Biochimica et biophysica acta. Molecular basis of disease最新文献_第4页

Piplartine alleviates sepsis-induced acute kidney injury by inhibiting TSPO-mediated macrophage pyroptosis

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-23 DOI: 10.1016/j.bbadis.2025.167687

Rui Gong , Gangyu Long , Qian Wang , Xujuan Hu , Hong Luo , Dingyu Zhang , Jun Shang , Yang Han , Chaolin Huang , You Shang

Sepsis-induced acute kidney injury (SI-AKI) is the most common organ dysfunction of sepsis, characterized with prolonged hospitalization periods and significantly elevated mortality rates. Piplartine (PLG), an alkaloid extracted from Piper longum within the Piperaceae family, has exhibited diverse pharmacological activities, including anti-inflammatory, anti-atherosclerotic, and anti-tumor effects. Herein, we investigated whether the PLG could reverse SI-AKI and explore its possible anti-inflammatory mechanisms. We constructed an SI-AKI model using cecal ligation and puncture (CLP) and systematically evaluated the protective effect of PLG administered by gavage in the SI-AKI mice. Subsequently, we performed proteomic sequencing of the kidney and integrated data from the GeneCards and SwissTargetPrediction databases to identify potential targets and mechanisms. Immunofluorescence and western blotting were used to examine the expression of relevant targets and pathways in vivo and in vitro. The influence of PLG on the predicted target and pathway was verified using an agonist of the target protein and a series of biochemical experiments. PLG exhibited significant efficacy against pathological damage, neutrophil and macrophage infiltration, and macrophage pyroptosis in kidneys at 30 mg/kg. An integrated analysis of proteomic data identified the translocator protein (TSPO) as a potential target for the renoprotective effects of PLG. Moreover, a TSPO agonist (RO5–4864) prominently reversed the protective effect of PLG in SI-AKI mice, as manifested by a deterioration in renal function, histopathological lesions and macrophage pyroptosis in the kidneys. Our results suggest that PLG may ameliorate SI-AKI, potentially through partial inhibition of the TSPO-macrophage pyroptosis pathway.

{"title":"Piplartine alleviates sepsis-induced acute kidney injury by inhibiting TSPO-mediated macrophage pyroptosis","authors":"Rui Gong , Gangyu Long , Qian Wang , Xujuan Hu , Hong Luo , Dingyu Zhang , Jun Shang , Yang Han , Chaolin Huang , You Shang","doi":"10.1016/j.bbadis.2025.167687","DOIUrl":"10.1016/j.bbadis.2025.167687","url":null,"abstract":"<div><div>Sepsis-induced acute kidney injury (SI-AKI) is the most common organ dysfunction of sepsis, characterized with prolonged hospitalization periods and significantly elevated mortality rates. Piplartine (PLG), an alkaloid extracted from <em>Piper longum</em> within the Piperaceae family, has exhibited diverse pharmacological activities, including anti-inflammatory, anti-atherosclerotic, and anti-tumor effects. Herein, we investigated whether the PLG could reverse SI-AKI and explore its possible anti-inflammatory mechanisms. We constructed an SI-AKI model using cecal ligation and puncture (CLP) and systematically evaluated the protective effect of PLG administered by gavage in the SI-AKI mice. Subsequently, we performed proteomic sequencing of the kidney and integrated data from the GeneCards and SwissTargetPrediction databases to identify potential targets and mechanisms. Immunofluorescence and western blotting were used to examine the expression of relevant targets and pathways in vivo and in vitro. The influence of PLG on the predicted target and pathway was verified using an agonist of the target protein and a series of biochemical experiments. PLG exhibited significant efficacy against pathological damage, neutrophil and macrophage infiltration, and macrophage pyroptosis in kidneys at 30 mg/kg. An integrated analysis of proteomic data identified the translocator protein (TSPO) as a potential target for the renoprotective effects of PLG. Moreover, a TSPO agonist (RO5–4864) prominently reversed the protective effect of PLG in SI-AKI mice, as manifested by a deterioration in renal function, histopathological lesions and macrophage pyroptosis in the kidneys. Our results suggest that PLG may ameliorate SI-AKI, potentially through partial inhibition of the TSPO-macrophage pyroptosis pathway.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167687"},"PeriodicalIF":4.2,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular mechanism of mitochondrial autophagy mediating impaired energy metabolism leading to osteoporosis

