Life sciences最新文献_第6页

Oxalate stimulates macrophage secretion of prostaglandin E2 to promote renal tubular epithelial cell osteogenesis

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-20 DOI: 10.1016/j.lfs.2025.123476

Qianlin Song , Xin Chen , Qinhong Jiang , Ziqi He , Xiaozhe Su , Caitao Dong , Heng Xiang , Chao Song , Yunhe Xiong , Sixing Yang

Osteogenesis of renal tubular epithelial cells (RTEC) is an important trigger for calcium oxalate (CaOx) kidney stone formation, but whether macrophages are involved in RTEC osteogenesis is unclear. The purpose of this study was to investigate the role and mechanism of macrophages in CaOx kidney stones on RTEC osteogenesis. Oxalate or ethylene glycol was used to construct in vitro and in vivo CaOx kidney stone models, respectively. Macrophage-derived conditioned medium was used to induce osteogenesis in HK-2 cells, and genetic controls and pharmacological interventions were used to investigate the underlying mechanism. The results demonstrated that macrophage-conditioned medium under oxalate intervention facilitated the increase of alkaline phosphatase and calcium salts as well as the upregulation of osteogenic marker genes (BMP2 and RUNX2) expression in HK-2 cells. On the one hand, the knockdown of the JAK2 gene in HK-2 cells reverses the role of macrophage-derived conditioned medium in promoting osteogenesis in HK-2 cells. On the other hand, inhibition of prostaglandin E2 (PGE2) generation in macrophages reverses osteogenesis in HK-2 cells. Moreover, inhibition of PGE2 generation would cure ethylene glycol-induced renal injury and calcium salt deposition, as well as osteogenesis of RTEC. This study illustrates that in the presence of oxalate, macrophages secret PGE2 to activate JAK2/STAT3 signaling in RTEC, which could trigger osteogenesis. It provides new insights into the mechanism of CaOx kidney stone formation.

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引用次数: 0

USP28-mediated deubiquitination of FOXK1 activates the Hippo signaling pathway to regulate cell proliferation and radiosensitivity in lung cancer

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123483

Yimei Meng , Yunhong Xu , Anchen Qiu , Ming Lin , Liu Yang , Yumei Huang

Aims

Radioresistance remains a significant challenge for lung cancer therapeutics. Forkhead box K1 (FOXK1) plays a role in regulating various biological processes and the progression of multiple cancers. However, the role of FOXK1 in lung cancer progression and radioresistance are not fully understood.

Main methods

Functional analyses were conducted on lung cancer cells transfected with specified siRNAs or plasmids. The ubiquitination of FOXK1 was evaluated by in vitro ubiquitination assays. RNA sequencing analysis was conducted to identify the downstream signaling pathway regulated by FOXK1. Mouse xenograft models were constructed using lung cancer cells with stable expression of either sh-NC or sh-FOXK1. Immunohistochemistry was used to assess FOXK1 and USP28 expression levels in lung cancer and paired normal lung tissues.

Key findings

We found that elevated FOXK1 expression markedly enhances radioresistance and tumorigenesis in lung cancer. Furthermore, we demonstrated that ubiquitin specific peptidase 28 (USP28) interacts with and targets FOXK1 for deubiquitination and stabilization. Moreover, we showed that FOXK1 exerts its biological function via activating the Hippo pathway.

Significance

Our research showed that FOXK1 is deubiquitinated by USP28 and facilitates cell proloferation and radioresistance by activating the Hippo pathway, suggesting that FOXK1 may act as a potential radiosensitizing target for lung cancer.

{"title":"USP28-mediated deubiquitination of FOXK1 activates the Hippo signaling pathway to regulate cell proliferation and radiosensitivity in lung cancer","authors":"Yimei Meng , Yunhong Xu , Anchen Qiu , Ming Lin , Liu Yang , Yumei Huang","doi":"10.1016/j.lfs.2025.123483","DOIUrl":"10.1016/j.lfs.2025.123483","url":null,"abstract":"<div><h3>Aims</h3><div>Radioresistance remains a significant challenge for lung cancer therapeutics. Forkhead box K1 (FOXK1) plays a role in regulating various biological processes and the progression of multiple cancers. However, the role of FOXK1 in lung cancer progression and radioresistance are not fully understood.</div></div><div><h3>Main methods</h3><div>Functional analyses were conducted on lung cancer cells transfected with specified siRNAs or plasmids. The ubiquitination of FOXK1 was evaluated by <em>in vitro</em> ubiquitination assays. RNA sequencing analysis was conducted to identify the downstream signaling pathway regulated by FOXK1. Mouse xenograft models were constructed using lung cancer cells with stable expression of either sh-NC or sh-FOXK1. Immunohistochemistry was used to assess FOXK1 and USP28 expression levels in lung cancer and paired normal lung tissues.</div></div><div><h3>Key findings</h3><div>We found that elevated FOXK1 expression markedly enhances radioresistance and tumorigenesis in lung cancer. Furthermore, we demonstrated that ubiquitin specific peptidase 28 (USP28) interacts with and targets FOXK1 for deubiquitination and stabilization. Moreover, we showed that FOXK1 exerts its biological function <em>via</em> activating the Hippo pathway.</div></div><div><h3>Significance</h3><div>Our research showed that FOXK1 is deubiquitinated by USP28 and facilitates cell proloferation and radioresistance by activating the Hippo pathway, suggesting that FOXK1 may act as a potential radiosensitizing target for lung cancer.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"366 ","pages":"Article 123483"},"PeriodicalIF":5.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452829","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}

