Pub Date : 2024-10-03DOI: 10.1016/j.lfs.2024.123095
Aims
Due to the increasing global incidence rate of nonalcoholic steatohepatitis (NASH) combined with the lack of effective treatment methods for this disease, there is an urgent need to find new treatment strategies. The aim of this study was to investigate the efficacy of rifaximin in preventing and treating NASH and the related mechanism.
Materials and methods
A NASH model was constructed by feeding male C57BL/6 mice a methionine-choline-deficient (MCD) diet for 4 weeks. Rifaximin was administered for 1 week before MCD diet feeding or during the last week of MCD diet feeding to investigate its preventive or therapeutic effects. Liver pathology, hepatic enzyme levels and metabolic indices were measured to evaluate the effects of rifaximin on NASH. Intestinal barrier integrity was measured via the Ussing chamber system and western blotting. 16S rDNA sequencing was conducted to investigate the fecal microbiota composition. Western blotting was performed to evaluate peroxisome proliferator activated receptor (PPAR)α and PPARγ protein levels.
Key findings
Rifaximin effectively alleviated MCD diet-induced NASH. The microbiota composition in MCD diet-fed mice was significantly altered, and intestinal barrier integrity was disrupted. Dysbiosis and intestinal barrier dysfunction were reversed by rifaximin. In addition, rifaximin modulated PPARα and PPARγ expression in the liver.
Significance
Rifaximin effectively alleviated MCD diet-induced NASH by restoring the gut microbiota and reversing intestinal barrier dysfunction, suggesting that rifaximin treatment is a new approach for preventing and treating NASH.
目的：由于非酒精性脂肪性肝炎（NASH）在全球的发病率不断上升，且缺乏有效的治疗方法，因此迫切需要寻找新的治疗策略。本研究旨在探讨利福昔明预防和治疗NASH的疗效及相关机制：用蛋氨酸-胆碱缺乏（MCD）饮食喂养雄性C57BL/6小鼠4周，建立NASH模型。在MCD饮食喂养前一周或MCD饮食喂养的最后一周服用利福昔明，以研究其预防或治疗作用。对肝脏病理学、肝酶水平和代谢指数进行了测定，以评估利福昔明对NASH的影响。通过乌星室系统和 Western 印迹法测量肠道屏障的完整性。16S rDNA测序用于研究粪便微生物群的组成。采用 Western 印迹法评估过氧化物酶体增殖激活受体（PPAR）α 和 PPARγ 蛋白水平：利福昔明有效缓解了MCD饮食诱导的NASH。研究结果：利福昔明能有效缓解 MCD 膳食诱发的 NASH。利福昔明逆转了菌群失调和肠屏障功能障碍。此外，利福昔明还能调节肝脏中PPARα和PPARγ的表达：利福昔明通过恢复肠道微生物群和逆转肠屏障功能障碍，有效缓解了MCD饮食诱导的NASH，表明利福昔明治疗是预防和治疗NASH的一种新方法。
{"title":"Rifaximin alleviates MCD diet-induced NASH in mice by restoring the gut microbiota and intestinal barrier","authors":"","doi":"10.1016/j.lfs.2024.123095","DOIUrl":"10.1016/j.lfs.2024.123095","url":null,"abstract":"<div><h3>Aims</h3><div>Due to the increasing global incidence rate of nonalcoholic steatohepatitis (NASH) combined with the lack of effective treatment methods for this disease, there is an urgent need to find new treatment strategies. The aim of this study was to investigate the efficacy of rifaximin in preventing and treating NASH and the related mechanism.</div></div><div><h3>Materials and methods</h3><div>A NASH model was constructed by feeding male C57BL/6 mice a methionine-choline-deficient (MCD) diet for 4 weeks. Rifaximin was administered for 1 week before MCD diet feeding or during the last week of MCD diet feeding to investigate its preventive or therapeutic effects. Liver pathology, hepatic enzyme levels and metabolic indices were measured to evaluate the effects of rifaximin on NASH. Intestinal barrier integrity was measured via the Ussing chamber system and western blotting. 16S rDNA sequencing was conducted to investigate the fecal microbiota composition. Western blotting was performed to evaluate peroxisome proliferator activated receptor (PPAR)α and PPARγ protein levels.