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-20 DOI: 10.1016/j.bbadis.2025.167685

Yuheng He , Tao Liu , Xin Peng , Chaorui Yao , Daqian Zhou , Chao Song , Zhangchao Wei , Jinwen Chen , Zongchao Liu , Feng Jiang

Osteoporosis (OP) is a bone metabolic disease caused by decreased bone mass leading to destruction of bone microstructure. Treatment of OP is characterized by a lifelong nature, causing extreme financial and psychological burdens to patients. Hormonal abnormalities, cellular autophagy, Ferroptosis, and oxidative stress are all part of the intricate and varied pathophysiology of OP. Recent research has revealed that mitochondrial dysfunction is a significant factor in the onset and progression of OP. By regulating bone marrow mesenchymal stem cell differentiation through various signaling pathways and cytokines, abnormal mitochondrial energy metabolism brought on by oxidative stress processes impacts osteoblast and osteoclast proliferation and differentiation, causing an imbalance in bone metabolism that ultimately results in OP. Therefore, one possible method to prevent and manage OP may be to use mitochondria as a carrier to trigger osteogenic differentiation of bone marrow mesenchymal stem cells from mitochondrial energy consumption, oxidative stress, autophagy, and osteoclast death. In order to offer some theoretical references and therapeutic approaches for the clinical prevention and treatment of OP, we will examine the pathophysiology of OP from mitochondrial dysfunction in this work.

{"title":"Molecular mechanism of mitochondrial autophagy mediating impaired energy metabolism leading to osteoporosis","authors":"Yuheng He , Tao Liu , Xin Peng , Chaorui Yao , Daqian Zhou , Chao Song , Zhangchao Wei , Jinwen Chen , Zongchao Liu , Feng Jiang","doi":"10.1016/j.bbadis.2025.167685","DOIUrl":"10.1016/j.bbadis.2025.167685","url":null,"abstract":"<div><div>Osteoporosis (OP) is a bone metabolic disease caused by decreased bone mass leading to destruction of bone microstructure. Treatment of OP is characterized by a lifelong nature, causing extreme financial and psychological burdens to patients. Hormonal abnormalities, cellular autophagy, Ferroptosis, and oxidative stress are all part of the intricate and varied pathophysiology of OP. Recent research has revealed that mitochondrial dysfunction is a significant factor in the onset and progression of OP. By regulating bone marrow mesenchymal stem cell differentiation through various signaling pathways and cytokines, abnormal mitochondrial energy metabolism brought on by oxidative stress processes impacts osteoblast and osteoclast proliferation and differentiation, causing an imbalance in bone metabolism that ultimately results in OP. Therefore, one possible method to prevent and manage OP may be to use mitochondria as a carrier to trigger osteogenic differentiation of bone marrow mesenchymal stem cells from mitochondrial energy consumption, oxidative stress, autophagy, and osteoclast death. In order to offer some theoretical references and therapeutic approaches for the clinical prevention and treatment of OP, we will examine the pathophysiology of OP from mitochondrial dysfunction in this work.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167685"},"PeriodicalIF":4.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gelsolin traps ribosomal protein SA (RPSA) within lipid nanodomains of the plasma membrane and modulates the level of protein synthesis in the submembranous region of human skin melanoma cells

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-20 DOI: 10.1016/j.bbadis.2025.167686

Ewa Mazurkiewicz-Stanek , Joanna Machnik , Iryna Kopernyk , Wojciech Wiertelak , Dorota Maszczak-Seneczko , Estera Jeruzalska , Agnieszka Biernatowska , Aleksandra Makowiecka , Michał Majkowski , Przemysław Biecek , Tomasz Trombik , Piotr Donizy , Antonina J. Mazur