引用次数: 0

Targeting the HDAC6/Hint2/MICU1 axis to ameliorate acute liver failure via inhibiting NETosis

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123498

Jin Guo, Chunxia Shi, Yukun Wang, Danmei Zhang, Qingqi Zhang, Xiaoya Zhang, Luwen Wang, Zuojiong Gong

Aims

Acute liver failure (ALF) is marked by extensive inflammation and immune dysregulation, which are closely associated with neutrophil infiltration and NETosis. However, the specific mechanisms that drive NETosis in ALF remain poorly understood.

Materials and methods

We employed flow cytometry, western blot, qRT-PCR, and cf-DNA assay to investigate the link between NETosis and ALF. The role of HDAC6-mediated deacetylation of histidine triad nucleotide-binding protein 2 (Hint2) was assessed, along with the effects of lentiviral vector-based overexpression and knockdown of Hint2 on mitochondrial function and NETosis. Additionally, CO-IP, IF, protein docking analysis, mCa²⁺ uptake assay, and mtROS measurement were used to explore the interaction between Hint2 and mitochondrial calcium uniporter complex (MCUc). Finally, experimental neutrophil depletion in mice was conducted to confirm the protective effect of NETosis inhibition in ALF.

Key findings

Our study demonstrated that Hint2 undergoes HDAC6-mediated deacetylation, disrupting mitochondrial dynamics and triggering NETosis during ALF. Furthermore, MICU1 bridges Hint2 and NETosis by regulating mCa²⁺ homeostasis and mtROS production. Activation of Hint2, either through the HDAC6 inhibitor ACY1215 or via overexpression, increased the level of MICU1 to suppress the opening of the MCUc and the associated mtROS release, thereby inhibiting NETosis. Conversely, Hint2 knockdown induced NETosis by surging mCa²⁺ overload and mtROS production, while the MCUc inhibitor RU265 mitigates NETosis by blocking mCa²⁺ influx.

Significance

Our findings recognized the HDAC6/Hint2/MICU1 axis as a novel pathway in neutrophils, the inhibition of which intercepts mCa²⁺ overload and mtROS accumulation, thereby reducing NETosis and facilitating liver recovery during ALF.

{"title":"Targeting the HDAC6/Hint2/MICU1 axis to ameliorate acute liver failure via inhibiting NETosis","authors":"Jin Guo, Chunxia Shi, Yukun Wang, Danmei Zhang, Qingqi Zhang, Xiaoya Zhang, Luwen Wang, Zuojiong Gong","doi":"10.1016/j.lfs.2025.123498","DOIUrl":"10.1016/j.lfs.2025.123498","url":null,"abstract":"<div><h3>Aims</h3><div>Acute liver failure (ALF) is marked by extensive inflammation and immune dysregulation, which are closely associated with neutrophil infiltration and NETosis. However, the specific mechanisms that drive NETosis in ALF remain poorly understood.</div></div><div><h3>Materials and methods</h3><div>We employed flow cytometry, western blot, qRT-PCR, and cf-DNA assay to investigate the link between NETosis and ALF. The role of HDAC6-mediated deacetylation of histidine triad nucleotide-binding protein 2 (Hint2) was assessed, along with the effects of lentiviral vector-based overexpression and knockdown of Hint2 on mitochondrial function and NETosis. Additionally, CO-IP, IF, protein docking analysis, mCa<sup>2+</sup> uptake assay, and mtROS measurement were used to explore the interaction between Hint2 and mitochondrial calcium uniporter complex (MCUc). Finally, experimental neutrophil depletion in mice was conducted to confirm the protective effect of NETosis inhibition in ALF.</div></div><div><h3>Key findings</h3><div>Our study demonstrated that Hint2 undergoes HDAC6-mediated deacetylation, disrupting mitochondrial dynamics and triggering NETosis during ALF. Furthermore, MICU1 bridges Hint2 and NETosis by regulating mCa<sup>2+</sup> homeostasis and mtROS production. Activation of Hint2, either through the HDAC6 inhibitor ACY1215 or via overexpression, increased the level of MICU1 to suppress the opening of the MCUc and the associated mtROS release, thereby inhibiting NETosis. Conversely, Hint2 knockdown induced NETosis by surging mCa<sup>2+</sup> overload and mtROS production, while the MCUc inhibitor RU265 mitigates NETosis by blocking mCa<sup>2+</sup> influx.</div></div><div><h3>Significance</h3><div>Our findings recognized the HDAC6/Hint2/MICU1 axis as a novel pathway in neutrophils, the inhibition of which intercepts mCa<sup>2+</sup> overload and mtROS accumulation, thereby reducing NETosis and facilitating liver recovery during ALF.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"366 ","pages":"Article 123498"},"PeriodicalIF":5.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452830","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}