</div></div><div><h3>Key findings</h3><div>Rifaximin effectively alleviated MCD diet-induced NASH. The microbiota composition in MCD diet-fed mice was significantly altered, and intestinal barrier integrity was disrupted. Dysbiosis and intestinal barrier dysfunction were reversed by rifaximin. In addition, rifaximin modulated PPARα and PPARγ expression in the liver.</div></div><div><h3>Significance</h3><div>Rifaximin effectively alleviated MCD diet-induced NASH by restoring the gut microbiota and reversing intestinal barrier dysfunction, suggesting that rifaximin treatment is a new approach for preventing and treating NASH.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378004","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 : 2024-10-03DOI: 10.1016/j.lfs.2024.123092
Diabetic retinopathy (DR) is a microvascular complication of diabetes that leads to vision loss. The striking features of DR are hard exudate, cotton-wool spots, hemorrhage, and neovascularization. The dysregulated retinal cells, encompassing microvascular endothelial cells, pericytes, Müller cells, and adjacent retinal pigment epithelial cells, are involved in the pathological processes of DR. According to recent research, oxidative stress, inflammation, ferroptosis, pyroptosis, apoptosis, and angiogenesis contribute to DR. Recent advancements have highlighted that noncoding RNAs could regulate diverse targets in pathological processes that contribute to DR. Noncoding RNAs, including long noncoding RNAs, microRNAs (miRNA), and circular RNAs, are dysregulated in DR, and interact with miRNA, mRNA, or proteins to control the pathological processes of DR. Hence, modulation of noncoding RNAs may have therapeutic effects on DR. Small extracellular vesicles may be valuable tools for transferring noncoding RNAs and regulating the genes involved in progression of DR. However, the roles of noncoding RNA in developing DR are not fully understood; it is critical to summarize the mechanisms for noncoding RNA regulation of pathological processes and pathways related to DR. This review provides a fundamental understanding of the relationship between noncoding RNAs and DR, exploring the mechanism of how noncoding RNA modulates different signaling pathways, and pave the way for finding potential therapeutic strategies for DR.
糖尿病视网膜病变（DR）是一种导致视力丧失的糖尿病微血管并发症。糖尿病视网膜病变的显著特征是硬性渗出、棉絮状斑点、出血和新生血管。包括微血管内皮细胞、周细胞、Müller 细胞和邻近视网膜色素上皮细胞在内的视网膜细胞失调参与了 DR 的病理过程。最新研究表明，氧化应激、炎症、铁跃变、热跃变、细胞凋亡和血管生成是导致 DR 的原因。最近的研究进展突出表明，非编码 RNA 可在导致 DR 的病理过程中调控不同的靶点。非编码 RNA（包括长非编码 RNA、microRNA（miRNA）和环状 RNA）在 DR 中调控失调，并与 miRNA、mRNA 或蛋白质相互作用，控制 DR 的病理过程。因此，调节非编码 RNA 可能对 DR 有治疗作用。细胞外小泡可能是转移非编码 RNA 和调控参与 DR 进展的基因的重要工具。然而，非编码 RNA 在发展中的 DR 中的作用并不完全清楚；总结非编码 RNA 对与 DR 相关的病理过程和途径的调控机制至关重要。这篇综述提供了非编码 RNA 与 DR 之间关系的基本认识，探讨了非编码 RNA 如何调节不同信号通路的机制，并为寻找 DR 的潜在治疗策略铺平了道路。
{"title":"Roles of noncoding RNAs in diabetic retinopathy: Mechanisms and therapeutic implications","authors":"","doi":"10.1016/j.lfs.2024.123092","DOIUrl":"10.1016/j.lfs.2024.123092","url":null,"abstract":"<div><div>Diabetic retinopathy (DR) is a microvascular complication of diabetes that leads to vision loss. The striking features of DR are hard exudate, cotton-wool spots, hemorrhage, and neovascularization. The dysregulated retinal cells, encompassing microvascular endothelial cells, pericytes, Müller cells, and adjacent retinal pigment epithelial cells, are involved in the pathological processes of DR. According to recent research, oxidative stress, inflammation, ferroptosis, pyroptosis, apoptosis, and angiogenesis contribute to DR. Recent advancements have highlighted that noncoding RNAs could regulate diverse