The connection between the F-actin and ribosome docking to the PM has been reported, but the exact mechanism has remained unclear. Previously, we discovered that gelsolin (GSN) forms complexes with numerous ribosomal proteins, including ribosomal protein SA (RPSA). Now, we have unraveled the mechanism of ribosome recruitment to the lipid nanodomains of the PM, with GSN playing a pivotal role in this process. We demonstrate that GSN directly interacts with RPSA, and microscopic analyses reveal their colocalization in the cell's submembranous region. Through spot variation fluorescence correlation spectroscopy, we confirm that GSN is responsible for trapping RPSA within PM's lipid nanodomains, a process dependent on F-actin. Importantly, we establish a correlation between the GSN level and the level of protein synthesis in melanoma cells. Furthermore, we present compelling evidence that high levels of GSN and RPSA are associated with the progression of cutaneous melanoma and a poorer prognosis for patients.

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引用次数: 0

Unlocking the therapeutic potential of canagliflozin in NAFLD: Insights into AMPK/SIRT1-mediated lipophagy 解锁卡格列净在NAFLD中的治疗潜力：对AMPK/ sirt1介导的脂肪吞噬的见解。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-20 DOI: 10.1016/j.bbadis.2025.167666

Nahla E. El-Ashmawy , Ghada M. Al-Ashmawy , Asmaa A. Kamel , Eman G. Khedr

Nonalcoholic fatty liver disease (NAFLD) is a rising global health problem. The antidiabetic canagliflozin (CANA) has been proposed to ameliorate the metabolic abnormalities in NAFLD.

Aim

This study aimed to explore the possible anti-NAFLD effects of CANA in rats and HepG2 cells, focusing on AMPK/SIRT1-mediated lipophagy.

Methods

Wistar rats were assigned to four groups: control group, NAFLD group, NAFLD+CANA group, and NAFLD+CANA+chloroquine (CQ) group, where CQ served as autophagy inhibitor. HepG2 cells were also divided into four groups: control group, NAFLD group, NAFLD+CANA group, and NAFLD+CANA+compound C (Comp C) group, where Comp C served as AMPK inhibitor.

Results

The histopathological examination showed that CANA alleviated hepatic and intracellular lipid deposition in rats and HepG2 cells. CANA induced lipophagy by increasing LC3-II levels and lowering both p62 and perilipin 2 levels in rats and HepG2 cells, in addition to decreasing mTOR protein expression in rats' livers. These outcomes were associated with upregulation of the lipophagy regulator Rab7 and downregulation of the ER stress-related protein CHOP. CANA enhanced autophagic engulfment of lipid droplets while decreased ER stress and mitochondrial damage in rats' livers, as demonstrated by TEM. In rats, CANA improved hyperglycemia, hyperinsulinemia, dyslipidemia, and obesity. In HepG2 cells, CANA's effects were linked to increased phosphorylated AMPK level and enhanced SIRT1 level and expression. However, blocking lipophagy in rats and AMPK in HepG2 cells markedly weakened CANA's protective effects against NAFLD.

Conclusion

CANA ameliorated NAFLD via enhancing AMPK/SIRT1-mediated lipophagy, suggesting its potential as a therapeutic intervention for this metabolic disorder.