引用次数: 0

Alda-1 mediates cell senescence and counteracts bone loss in weightlessness through regulating mitophagy

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123482

Jinpeng Wang , Sen Li , Qiao Li , Qiuxin Yan , Yunhao Wang , Xiangyin Zeng , Fan Yang , Siyu Jiang , Manrui Zhang , Yaning Pi , Raza Tahir , Lijun Wei

Aims

Astronauts experience weightlessness-induced bone loss (WIBL) due to an imbalanced bone remodeling process involving bone mesenchymal stem cells (BMSCs), osteoblasts, and osteoclasts. Senescence is an important factor contributes to WIBL. In the current study, the effects of Alda-1 on senescence and WIBL were evaluated.

Materials and methods

We used the 2D-Rotating Wall Vessel bioreactor and hindlimb suspension rats, the classic cellular and animal models simulating microgravity (SMG). Aging, osteogenic differentiation, osteoclastic differentiation, and lipogenic differentiation were evaluated in the cell and animal models. Differentially expressed proteins in the femurs of rats were further analyzed using bioinformatics analysis. In addition, mitochondrial membrane potential, reactive oxygen species (ROS) production, and mitophagy markers were identified to estimate mitochondrial activity.

Key findings

It was revealed that SMG accelerated senescence including osteoblasts, BMSCs, and inhibited senescence of RAW264.7 cells. SMG suppressed osteogenesis while promoting osteoclastogenesis and adipogenesis during cell senescence and bone loss. Aldehyde dehydrogenase-2 (ALDH2) was negatively related to WIBL. It was mainly enriched in mitochondria and involved in oxidative stress pathways. Finally, it was proved that Alda-1 significantly promoted ALDH2 levels. Alda-1 exhibited a robust protective response against senescence and WIBL by eliminating ROS accumulation, restoring mitophagy, and protecting cells and bone from apoptosis.

Significance

Our study indicate that Alda-1 exerts a protective effect against SMG-induced skeletal aging and bone loss through mitophagy. It provides a theoretical basis for advancing therapeutic options against WIBL in space.

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引用次数: 0

Benzbromarone improves blood hypercoagulability after TBI by reducing phosphatidylserine externalization through inhibition of TMEM16F expression 苯溴马隆通过抑制 TMEM16F 的表达减少磷脂酰丝氨酸的外化，从而改善创伤性脑损伤后的血液高凝状态

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123501

Kaiji Li , Jinchao Wang , Yalong Gao , Xin Chen , Ruilong Peng , Lei Li , Cong Wang , Tuo Li , Shu Zhang , Guili Yang , Jianning Zhang

Aims

Traumatic brain injury-induced coagulopathy (TBI-IC) frequently occurs after TBI, exacerbating the severity of TBI and affecting patient prognosis. Benzbromarone (BBR) is commonly used to treat hyperuricemia; however, its protective effects against TBI-IC remain unknown. Therefore, we explored whether BBR could improve TBI.

Materials and methods

C57BL/6 wild-type mice were subjected to fluid percussion injury to mimic TBI, and BBR was administered intraperitoneally 30 min after TBI. Magnetic resonance imaging (MRI) and Evans blue dye extravasation were used to assess the prognosis, tail bleeding time, ELISA, and coagulation tests assess coagulation function. We further explored the potential mechanism by which BBR alleviates hypercoagulation after TBI using flow cytometry.

Key findings

The intraperitoneally injected BBR group showed improved survival and neurological severity scores compared to the TBI group. Subsequently, we found that hypercoagulability developed 3 h after TBI and that the administration of BBR improved this hypercoagulability. BBR also reduced the degree of platelet phosphatidylserine (PS) exposure after TBI, platelet activation, and Ca2+ overload, in addition to inhibition of scramblase activity in procoagulant platelets.

