinson's disease (PD), a neurodegenerative disorder characterized by impaired motor function, is typically treated with medications and surgery. However, recent studies have validated physical exercise as an effective adjunct therapy, significantly improving both motor and non-motor symptoms in PD patients. Irisin, a myokine, has garnered increasing attention for its beneficial effects on the nervous system. Research has shown that irisin plays a crucial role in regulating metabolic balance, optimizing autophagy, maintaining mitochondrial quality, alleviating oxidative stress and neuroinflammation, and regulating cell death—all processes intricately linked to the pathogenesis of PD. This review examines the mechanisms through which irisin may counteract PD, provides insights into its biological effects, and considers its potential as a target for therapeutic strategies.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.lfs.2024.123086
Peripheral nerve injury (PNI) can cause nerve demyelination, neuronal apoptosis, axonal atrophy, inflammatory infiltration, glial scar formation, and other pathologies that can lead to sensory and motor dysfunction and seriously affect the psychosomatic health of patients. There is currently no effective treatment method, so exploring a promising treatment method is of great significance. Several studies have revealed the therapeutic roles of Schwann cells (SCs) and their exosomes in nerve injury repair. Exosomes are extracellular nanovesicles secreted by cells that act as key molecules in intercellular communication. Progress has been made in understanding the role of exosomes derived from SCs (SC-EXOs) in peripheral nerve regeneration, including the promotion of axonal regeneration and myelin formation, anti-inflammation, vascular regeneration, neuroprotection, and neuroregulation. Therefore, in this paper, we summarize the functional characteristics of SC-EXOs and discuss their potential therapeutic effects on PNI repair as well as some existing problems and future challenges.
{"title":"Therapeutic effect of exosomes derived from Schwann cells in the repair of peripheral nerve injury","authors":"","doi":"10.1016/j.lfs.2024.123086","DOIUrl":"10.1016/j.lfs.2024.123086","url":null,"abstract":"<div><div>Peripheral nerve injury (PNI) can cause nerve demyelination, neuronal apoptosis, axonal atrophy, inflammatory infiltration, glial scar formation, and other pathologies that can lead to sensory and motor dysfunction and seriously affect the psychosomatic health of patients. There is currently no effective treatment method, so exploring a promising treatment method is of great significance. Several studies have revealed the therapeutic roles of Schwann cells (SCs) and their exosomes in nerve injury repair. Exosomes are extracellular nanovesicles secreted by cells that act as key molecules in intercellular communication. Progress has been made in understanding the role of exosomes derived from SCs (SC-EXOs) in peripheral nerve regeneration, including the promotion of axonal regeneration and myelin formation, anti-inflammation, vascular regeneration, neuroprotection, and neuroregulation. Therefore, in this paper, we summarize the functional characteristics of SC-EXOs and discuss their potential therapeutic effects on PNI repair as well as some existing problems and future challenges.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-27DOI: 10.1016/j.lfs.2024.123083
Ultraviolet (UV) B-induced damage in human epidermal keratinocytes (HEKs) initiates photocarcinogenesis. However, how diabetes influences photocarcinogenesis is not well understood. To investigate the impact of high-glucose environments on responses to UVB, we cultured HEKs in normal-glucose (NG) or high-glucose (HG) conditions (G6 and G26), followed by UVB irradiation at 25 mJ/cm2 (G6UVB and G26UVB). We performed next-generation sequencing and analyzed HEKs' expression profiles bioinformatically to identify candidate genes and cellular responses involved. We found UVB induced consistent responses in both NG- and HG-cultivated HEKs, but it also triggered certain distinct processes and pathways specifically in the HG groups. The 459 differentially expressed (DE) genes in the HG groups revealed their roles in chromatin remodeling, nucleosome assembly, and interferon signaling activation. Moreover, the 29 DE genes identified in G26UVB/G6UVB comparison, including the potent tumor suppressor gene TFPI2, were considered key genes contributing to HEKs' altered response to UVB in HG environments. UVB irradiation induced significantly higher TFPI2 expression in HG-cultivated HEKs than their NG-cultivated counterpart. Finally, HG-cultivation significantly increased oxidative stress, cyclobutane pyrimidine dimer formation, and apoptosis, while reducing HEKs' viability after UVB irradiation. These changes under HG conditions probably mediate cell fate toward death and tumor regression. Overall, our findings provide evidence and associated molecular basis on how HG conditions reduce keratinocytes' photocarcinogenic potential following UVB exposure.