非酒精性脂肪性肝病（NAFLD）是一个日益严重的全球性健康问题。抗糖尿病药物加格列净（canagliflozin， CANA）已被提出用于改善NAFLD的代谢异常。目的：本研究旨在探讨CANA在大鼠和HepG2细胞中可能的抗nafld作用，重点关注AMPK/ sirt1介导的脂质吞噬。方法：Wistar大鼠分为4组：对照组、NAFLD组、NAFLD+CANA组、NAFLD+CANA+氯喹（CQ）组，CQ作为自噬抑制剂。HepG2细胞也分为4组：对照组、NAFLD组、NAFLD+CANA组、NAFLD+CANA+化合物C （Comp C）组，Comp C作为AMPK抑制剂。结果：组织病理学检查显示，CANA可减轻大鼠肝脏及HepG2细胞内脂质沉积。CANA通过增加大鼠和HepG2细胞的LC3-II水平，降低p62和perilipin 2水平，以及降低大鼠肝脏中mTOR蛋白的表达来诱导脂肪吞噬。这些结果与脂噬调节因子Rab7上调和内质网应激相关蛋白CHOP下调有关。透射电镜显示，CANA增强了脂滴的自噬吞噬，同时降低了大鼠肝脏内质网应激和线粒体损伤。在大鼠中，CANA改善了高血糖、高胰岛素血症、血脂异常和肥胖。在HepG2细胞中，CANA的作用与磷酸化AMPK水平的增加和SIRT1水平和表达的增强有关。然而，阻断大鼠的脂噬和HepG2细胞中的AMPK显著削弱了CANA对NAFLD的保护作用。结论：CANA通过增强AMPK/ sirt1介导的脂肪吞噬来改善NAFLD，表明其作为这种代谢紊乱的治疗干预手段的潜力。

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引用次数: 0

Mitochondrial regulation of obesity by POMC neurons POMC神经元对肥胖的线粒体调控。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-19 DOI: 10.1016/j.bbadis.2025.167682

Xing-dan Luo , Si Tang , Xiang-yun Luo , Luosang Quzhen , Ruo-han Xia , Xian-wang Wang

Pro-opiomelanocortin (POMC) neurons, nestled in the hypothalamus, play a pivotal role in the intricate coordination of energy homeostasis and metabolic pathways. These neurons' mitochondria, often hailed as the cell's powerhouses, are crucial for maintaining cellular energy equilibrium and metabolic functionality. Recent research has illuminated the complex interplay between mitochondrial dynamics and POMC neuronal activity, underscoring their critical involvement in the pathogenesis of a spectrum of metabolic disorders, notably obesity and diabetes. This comprehensive review delves into the molecular mechanisms that underlie how mitochondrial function within POMC neurons modulates metabolic regulation. We dissect the impact of mitochondrial dynamics, encompassing fusion, fission, mitophagy, and biogenesis, on the regulation of POMC neuronal activity. Furthermore, we scrutinize the role of mitochondrial dysfunction in POMC neurons in the etiology of obesity, identifying key therapeutic targets within these pathways. We offer an in-depth perspective on the indispensable role of POMC neuronal mitochondria in metabolic regulation and chart future research directions to bridge the existing knowledge gaps in this field.

opiomelanocortin （POMC）前神经元位于下丘脑，在能量稳态和代谢途径的复杂协调中起着关键作用。这些神经元的线粒体通常被誉为细胞的“发电站”，对维持细胞能量平衡和代谢功能至关重要。最近的研究已经阐明了线粒体动力学和POMC神经元活动之间复杂的相互作用，强调了它们在一系列代谢紊乱，特别是肥胖和糖尿病的发病机制中的关键作用。这篇全面的综述深入研究了POMC神经元内线粒体功能如何调节代谢调节的分子机制。我们剖析了线粒体动力学的影响，包括融合、裂变、线粒体自噬和生物发生，对POMC神经元活动的调节。此外，我们仔细研究了POMC神经元线粒体功能障碍在肥胖病因学中的作用，确定了这些途径中的关键治疗靶点。我们对POMC神经元线粒体在代谢调节中不可或缺的作用提供了深入的视角，并绘制了未来的研究方向，以弥补该领域现有的知识空白。

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引用次数: 0

DEF6 regulates renal ischemia reperfusion injury through suppressing the WWP2 mediated ubiquitination of PARP1 DEF6通过抑制WWP2介导的PARP1泛素化调控肾缺血再灌注损伤。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-19 DOI: 10.1016/j.bbadis.2025.167681

Haochong Hu , Yiting Liu , Shangting Han , Jiayu Guo , Jiangqiao Zhou , Tao Qiu

Background

Renal ischemia-reperfusion injury (RIRI) stands as an unavoidable complication arising from kidney surgery, profoundly intertwined with its prognosis. The role of differentially expressed in FDCP 6 homolog (DEF6) in RIRI remains elusive, despite its confirmation as a potential therapeutic target for diverse diseases. Here, we investigated the mechanism by which DEF6 regulated RIRI.