targets in pathological processes that contribute to DR. Noncoding RNAs, including long noncoding RNAs, microRNAs (miRNA), and circular RNAs, are dysregulated in DR, and interact with miRNA, mRNA, or proteins to control the pathological processes of DR. Hence, modulation of noncoding RNAs may have therapeutic effects on DR. Small extracellular vesicles may be valuable tools for transferring noncoding RNAs and regulating the genes involved in progression of DR. However, the roles of noncoding RNA in developing DR are not fully understood; it is critical to summarize the mechanisms for noncoding RNA regulation of pathological processes and pathways related to DR. This review provides a fundamental understanding of the relationship between noncoding RNAs and DR, exploring the mechanism of how noncoding RNA modulates different signaling pathways, and pave the way for finding potential therapeutic strategies for DR.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378005","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 : 2024-10-02DOI: 10.1016/j.lfs.2024.123101
The SH2-containing inositol 5′-phosphatase SHIP2 plays a crucial role in negative regulation of the PI3K/AKT signaling pathway. Putative small molecule inhibitors of SHIP2, AS1949490 and K149 have been reported to elicit a range of beneficial effects in treating or preventing obesity as well as killing cancer cells. However, whether these effects are direct results of SHIP2 inhibition has not been carefully assessed, e.g., in the absence of expression of the protein. Here, we show that these inhibitors alter the PI3K/AKT signaling pathway irrespective of SHIP2 protein expression. Moreover, we found that AS1949490 and K149 alter cell growth in normal and cancer cells lacking both SHIP1 and SHIP2. Overall, our data provide evidence that the antiproliferative effects of AS1949490 and K149 cannot be attributed to SHIP1/2 inhibition.
{"title":"Drugs targeting SHIP2 demonstrate potent antiproliferative effects irrespective of SHIP2 inhibition","authors":"","doi":"10.1016/j.lfs.2024.123101","DOIUrl":"10.1016/j.lfs.2024.123101","url":null,"abstract":"<div><div>The SH2-containing inositol 5′-phosphatase SHIP2 plays a crucial role in negative regulation of the PI3K/AKT signaling pathway. Putative small molecule inhibitors of SHIP2, AS1949490 and K149 have been reported to elicit a range of beneficial effects in treating or preventing obesity as well as killing cancer cells. However, whether these effects are direct results of SHIP2 inhibition has not been carefully assessed, e.g., in the absence of expression of the protein. Here, we show that these inhibitors alter the PI3K/AKT signaling pathway irrespective of SHIP2 protein expression. Moreover, we found that AS1949490 and K149 alter cell growth in normal and cancer cells lacking both SHIP1 and SHIP2. Overall, our data provide evidence that the antiproliferative effects of AS1949490 and K149 cannot be attributed to SHIP1/2 inhibition.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375670","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}
Aims: Bisphenol A (BPA), xenoestrogen, is an environmental toxicant, that generates oxidative stress leading to, cardiotoxicity, The oxidative stress can be neutralized by natural and synthetic antioxidants. The present study elucidates the highly selective antioxidative potential of synthetic tetra aniline polymers Es-37 and L-37 against Bisphenol A-induced cardiac cellular impairments and the role of miRNA-15a-5p in the regulation of different apoptotic proteins.