Significance

Our findings indicate that BBR reduces PS externalization by inhibiting TMEM16F expression, thereby improving blood hypercoagulability after TBI.

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引用次数: 0

Linking KATP channel activation to p-AKT/mTORC1/eEF2/BDNF axis unravels Nicorandil's promise in countering acetaminophen-induced hepatic encephalopathy in mice

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123477

Reham M. Essam , Yasmin S. Mohamed , Sarah S. El-Sayed , Nada M. Kamel

Nicorandil (NIC), an antianginal agent that acts both as an opener of adenosine triphosphate-sensitive potassium (KATP) channels and a nitric oxide donor, has demonstrated protective and curative effects in various diseases. The predominance of these mechanisms varies based on the dose of NIC and the specific organ affected. This study scrutinized the possible beneficial effects of NIC in acetaminophen (APAP)-induced hepatic encephalopathy (HE) model through highlighting the role of KATP channels in mediating these effects. Forty-eight mice were randomly subdivided into four groups: control (saline), APAP model (1 g/kg, i.p.), NIC treatment (15 mg/kg/day p.o. for 14 days), and glibenclamide (GLIB “KATP blocker”, 5 mg/kg/day, p.o. 1 h before NIC for 14 days). NIC significantly mitigated APAP-induced liver injury, hyperammonemia, and cognitive deficits, as evidenced by reduced serum alanine aminotransferase, aspartate aminotransferase, ammonia levels, and improved performance in Y-maze and Morris Water Maze tests. Mechanistically, NIC suppressed hippocampal glutamate, activated phosphoserine 473 protein kinase B (p-AKT(Ser473))/mammalian target of rapamycin complex 1 (mTORC1) pathway, lessened the inactive phosphorylation of eukaryotic elongation factor 2 (eEF2), upsurged brain-derived neurotrophic factor (BDNF), leading to reduced neuroinflammation proved by nuclear factor-kappa B and tumor necrosis factor-alpha suppression. Histopathological analyses revealed improved liver and hippocampal morphology, while immunohistochemistry showed reduced astrocyte activation with NIC treatment. These effects were abolished by GLIB pre-treatment, indicating the crucial role of KATP channel. Accordingly, NIC could alleviate APAP-induced liver injury and HE mainly dependent on KATP channel opening, with resultant inhibition of glutamate signaling, activation of p-AKT/mTORC1/eEF2/BDNF trajectory, and abating hippocampal inflammation.

{"title":"Linking KATP channel activation to p-AKT/mTORC1/eEF2/BDNF axis unravels Nicorandil's promise in countering acetaminophen-induced hepatic encephalopathy in mice","authors":"Reham M. Essam , Yasmin S. Mohamed , Sarah S. El-Sayed , Nada M. Kamel","doi":"10.1016/j.lfs.2025.123477","DOIUrl":"10.1016/j.lfs.2025.123477","url":null,"abstract":"<div><div>Nicorandil (NIC), an antianginal agent that acts both as an opener of adenosine triphosphate-sensitive potassium (KATP) channels and a nitric oxide donor, has demonstrated protective and curative effects in various diseases. The predominance of these mechanisms varies based on the dose of NIC and the specific organ affected. This study scrutinized the possible beneficial effects of NIC in acetaminophen (APAP)-induced hepatic encephalopathy (HE) model through highlighting the role of KATP channels in mediating these effects. Forty-eight mice were randomly subdivided into four groups: control (saline), APAP model (1 g/kg, i.p.), NIC treatment (15 mg/kg/day p.o. for 14 days), and glibenclamide (GLIB “KATP blocker”, 5 mg/kg/day, p.o. 1 h before NIC for 14 days). NIC significantly mitigated APAP-induced liver injury, hyperammonemia, and cognitive deficits, as evidenced by reduced serum alanine aminotransferase, aspartate aminotransferase, ammonia levels, and improved performance in Y-maze and Morris Water Maze tests. Mechanistically, NIC suppressed hippocampal glutamate, activated phosphoserine 473 protein kinase B (<em>p</em>-AKT(Ser473))/mammalian target of rapamycin complex 1 (mTORC1) pathway, lessened the inactive phosphorylation of eukaryotic elongation factor 2 (eEF2), upsurged brain-derived neurotrophic factor (BDNF), leading to reduced neuroinflammation proved by nuclear factor-kappa B and tumor necrosis factor-alpha suppression. Histopathological analyses revealed improved liver and hippocampal morphology, while immunohistochemistry showed reduced astrocyte activation with NIC treatment. These effects were abolished by GLIB pre-treatment, indicating the crucial role of KATP channel. Accordingly, NIC could alleviate APAP-induced liver injury and HE mainly dependent on KATP channel opening, with resultant inhibition of glutamate signaling, activation of <em>p</em>-AKT/mTORC1/eEF2/BDNF trajectory, and abating hippocampal inflammation.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"366 ","pages":"Article 123477"},"PeriodicalIF":5.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452771","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}