Methods

RNA sequencing data and IP-MS were used to identify the expression and potential targets of DEF6 through bioinformatics analysis. To elucidate the impact of DEF6 on RIRI, both an in vivo model of RIRI in mice and an in vitro model of kidney cell hypoxia/reoxygenation were established. Biochemical and histological analyses were used to investigate the influence of DEF6 on kidney damage mediated by RIRI.

Results

We confirmed that DEF6 was upregulated during RIRI and had a close correlation with RIRI-related inflammation and apoptosis. Moreover, inhibition of DEF6 could mitigate RIRI-induced kidney damage, inflammation, and apoptosis. Through our comprehensive mechanistic investigation, we revealed that DEF6 interacts with poly ADP-ribose polymerase 1 (PARP1) and suppresses the ubiquitination of PARP1. Inhibition of DEF6 resulted in reduced cleaveage of PARP1, leading to a marked suppression of PARP1-mediated apoptosis activation. The aggravation effect on inflammation and apoptosis achieved through DEF6 was nullified by the inhibition of NF-κB and Bax/Bcl2 signaling activation through PARP1 deletion.

Conclusions

The findings from our study indicate that DEF6 suppressed the WWP2 mediated ubiquitination of PARP1 and modulates the activation of NF-κB and Bax/Bcl2 pathway, thus involved in RIRI-induced inflammation and apoptosis. These results suggest that DEF6 holds promise as a potential therapeutic target for mitigating RIRI.

背景：肾缺血再灌注损伤（RIRI）是肾脏手术不可避免的并发症，与预后密切相关。差异表达的fdcp6同源物（DEF6）在RIRI中的作用仍然难以捉摸，尽管它被证实是多种疾病的潜在治疗靶点。在这里，我们研究了DEF6调控RIRI的机制。方法：采用RNA测序数据和IP-MS技术，通过生物信息学分析，鉴定DEF6的表达和潜在靶点。为了阐明DEF6对RIRI的影响，我们建立了小鼠体内RIRI模型和肾细胞缺氧/再氧化体外模型。采用生化和组织学分析探讨DEF6对RIRI介导的肾损害的影响。结果：我们证实了DEF6在RIRI过程中表达上调，并且与RIRI相关的炎症和细胞凋亡密切相关。此外，抑制DEF6可以减轻riri诱导的肾损伤、炎症和细胞凋亡。通过全面的机制研究，我们发现DEF6与聚adp核糖聚合酶1 （PARP1）相互作用并抑制PARP1的泛素化。抑制DEF6导致PARP1的切割减少，从而显著抑制PARP1介导的细胞凋亡激活。通过PARP1缺失抑制NF-κB和Bax/Bcl2信号激活，抵消了DEF6对炎症和细胞凋亡的加重作用。结论：我们的研究结果表明，DEF6抑制WWP2介导的PARP1泛素化，调节NF-κB和Bax/Bcl2通路的激活，参与iri诱导的炎症和细胞凋亡。这些结果表明，DEF6有望成为缓解RIRI的潜在治疗靶点。