Materials and methods: The molecular docking of L-37 and Es-37 with three proteins (p53, Cytochrome c, and Bcl-2) were performed. The dose of 1 mg/kg BW of BPA, 1 mg/kg BW Es-37 and L-37 and 50 mg/kg BW N-acetyl cysteine (NAC) was administered to Sprague Dawley rats. The miRNA and target gene expression were confirmed by qRt-PCR and Immunoblotting.
Key findings: In our results, BPA administration significantly elevated the reactive oxygen species (ROS), p53, cytochrome c, and particularly miRNA-15a-5p expression; however: these changes were notably averted and reversed by Es-37 and L-37 treatment. Additionally, molecular docking of synthetic polymers validated that L-37 has a greater binding affinity with the target proteins compared to Es-37, with the highest binding values reported for the enzymatic protein cytochrome c.
Significance: These results suggest that both synthetic polymers Es-37 and L-37 have the potential to scavenge free radicals, boost-up antioxidant enzyme activities, and avert (BPA-induced) toxicity, thus, may serve as cardioprotective agents. Moreover, this study first time proposes that miRNA-15a-5p overexpression is associated with oxidative stress and coincides with BPA induced cardiotoxicity, thus may serve as potential therapeutic target in future.
目的：双酚 A（BPA）是一种异雌激素，是一种环境毒物，会产生氧化应激，导致心脏毒性。本研究阐明了合成四苯胺聚合物 Es-37 和 L-37 对双酚 A 诱导的心脏细胞损伤的高选择性抗氧化潜力，以及 miRNA-15a-5p 在调节不同凋亡蛋白中的作用：L-37 和 Es-37 与三种蛋白质（p53、细胞色素 c 和 Bcl-2）进行了分子对接。给 Sprague Dawley 大鼠注射 1 毫克/千克体重的双酚 A、1 毫克/千克体重的 Es-37 和 L-37，以及 50 毫克/千克体重的 N-乙酰半胱氨酸（NAC）。qRt-PCR 和免疫印迹法证实了 miRNA 和靶基因的表达：我们的研究结果表明，服用双酚 A 会显著提高活性氧（ROS）、p53、细胞色素 c，尤其是 miRNA-15a-5p 的表达。此外，合成聚合物的分子对接证实，与 Es-37 相比，L-37 与目标蛋白的结合亲和力更大，其中细胞色素 c 的结合值最高：这些结果表明，合成聚合物 Es-37 和 L-37 都具有清除自由基、提高抗氧化酶活性和避免（双酚 A 诱导的）毒性的潜力，因此可作为心脏保护剂。此外，本研究首次提出 miRNA-15a-5p 的过表达与氧化应激有关，并与双酚 A 诱导的心脏毒性相吻合，因此可作为未来的潜在治疗靶点。
{"title":"Tetra aniline-based polymers ameliorate BPA-induced cardiotoxicity in Sprague Dawley rats, in silico and in vivo analysis.","authors":"Ayesha Ishtiaq, Irrum Mushtaq, Hina Rehman, Iqra Mushtaq, Iram Mushtaq, Sumra Wajid Abbasi, Faroha Liaqat, Ammarah Rasheed, Sajjad Ahmad, Zareen Akhtar, Iram Murtaza","doi":"10.1016/j.lfs.2024.123104","DOIUrl":"10.1016/j.lfs.2024.123104","url":null,"abstract":"<p><strong>Aims: </strong>Bisphenol A (BPA), xenoestrogen, is an environmental toxicant, that generates oxidative stress leading to, cardiotoxicity, The oxidative stress can be neutralized by natural and synthetic antioxidants. The present study elucidates the highly selective antioxidative potential of synthetic tetra aniline polymers Es-37 and L-37 against Bisphenol A-induced cardiac cellular impairments and the role of miRNA-15a-5p in the regulation of different apoptotic proteins.</p><p><strong>Materials and methods: </strong>The molecular docking of L-37 and Es-37 with three proteins (p53, Cytochrome c, and Bcl-2) were performed. The dose of 1 mg/kg BW of BPA, 1 mg/kg BW Es-37 and L-37 and 50 mg/kg BW N-acetyl cysteine (NAC) was administered to Sprague Dawley rats. The miRNA and target gene expression were confirmed by qRt-PCR and Immunoblotting.</p><p><strong>Key findings: </strong>In our results, BPA administration significantly elevated the reactive oxygen species (ROS), p53, cytochrome c, and particularly miRNA-15a-5p expression; however: these changes were notably averted and reversed by Es-37 and L-37 treatment. Additionally, molecular docking of synthetic polymers validated that L-37 has a greater binding affinity with the target proteins compared to Es-37, with the highest binding values reported for the enzymatic protein cytochrome c.</p><p><strong>Significance: </strong>These results suggest that both synthetic polymers Es-37 and L-37 have the potential to scavenge free radicals, boost-up antioxidant enzyme activities, and avert (BPA-induced) toxicity, thus, may serve as cardioprotective agents. Moreover, this study first time proposes that miRNA-15a-5p overexpression is associated with oxidative stress and coincides with BPA induced cardiotoxicity, thus may serve as potential therapeutic target in future.</p>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375672","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 : 2024-10-02DOI: 10.1016/j.lfs.2024.123087