引用次数: 0

Mitigating seizure-induced cognitive deficits in mice induced with pentylenetetrazol by roflumilast through targeting the NLRP3 inflammasome/BDNF/SIRT3 pathway and regulating ferroptosis

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123488

Mohamed N. Fawzy , Enas A. Abd El-Haleim , Hala F. Zaki , Hesham A. Salem , Rehab M. El-Sayed

Aims

Comorbidities with epilepsy and antiseizure medications (ASMs) are currently the main challenges in treating epilepsy. The current study evaluates for the first time the neuroprotective effect of roflumilast (ROF) alone or combined with phenytoin (PHT) against pentylenetetrazol (PTZ)-induced kindling in mice. It focuses on the crosstalk between the NOD-like receptor protein 3 (NLRP3)/caspase 1/interleukin 1β (IL-1β) cascade and the brain-derived neurotrophic factor (BDNF)/sirtuin 3 (SIRT3) pathway as possible strategies to treat epilepsy.

Main methods

The kindled mouse model was induced via fifteen (35 mg/kg) intraperitoneal injections every other day. Roflumilast (0.4 mg/kg) and phenytoin (30 mg/kg) were orally administered daily from the start until the end of the experiment. Following the PTZ injection, the seizure severity score was assessed. The Morris water maze (MWM) test was performed to evaluate cognition. Histopathological examinations of hippocampi were conducted.

Key findings

Roflumilast significantly improved neurobehavioral and histological assessments, whereas Racine scores declined. The improvement was confirmed through BDNF upregulation in contrast to NLRP3 and caspase-1 in the hippocampus, as revealed immunohistochemically. In addition, roflumilast induced a prominent elevation in gamma-aminobutyric acid (GABA), sirtuin 3 (SIRT3), and glutathione peroxidase (GPX4), whereas malondialdehyde (MDA), and arachidonic acid 15-lipoxygenase (ALOX15) expressions were downregulated.

Significance

Our findings demonstrate that roflumilast conferred neuroprotective benefits against PTZ-induced kindling seizures, suggesting its potential as a novel adjuvant therapy for epilepsy-related disorders. This effect might be due to the modification of the NLRP3 inflammasome/BDNF pathway, ferroptosis, and a decrease in oxidative stress and neuroinflammation.

{"title":"Mitigating seizure-induced cognitive deficits in mice induced with pentylenetetrazol by roflumilast through targeting the NLRP3 inflammasome/BDNF/SIRT3 pathway and regulating ferroptosis","authors":"Mohamed N. Fawzy , Enas A. Abd El-Haleim , Hala F. Zaki , Hesham A. Salem , Rehab M. El-Sayed","doi":"10.1016/j.lfs.2025.123488","DOIUrl":"10.1016/j.lfs.2025.123488","url":null,"abstract":"<div><h3>Aims</h3><div>Comorbidities with epilepsy and antiseizure medications (ASMs) are currently the main challenges in treating epilepsy. The current study evaluates for the first time the neuroprotective effect of roflumilast (ROF) alone or combined with phenytoin (PHT) against pentylenetetrazol (PTZ)-induced kindling in mice. It focuses on the crosstalk between the NOD-like receptor protein 3 (NLRP3)/caspase 1/interleukin 1β (IL-1β) cascade and the brain-derived neurotrophic factor (BDNF)/sirtuin 3 (SIRT3) pathway as possible strategies to treat epilepsy.</div></div><div><h3>Main methods</h3><div>The kindled mouse model was induced via fifteen (35 mg/kg) intraperitoneal injections every other day. Roflumilast (0.4 mg/kg) and phenytoin (30 mg/kg) were orally administered daily from the start until the end of the experiment. Following the PTZ injection, the seizure severity score was assessed. The Morris water maze (MWM) test was performed to evaluate cognition. Histopathological examinations of hippocampi were conducted.</div></div><div><h3>Key findings</h3><div>Roflumilast significantly improved neurobehavioral and histological assessments, whereas Racine scores declined. The improvement was confirmed through BDNF upregulation in contrast to NLRP3 and caspase-1 in the hippocampus, as revealed immunohistochemically. In addition, roflumilast induced a prominent elevation in gamma-aminobutyric acid (GABA), sirtuin 3 (SIRT3), and glutathione peroxidase (GPX4), whereas malondialdehyde (MDA), and arachidonic acid 15-lipoxygenase (ALOX15) expressions were downregulated.</div></div><div><h3>Significance</h3><div>Our findings demonstrate that roflumilast conferred neuroprotective benefits against PTZ-induced kindling seizures, suggesting its potential as a novel adjuvant therapy for epilepsy-related disorders. This effect might be due to the modification of the NLRP3 inflammasome/BDNF pathway, ferroptosis, and a decrease in oxidative stress and neuroinflammation.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"366 ","pages":"Article 123488"},"PeriodicalIF":5.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452926","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}