{"title":"DEF6 regulates renal ischemia reperfusion injury through suppressing the WWP2 mediated ubiquitination of PARP1","authors":"Haochong Hu , Yiting Liu , Shangting Han , Jiayu Guo , Jiangqiao Zhou , Tao Qiu","doi":"10.1016/j.bbadis.2025.167681","DOIUrl":"10.1016/j.bbadis.2025.167681","url":null,"abstract":"<div><h3>Background</h3><div>Renal ischemia-reperfusion injury (RIRI) stands as an unavoidable complication arising from kidney surgery, profoundly intertwined with its prognosis. The role of differentially expressed in FDCP 6 homolog (DEF6) in RIRI remains elusive, despite its confirmation as a potential therapeutic target for diverse diseases. Here, we investigated the mechanism by which DEF6 regulated RIRI.</div></div><div><h3>Methods</h3><div>RNA sequencing data and IP-MS were used to identify the expression and potential targets of DEF6 through bioinformatics analysis. To elucidate the impact of DEF6 on RIRI, both an in vivo model of RIRI in mice and an in vitro model of kidney cell hypoxia/reoxygenation were established. Biochemical and histological analyses were used to investigate the influence of DEF6 on kidney damage mediated by RIRI.</div></div><div><h3>Results</h3><div>We confirmed that DEF6 was upregulated during RIRI and had a close correlation with RIRI-related inflammation and apoptosis. Moreover, inhibition of DEF6 could mitigate RIRI-induced kidney damage, inflammation, and apoptosis. Through our comprehensive mechanistic investigation, we revealed that DEF6 interacts with poly ADP-ribose polymerase 1 (PARP1) and suppresses the ubiquitination of PARP1. Inhibition of DEF6 resulted in reduced cleaveage of PARP1, leading to a marked suppression of PARP1-mediated apoptosis activation. The aggravation effect on inflammation and apoptosis achieved through DEF6 was nullified by the inhibition of NF-κB and Bax/Bcl2 signaling activation through PARP1 deletion.</div></div><div><h3>Conclusions</h3><div>The findings from our study indicate that DEF6 suppressed the WWP2 mediated ubiquitination of PARP1 and modulates the activation of NF-κB and Bax/Bcl2 pathway, thus involved in RIRI-induced inflammation and apoptosis. These results suggest that DEF6 holds promise as a potential therapeutic target for mitigating RIRI.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167681"},"PeriodicalIF":4.2,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The lipocalin saga: Insights into its role in cancer-associated cachexia 脂质体传奇：洞察其在癌症相关恶病质中的作用。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-19 DOI: 10.1016/j.bbadis.2025.167684

Srusti Dave, Bhoomika Patel

Cancer-associated cachexia (CAC) is a debilitating condition, observed in patients with advanced stages of cancer. It is marked by ongoing weight loss, weakness, and nutritional impairment. Lower tolerance of chemotherapeutic agents and radiation therapy makes it difficult to treat CAC. Anorexia is a significant contributor to worsening CAC. Anorexia can be found in the early or advanced stages of cancer. Anorexia in cancer patients arises from a confluence of factors. Tumor-related inflammatory cytokines can directly impact the gastrointestinal tract, leading to dysphagia and compromised gut function. Additionally, increased serotonin and hormonal disruptions lead to early satiety, suppressing appetite. Due to the complexities in the pathogenesis of the disease, identifying druggable targets is a challenge. Research is ongoing to identify novel targets for the treatment of this condition. Recent research suggests a potential link between elevated levels of Lipocalin 2 (LCN2) and cachexia in cancer patients. LCN2, a glycoprotein primarily released by neutrophils, is implicated in numerous illnesses, including skin disorders, cancer, atherosclerosis, and type 2 diabetes. LCN2 suppresses hunger by binding to the melanocortin-4 receptors. Several in vitro, in vivo, and clinical studies indicate the association between LCN2 levels and appetite suppression. Further research should be explored emphasizing the significance of well-crafted clinical trials to confirm LCN2's usefulness as a therapeutic target and its ability to help cancer patients who are suffering from the fatal hallmark of cachexia. This review explores LCN2's function in the multifaceted dynamics of CAC and anorexia.