Being a member of the EGFR tyrosine kinase family, HER3 has been shown to be overexpressed in a number of cancers, including breast cancer (BC). The kinase activity of HER3 is extremely low, and it forms heterodimers with partners, HER2 in particular, that promote biological processes like cell migration, survival, and proliferation by activating downstream carcinogenic signaling pathways. The overexpression of HER3 is also directly linked to tumor invasion, metastasis, and a poor prognosis. Despite the relatively low expression of HER3 compared to EGFR and HER2, a lot of targeted drugs are making their way into clinical trials and seem to have a bright further. This review aims to summarize the relationship between HER3 overexpression, mutations, and carcinogenicity and drug resistance, starting from the unique structure and kinase activity of HER3. Simultaneously, numerous approaches to HER3 targeted therapy are enumerated, and the clinical detection methods for HER3 that are commonly employed in pathology are sorted and contrasted to offer physicians a range of options. We think that a better knowledge of the mechanisms underlying HER3 in tumors and the advancement of targeted HER3 therapy will contribute to an improved prognosis for cancer patients and an increase in the efficacy of anticancer therapies.
{"title":"HER3: Updates and current biology function, targeted therapy and pathologic detecting methods","authors":"","doi":"10.1016/j.lfs.2024.123087","DOIUrl":"10.1016/j.lfs.2024.123087","url":null,"abstract":"<div><div>Being a member of the EGFR tyrosine kinase family, HER3 has been shown to be overexpressed in a number of cancers, including breast cancer (BC). The kinase activity of HER3 is extremely low, and it forms heterodimers with partners, HER2 in particular, that promote biological processes like cell migration, survival, and proliferation by activating downstream carcinogenic signaling pathways. The overexpression of HER3 is also directly linked to tumor invasion, metastasis, and a poor prognosis. Despite the relatively low expression of HER3 compared to EGFR and HER2, a lot of targeted drugs are making their way into clinical trials and seem to have a bright further. This review aims to summarize the relationship between HER3 overexpression, mutations, and carcinogenicity and drug resistance, starting from the unique structure and kinase activity of HER3. Simultaneously, numerous approaches to HER3 targeted therapy are enumerated, and the clinical detection methods for HER3 that are commonly employed in pathology are sorted and contrasted to offer physicians a range of options. We think that a better knowledge of the mechanisms underlying HER3 in tumors and the advancement of targeted HER3 therapy will contribute to an improved prognosis for cancer patients and an increase in the efficacy of anticancer therapies.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375671","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 : 2024-10-02DOI: 10.1016/j.lfs.2024.123102
Aims
Clinical data supports electroacupuncture (EA) as an effective treatment for female reproductive disorders especially gonadotropin abnormalities. This study aims to detect the mechanism of EA that improves the neuroendocrine defects particularly the luteinizing hormone (LH) surge failure in early reproductive aging females.