引用次数: 0

Extracellular vesicles derived from mesenchymal stem cells alleviate depressive-like behavior in a rat model of chronic stress

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123479

Zaquer Suzana Munhoz Costa-Ferro , Rachel Santana Cunha , Erik Aranha Rossi , Erick Correia Loiola , Barbara Porto Cipriano , Júlio César Queiroz Figueiredo , Elisama Araújo da Silva , Adne Vitória Rocha de Lima , Adlas Michel de Jesus Ribeiro , Valdomiro Silveira Moitinho Junior , Corynne Stephanie Ahouefa Adanho , Carolina Kymie Vasques Nonaka , Ananssa Maíra dos Santos Silva , Kátia Nunes da Silva , Gisele Vieira Rocha , Fernanda Guarino De Felice , Pedro Antônio Schmidt do Prado-Lima , Bruno Solano de Freitas Souza

Depression is a prevalent chronic psychiatric disorder with a growing impact on global health. Current treatments often fail to achieve full remission, highlighting the need for alternative therapeutic strategies. Mesenchymal stem cells (MSCs) have attracted significant interest for their therapeutic potential in neuropsychiatric disorders, primarily due to their capacity to target neuroinflammation. This study aimed to investigate if extracellular vesicles derived from human umbilical MSCs (hucMSCs) promote behavioral beneficial actions in a rat model of chronic unpredictable mild stress (CUMS). We show that a single dose of hucMSCs or their derived EVs (hucMSC-EVs) via the tail vein alleviated depressive-like behavior in rats, reduced markers of neuroinflammation, reduced pro-inflammatory cytokines (IL-1β and TNF-α), and increased the number and dendritic complexity of DCX-positive cells in the dentate gyrus. Proteomic analysis of EVs revealed the presence of proteins involved in modulation of inflammatory processes and cell activation. Our study demonstrates EVs derived from hucMSCs can effectively mitigate depressive symptoms by modulating neuroinflammatory pathways and enhancing neurogenesis. These findings support further exploration of MSC-derived EVs as a novel therapeutic option for neuropsychiatric disorders.

{"title":"Extracellular vesicles derived from mesenchymal stem cells alleviate depressive-like behavior in a rat model of chronic stress","authors":"Zaquer Suzana Munhoz Costa-Ferro , Rachel Santana Cunha , Erik Aranha Rossi , Erick Correia Loiola , Barbara Porto Cipriano , Júlio César Queiroz Figueiredo , Elisama Araújo da Silva , Adne Vitória Rocha de Lima , Adlas Michel de Jesus Ribeiro , Valdomiro Silveira Moitinho Junior , Corynne Stephanie Ahouefa Adanho , Carolina Kymie Vasques Nonaka , Ananssa Maíra dos Santos Silva , Kátia Nunes da Silva , Gisele Vieira Rocha , Fernanda Guarino De Felice , Pedro Antônio Schmidt do Prado-Lima , Bruno Solano de Freitas Souza","doi":"10.1016/j.lfs.2025.123479","DOIUrl":"10.1016/j.lfs.2025.123479","url":null,"abstract":"<div><div>Depression is a prevalent chronic psychiatric disorder with a growing impact on global health. Current treatments often fail to achieve full remission, highlighting the need for alternative therapeutic strategies. Mesenchymal stem cells (MSCs) have attracted significant interest for their therapeutic potential in neuropsychiatric disorders, primarily due to their capacity to target neuroinflammation. This study aimed to investigate if extracellular vesicles derived from human umbilical MSCs (hucMSCs) promote behavioral beneficial actions in a rat model of chronic unpredictable mild stress (CUMS). We show that a single dose of hucMSCs or their derived EVs (hucMSC-EVs) via the tail vein alleviated depressive-like behavior in rats, reduced markers of neuroinflammation, reduced pro-inflammatory cytokines (IL-1β and TNF-α), and increased the number and dendritic complexity of DCX-positive cells in the dentate gyrus. Proteomic analysis of EVs revealed the presence of proteins involved in modulation of inflammatory processes and cell activation. Our study demonstrates EVs derived from hucMSCs can effectively mitigate depressive symptoms by modulating neuroinflammatory pathways and enhancing neurogenesis. These findings support further exploration of MSC-derived EVs as a novel therapeutic option for neuropsychiatric disorders.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"366 ","pages":"Article 123479"},"PeriodicalIF":5.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463398","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}