{"title":"High-glucose impact on UVB responses in human epidermal keratinocytes: Insights on diabetic skin's resistance to photocarcinogenesis","authors":"","doi":"10.1016/j.lfs.2024.123083","DOIUrl":"10.1016/j.lfs.2024.123083","url":null,"abstract":"<div><div>Ultraviolet (UV) B-induced damage in human epidermal keratinocytes (HEKs) initiates photocarcinogenesis. However, how diabetes influences photocarcinogenesis is not well understood. To investigate the impact of high-glucose environments on responses to UVB, we cultured HEKs in normal-glucose (NG) or high-glucose (HG) conditions (G6 and G26), followed by UVB irradiation at 25 mJ/cm<sup>2</sup> (G6UVB and G26UVB). We performed next-generation sequencing and analyzed HEKs' expression profiles bioinformatically to identify candidate genes and cellular responses involved. We found UVB induced consistent responses in both NG- and HG-cultivated HEKs, but it also triggered certain distinct processes and pathways specifically in the HG groups. The 459 differentially expressed (DE) genes in the HG groups revealed their roles in chromatin remodeling, nucleosome assembly, and interferon signaling activation. Moreover, the 29 DE genes identified in G26UVB/G6UVB comparison, including the potent tumor suppressor gene <em>TFPI2,</em> were considered key genes contributing to HEKs' altered response to UVB in HG environments. UVB irradiation induced significantly higher <em>TFPI2</em> expression in HG-cultivated HEKs than their NG-cultivated counterpart. Finally, HG-cultivation significantly increased oxidative stress, cyclobutane pyrimidine dimer formation, and apoptosis, while reducing HEKs' viability after UVB irradiation. These changes under HG conditions probably mediate cell fate toward death and tumor regression. Overall, our findings provide evidence and associated molecular basis on how HG conditions reduce keratinocytes' photocarcinogenic potential following UVB exposure.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142349483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-26DOI: 10.1016/j.lfs.2024.123081
Post traumatic stress disorder (PTSD) and sleep disorders are prevalent among patients with long COVID. The intersection of PTSD and/or sleep disorders with long COVID is complex. Thus, use of a biopsychosocial lens for assessment and treatment along with a trauma-informed approach to clinical care is recommended. This review provides an overview of the literature on PTSD and sleep disorders among patients with long COVID, including prevalence rates, risk factors, and potential pathophysiology. Pharmacological and non-pharmacological treatment options are reviewed. Also, we provide actionable steps clinicians can integrate into their practice to help effectively assess and treat PTSD and sleep disorders, including validated symptom assessments, recommended referrals, and specific components of non-pharmacological interventions.
{"title":"Post traumatic stress and sleep disorders in long COVID: Patient management and treatment","authors":"","doi":"10.1016/j.lfs.2024.123081","DOIUrl":"10.1016/j.lfs.2024.123081","url":null,"abstract":"<div><div>Post traumatic stress disorder (PTSD) and sleep disorders are prevalent among patients with long COVID. The intersection of PTSD and/or sleep disorders with long COVID is complex. Thus, use of a biopsychosocial lens for assessment and treatment along with a trauma-informed approach to clinical care is recommended. This review provides an overview of the literature on PTSD and sleep disorders among patients with long COVID, including prevalence rates, risk factors, and potential pathophysiology. Pharmacological and non-pharmacological treatment options are reviewed. Also, we provide actionable steps clinicians can integrate into their practice to help effectively assess and treat PTSD and sleep disorders, including validated symptom assessments, recommended referrals, and specific components of non-pharmacological interventions.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142349489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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