Materials and methods
Middle-aged ovariectomized rats primed with hormone were treated by EA at acupoints CV4 and SP6 and undergone LH assay. Morphological experiments detected the activation of Kiss1 cells in the anteroventral periventricular nucleus (AVPV). Using targeted liquid chromatography with tandem mass spectrometry (LC-MS/MS) and RNA-sequencing, we determined the concentrations of neurotransmitter metabolites and transcriptomics in AVPV.
Key findings
EA significantly increased c-Fos and c-Fos-positive Kiss1 cells in the middle-aged AVPV as well as the total and peak LH release. Targeted LC-MS/MS and RNA-sequencing of AVPV identified differential neurotransmitters in the middle-aged females including Acetylcholine chloride, 5-Hydroxyindole-3-aceticacid, Kynurenine, Histamine, L-Histidine and L-Glycine, while EA decreased the concentration of Acetylcholine chloride. Totally 1255 differentially expressed genes modulated by EA were strongly implicated in neurotransmitter transport and KEGG pathways involved neuroactive ligand-receptor interaction, glutamatergic and gamma-aminobutyric acid-mediated synapse. Specifically, the mRNAs associated with the LH surge such as hormone receptor Pgr, adrenoceptor Adra1a, neurotransmitter transporters Slc17a6 and Slc32a1, glutamate decarboxylase Gad2 and Kiss1 were markedly altered by EA.
Significance
These findings showed that the age-related reduction of LH surge occurred via differential neurotransmitter metabolisms and altered transcriptions in AVPV, which proposed EA-based therapy for improving responsiveness of the hypothalamus to hormone in women with advanced age.
{"title":"Acupuncture improves neuroendocrine defects in a preclinical rat model of reproductive aging","authors":"","doi":"10.1016/j.lfs.2024.123102","DOIUrl":"10.1016/j.lfs.2024.123102","url":null,"abstract":"<div><h3>Aims</h3><div>Clinical data supports electroacupuncture (EA) as an effective treatment for female reproductive disorders especially gonadotropin abnormalities. This study aims to detect the mechanism of EA that improves the neuroendocrine defects particularly the luteinizing hormone (LH) surge failure in early reproductive aging females.</div></div><div><h3>Materials and methods</h3><div>Middle-aged ovariectomized rats primed with hormone were treated by EA at acupoints CV4 and SP6 and undergone LH assay. Morphological experiments detected the activation of Kiss1 cells in the anteroventral periventricular nucleus (AVPV). Using targeted liquid chromatography with tandem mass spectrometry (LC-MS/MS) and RNA-sequencing, we determined the concentrations of neurotransmitter metabolites and transcriptomics in AVPV.</div></div><div><h3>Key findings</h3><div>EA significantly increased c-Fos and c-Fos-positive Kiss1 cells in the middle-aged AVPV as well as the total and peak LH release. Targeted LC-MS/MS and RNA-sequencing of AVPV identified differential neurotransmitters in the middle-aged females including Acetylcholine chloride, 5-Hydroxyindole-3-aceticacid, Kynurenine, Histamine, L-Histidine and L-Glycine, while EA decreased the concentration of Acetylcholine chloride. Totally 1255 differentially expressed genes modulated by EA were strongly implicated in neurotransmitter transport and KEGG pathways involved neuroactive ligand-receptor interaction, glutamatergic and gamma-aminobutyric acid-mediated synapse. Specifically, the mRNAs associated with the LH surge such as hormone receptor <em>Pgr</em>, adrenoceptor <em>Adra1a</em>, neurotransmitter transporters <em>Slc17a6</em> and <em>Slc32a1</em>, glutamate decarboxylase <em>Gad2</em> and <em>Kiss1</em> were markedly altered by EA.</div></div><div><h3>Significance</h3><div>These findings showed that the age-related reduction of LH surge occurred via differential neurotransmitter metabolisms and altered transcriptions in AVPV, which proposed EA-based therapy for improving responsiveness of the hypothalamus to hormone in women with advanced age.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375669","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.2024.123105