引用次数: 0

The methyl-CpG-binding protein 2 (Mecp2) regulates the hypothalamic mitochondrial function and white adipose tissue lipid metabolism

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123478

Nuria Llontop , Cristian Mancilla , Patricia Ojeda-Provoste , Angie K. Torres , Alejandro Godoy , Cheril Tapia-Rojas , Bredford Kerr

Objective

The neuroepigenetic factor Mecp2 regulates gene expression and is thought to play a crucial role in energy homeostasis. Body weight is regulated at the hypothalamic level, where mitochondrial energy metabolism is necessary for its proper functioning, allowing the hypothalamus to respond to peripheral signals to maintain energy balance and modulate energy expenditure through the sympathetic nervous system. Since the mechanism by which genetic and environmental factors contribute to regulating energy balance is unclear, this study aims to understand the contribution of gene-environment interaction to maintaining energy balance and how its disruption alters hypothalamic cellular energy production, impacting the control of systemic metabolism.

Methods

We used a mouse model of epigenetic disruption (Mecp2-null) to evaluate the impact of Mecp2 deletion on systemic and hypothalamic metabolism using physiological and cellular approaches.

Results

Our study shows that the previously reported body weight gain in mice lacking the expression of Mecp2 is preceded by a hypothalamic mitochondrial dysfunction that disrupts hypothalamic function, leading to a dysfunctional communication between the hypothalamus and adipose tissue, thus impairing lipid metabolism. Our study has revealed three crucial aspects of the contribution of this critical epigenetic factor pivotal for a proper gene-environment interaction: i) Mecp2 drives a molecular mechanism to maintain cellular energy homeostasis, which is necessary for the proper functioning of the hypothalamus. ii) Mecp2 is necessary to maintain lipid metabolism in adipose tissue. iii) Mecp2 is a molecular bridge linking hypothalamic cellular energy metabolism and adipose tissue lipid metabolism.

Conclusions

Our results show that Mecp2 regulates the hypothalamic mitochondrial function and white adipose tissue lipid metabolism and probably alters the communication between these two tissues, which is critical for corporal energy homeostasis maintenance.

{"title":"The methyl-CpG-binding protein 2 (Mecp2) regulates the hypothalamic mitochondrial function and white adipose tissue lipid metabolism","authors":"Nuria Llontop , Cristian Mancilla , Patricia Ojeda-Provoste , Angie K. Torres , Alejandro Godoy , Cheril Tapia-Rojas , Bredford Kerr","doi":"10.1016/j.lfs.2025.123478","DOIUrl":"10.1016/j.lfs.2025.123478","url":null,"abstract":"<div><h3>Objective</h3><div>The neuroepigenetic factor Mecp2 regulates gene expression and is thought to play a crucial role in energy homeostasis. Body weight is regulated at the hypothalamic level, where mitochondrial energy metabolism is necessary for its proper functioning, allowing the hypothalamus to respond to peripheral signals to maintain energy balance and modulate energy expenditure through the sympathetic nervous system. Since the mechanism by which genetic and environmental factors contribute to regulating energy balance is unclear, this study aims to understand the contribution of gene-environment interaction to maintaining energy balance and how its disruption alters hypothalamic cellular energy production, impacting the control of systemic metabolism.</div></div><div><h3>Methods</h3><div>We used a mouse model of epigenetic disruption (<em>Mecp2</em>-null) to evaluate the impact of <em>Mecp2</em> deletion on systemic and hypothalamic metabolism using physiological and cellular approaches.</div></div><div><h3>Results</h3><div>Our study shows that the previously reported body weight gain in mice lacking the expression of Mecp2 is preceded by a hypothalamic mitochondrial dysfunction that disrupts hypothalamic function, leading to a dysfunctional communication between the hypothalamus and adipose tissue, thus impairing lipid metabolism. Our study has revealed three crucial aspects of the contribution of this critical epigenetic factor pivotal for a proper gene-environment interaction: i) Mecp2 drives a molecular mechanism to maintain cellular energy homeostasis, which is necessary for the proper functioning of the hypothalamus. ii) Mecp2 is necessary to maintain lipid metabolism in adipose tissue. iii) Mecp2 is a molecular bridge linking hypothalamic cellular energy metabolism and adipose tissue lipid metabolism.</div></div><div><h3>Conclusions</h3><div>Our results show that Mecp2 regulates the hypothalamic mitochondrial function and white adipose tissue lipid metabolism and probably alters the communication between these two tissues, which is critical for corporal energy homeostasis maintenance.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"366 ","pages":"Article 123478"},"PeriodicalIF":5.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471395","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}