癌症相关恶病质（CAC）是一种使人衰弱的疾病，见于癌症晚期患者。它的特点是持续的体重减轻、虚弱和营养不良。化疗药物和放射治疗的较低耐受性使CAC的治疗变得困难。厌食症是CAC恶化的重要原因。厌食症可以在癌症的早期或晚期发现。癌症患者的厌食症是多种因素共同作用的结果。肿瘤相关的炎性细胞因子可直接影响胃肠道，导致吞咽困难和肠道功能受损。此外，血清素增加和荷尔蒙紊乱会导致过早饱腹感，从而抑制食欲。由于该病发病机制的复杂性，确定可药物靶点是一项挑战。目前正在进行研究，以确定治疗这种疾病的新靶点。最近的研究表明，在癌症患者中，高水平的脂载蛋白2 （LCN2）与恶病质之间存在潜在的联系。LCN2是一种主要由中性粒细胞释放的糖蛋白，与许多疾病有关，包括皮肤病、癌症、动脉粥样硬化和2型糖尿病。LCN2通过结合黑素皮质素-4受体来抑制饥饿感。一些体外、体内和临床研究表明LCN2水平与食欲抑制之间存在关联。进一步的研究应强调精心设计的临床试验的重要性，以证实LCN2作为治疗靶点的有效性，以及它对患有恶病质致命标志的癌症患者的帮助能力。本文综述了LCN2在CAC和厌食症的多方面动态中的作用。

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引用次数: 0

An in-depth review of AI-powered advancements in cancer drug discovery 深入回顾人工智能在癌症药物发现方面的进展。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-19 DOI: 10.1016/j.bbadis.2025.167680

Minh Huu Nhat Le , Phat Ky Nguyen , Thi Phuong Trang Nguyen , Hien Quang Nguyen , Dao Ngoc Hien Tam , Han Hong Huynh , Phat Kim Huynh , Nguyen Quoc Khanh Le

The convergence of artificial intelligence (AI) and genomics is redefining cancer drug discovery by facilitating the development of personalized and effective therapies. This review examines the transformative role of AI technologies, including deep learning and advanced data analytics, in accelerating key stages of the drug discovery process: target identification, drug design, clinical trial optimization, and drug response prediction. Cutting-edge tools such as DrugnomeAI and PandaOmics have made substantial contributions to therapeutic target identification, while AI's predictive capabilities are driving personalized treatment strategies. Additionally, advancements like AlphaFold highlight AI's capacity to address intricate challenges in drug development. However, the field faces significant challenges, including the management of large-scale genomic datasets and ethical concerns surrounding AI deployment in healthcare. This review underscores the promise of data-centric AI approaches and emphasizes the necessity of continued innovation and interdisciplinary collaboration. Together, AI and genomics are charting a path toward more precise, efficient, and transformative cancer therapeutics.

人工智能（AI）和基因组学的融合通过促进个性化和有效疗法的发展，正在重新定义癌症药物的发现。本综述探讨了人工智能技术的变革作用，包括深度学习和高级数据分析，在加速药物发现过程的关键阶段：目标识别、药物设计、临床试验优化和药物反应预测。DrugnomeAI和PandaOmics等尖端工具为治疗靶点识别做出了重大贡献，而人工智能的预测能力正在推动个性化治疗策略。此外，像AlphaFold这样的进步凸显了人工智能解决药物开发中复杂挑战的能力。然而，该领域面临着重大挑战，包括大规模基因组数据集的管理以及围绕人工智能在医疗保健领域部署的伦理问题。这篇综述强调了以数据为中心的人工智能方法的前景，并强调了持续创新和跨学科合作的必要性。人工智能和基因组学共同绘制了一条通往更精确、更有效和更具变革性的癌症治疗方法的道路。

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引用次数: 0

Epithelium-derived exosomal dipeptidyl peptidase-4 involved in arecoline-induced oral submucous fibrosis 上皮源性外泌体二肽基肽酶-4参与丁香碱诱导的口腔黏膜下纤维化。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-19 DOI: 10.1016/j.bbadis.2025.167683

Tzong-Ming Shieh , Nan-Chin Lin , Yen-Wen Shen , Wan-Chen Lan , Yin-Hwa Shih

Introduction

Dipeptidyl peptidase-4 is known to be involved in the progression of several fibrogenic diseases, but its association with oral submucous fibrosis remains unclear. This study aims to ascertain whether dipeptidyl peptidase-4 plays a role in the pathogenesis of arecoline-induced oral submucous fibrosis.

Methods

We assessed the expression of dipeptidyl peptidase-4 in arecoline-treated epithelial cells and the exosomes derived from cells. We cocultured the fibroblast and exosomes derived from epithelium cells and assessed fibrogenic activity by measuring collagen secretion, α-SMA expression, and gel contraction capability. An animal study was conducted to confirm the fibrogenic activity of exosomes derived from arecoline-treated epithelial cells. Additionally, we employed a dipeptidyl peptidase-4 inhibitor to assess its efficacy in mitigating fibrogenesis.

Results

Following arecoline treatment, an increase dipeptidyl peptidase-4 expression was observed in exosomes from the treated epithelium cells. When these exosomes cocultured with fibroblast, fibrogenic gene α-SMA was upregulated, increased collagen secretion, and enhanced gel contraction capability. In a mouse model, the administration of arecoline-treated epithelium-derived exosomes induced oral submucous fibrosis phenotype, characterized by a reduction in incisal distance and epithelial atrophy.

Conclusions

These findings offer valuable insights into clinical strategies for combating oral fibrotic disease and contribute to the foundation of future research in this field.

简介：二肽基肽酶-4参与了几种纤维性疾病的进展，但其与口腔粘膜下纤维化的关系尚不清楚。本研究旨在确定二肽基肽酶-4是否在槟槟碱诱导的口腔粘膜下纤维化的发病机制中起作用。方法：检测槟榔碱处理的上皮细胞和来源于细胞的外泌体中二肽基肽酶-4的表达。我们共培养成纤维细胞和来源于上皮细胞的外泌体，并通过测量胶原分泌、α-SMA表达和凝胶收缩能力来评估成纤维活性。一项动物研究证实了槟榔碱处理的上皮细胞衍生的外泌体的纤维化活性。此外，我们采用二肽基肽酶-4抑制剂来评估其减轻纤维形成的功效。结果：槟榔碱处理后，经处理的上皮细胞外泌体中二肽基肽酶-4的表达增加。当这些外泌体与成纤维细胞共培养时，成纤维基因α-SMA上调，胶原分泌增加，凝胶收缩能力增强。在小鼠模型中，槟榔碱处理的上皮源性外泌体诱导口腔粘膜下纤维化表型，其特征是切口距离减少和上皮萎缩。结论：这些发现为临床治疗口腔纤维化疾病提供了有价值的见解，并为该领域的未来研究奠定了基础。

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引用次数: 0

The (un)known crosstalk between metabolism and mechanotransduction: Implications for metabolic syndrome (MetS)-associated neurological complications 代谢和机械转导之间的（不）已知的串扰：对代谢综合征（MetS）相关神经系统并发症的影响

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-01-18 DOI: 10.1016/j.bbadis.2025.167678

Heloísa Gerardo , Paulo J. Oliveira , Cláudia Cavadas , Mário Grãos , José Teixeira

Metabolic syndrome (MetS) has been associated with disruptions in tissue mechanical homeostasis and inflammatory and metabolic derangements. However, the direct correlation between metabolic alterations and changes in tissue stiffness, and whether they could play a role as upstream initiators of disease pathology remains to be investigated. This emerging concept has yet to be put into clinical practice as many questions concerning the interplay between extracellular matrix mechanical properties and regulation of metabolic pathways remain unsolved. This review will highlight key foundational studies examining mutual regulation of cell metabolism and mechanotransduction, and opening questions lying ahead for better understanding MetS pathophysiology.

代谢综合征（MetS）与组织机械稳态的破坏以及炎症和代谢紊乱有关。然而，代谢改变与组织硬度变化之间的直接关系，以及它们是否可以作为疾病病理的上游启动者，仍有待研究。由于许多关于细胞外基质力学特性与代谢途径调节之间相互作用的问题尚未解决，这一新兴概念尚未付诸临床实践。这篇综述将重点介绍细胞代谢和机械转导相互调节的关键基础研究，以及更好地理解MetS病理生理的开放性问题。

引用次数: 0