引用次数: 0

The lysosomal-associated membrane protein 2-macroautophagy pathway is involved in the regulatory effects of hippocampal aromatase on Aβ accumulation and AD-like behavior

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123484

Mingguang Sun , Xiaoxia Cai , Zhen Lan , Mengying Liu , Maohu Zhou , Yisha Tang , Yan Liu , Xuan Zhang , Xiao Zhao , Yue Zhou , Jiqiang Zhang , Zhaoyou Meng

Aims

Hippocampal aromatase (AROM) knockdown induces Aβ accumulation and Alzheimer's disease (AD)-like spatial learning and memory impairment, and early hippocampal AROM overexpression in APP/PS1 mice prevents Aβ deposition and memory loss later in life. The aim of this study was to elucidate the underlying mechanism and provide novel prevention and treatment targets for AD.

Materials and methods

AROM-inhibiting viral vectors were constructed and injected into the hippocampi of adult female mice, after which label-free LC–MS/MS proteomics and bioinformatics analysis were conducted. Additional viral vectors targeting LAMP2 or LC3 were constructed and used to treat HT22 cells. LAMP2 expression was verified, and macroautophagy levels, autophagosome formation and Aβ accumulation were examined. Additionally, ovariectomy combined with the hippocampal injection of LAMP2 inhibition/overexpression viral vectors was applied, and learning and memory abilities and Aβ accumulation were examined.

Key findings

Proteomics revealed the enrichment of CMA and autophagy, and LAMP2 was the most significantly upregulated protein. Higher LAMP2 levels were correlated with lower macroautophagy and autophagosomes levels but were correlated with higher Aβ accumulation, and vice versa. Additionally, hippocampal LAMP2 mediated the effects of ovariectomy on spatial memory and Aβ accumulation.

Significance

These results demonstrated the important role of the hippocampal LAMP2-macroautophagy pathway in mediating both hippocampal and ovarian estrogen regulation of Aβ accumulation and AD-like behavior, indicating that LAMP2 might be a novel target for both hippocampal and circulating estrogen deficiency-associated memory impairments, such as AD.

{"title":"The lysosomal-associated membrane protein 2-macroautophagy pathway is involved in the regulatory effects of hippocampal aromatase on Aβ accumulation and AD-like behavior","authors":"Mingguang Sun , Xiaoxia Cai , Zhen Lan , Mengying Liu , Maohu Zhou , Yisha Tang , Yan Liu , Xuan Zhang , Xiao Zhao , Yue Zhou , Jiqiang Zhang , Zhaoyou Meng","doi":"10.1016/j.lfs.2025.123484","DOIUrl":"10.1016/j.lfs.2025.123484","url":null,"abstract":"<div><h3>Aims</h3><div>Hippocampal aromatase (AROM) knockdown induces Aβ accumulation and Alzheimer's disease (AD)-like spatial learning and memory impairment, and early hippocampal AROM overexpression in APP/PS1 mice prevents Aβ deposition and memory loss later in life. The aim of this study was to elucidate the underlying mechanism and provide novel prevention and treatment targets for AD.</div></div><div><h3>Materials and methods</h3><div>AROM-inhibiting viral vectors were constructed and injected into the hippocampi of adult female mice, after which label-free LC–MS/MS proteomics and bioinformatics analysis were conducted. Additional viral vectors targeting LAMP2 or LC3 were constructed and used to treat HT22 cells. LAMP2 expression was verified, and macroautophagy levels, autophagosome formation and Aβ accumulation were examined. Additionally, ovariectomy combined with the hippocampal injection of LAMP2 inhibition/overexpression viral vectors was applied, and learning and memory abilities and Aβ accumulation were examined.</div></div><div><h3>Key findings</h3><div>Proteomics revealed the enrichment of CMA and autophagy, and LAMP2 was the most significantly upregulated protein. Higher LAMP2 levels were correlated with lower macroautophagy and autophagosomes levels but were correlated with higher Aβ accumulation, and vice versa. Additionally, hippocampal LAMP2 mediated the effects of ovariectomy on spatial memory and Aβ accumulation.</div></div><div><h3>Significance</h3><div>These results demonstrated the important role of the hippocampal LAMP2-macroautophagy pathway in mediating both hippocampal and ovarian estrogen regulation of Aβ accumulation and AD-like behavior, indicating that LAMP2 might be a novel target for both hippocampal and circulating estrogen deficiency-associated memory impairments, such as AD.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"366 ","pages":"Article 123484"},"PeriodicalIF":5.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452925","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}

引用次数: 0