Extracellular aggregation of amyloid-beta (Aβ) in the brain plays a central role in the onset and progression of Alzheimer's disease (AD). Moreover, intraneuronal accumulation of Aβ via oligomer internalization might play an important role in the progression of AD. Deficient autophagy, which is a lysosomal degradation process, occurs during the early stages of AD. Tripeptidyl peptidase-1 (TPP1) functions as a lysosomal enzyme, and TPP1 gene mutations are associated with type 2 late infantile neuronal ceroid lipofuscinosis (LINCL). Nevertheless, there is little information about the role of TPP1 in the pathogenesis of AD; therefore, the present study aimed to measure the decrease in intraneuronal Aβ accumulation by a recombinant analog of the TPP1 enzyme, cerliponase alfa (CER) (Brineura®), and to determine whether autophagy pathways play a role in this decrease. In this study, endogenous Aβ accumulation was induced by fAβ1–42 (a toxic fragment of full-length Aβ) exposure, and mouse hippocampal neuronal cells (HT-22) were treated with CER (human recombinant rhTPP1 1 mg mL−1). Soluble Aβ, TPP1, and the proteins involved in autophagy, including mammalian target of rapamycin (p-mTOR/mTOR), p62/sequestosome-1 (p62/SQSTM1), and microtubule-associated protein 1 A/1B-light chain 3 (LC3), were evaluated using western blotting. The sirtuin-1, beclin-1, and Atg5 genes were also studied using RT-PCR. Aβ and TPP1 localizations were observed via immunocytochemistry. CER reduced the Aβ load in HT-22 cells by inducing TPP1 expression and converting pro-TPP1 into the mature form. Furthermore, exposure to CER and fAβ1–42 induced the autophagy-regulatory/related pathways in HT-22 cells and exposure to CER alone increased sirtuin-1 activity. Based on the present findings, we suggest that augmentation of TPP1 with enzyme replacement therapy may be a potential therapeutic option for the treatment of AD.
{"title":"Cerliponase alfa decreases Aβ load and alters autophagy- related pathways in mouse hippocampal neurons exposed to fAβ1–42","authors":"","doi":"10.1016/j.lfs.2024.123105","DOIUrl":"10.1016/j.lfs.2024.123105","url":null,"abstract":"<div><div>Extracellular aggregation of amyloid-beta (Aβ) in the brain plays a central role in the onset and progression of Alzheimer's disease (AD). Moreover, intraneuronal accumulation of Aβ via oligomer internalization might play an important role in the progression of AD. Deficient autophagy, which is a lysosomal degradation process, occurs during the early stages of AD. Tripeptidyl peptidase-1 (TPP1) functions as a lysosomal enzyme, and TPP1 gene mutations are associated with type 2 late infantile neuronal ceroid lipofuscinosis (LINCL). Nevertheless, there is little information about the role of TPP1 in the pathogenesis of AD; therefore, the present study aimed to measure the decrease in intraneuronal Aβ accumulation by a recombinant analog of the TPP1 enzyme, cerliponase alfa (CER) (Brineura®), and to determine whether autophagy pathways play a role in this decrease. In this study, endogenous Aβ accumulation was induced by fAβ<sub>1–42</sub> (a toxic fragment of full-length Aβ) exposure, and mouse hippocampal neuronal cells (HT-22) were treated with CER (human recombinant rhTPP1 1 mg mL<sup>−1</sup>). Soluble Aβ, TPP1, and the proteins involved in autophagy, including mammalian target of rapamycin (p-mTOR/mTOR), p62/sequestosome-1 (p62/SQSTM1), and microtubule-associated protein 1 A/1B-light chain 3 (LC3), were evaluated using western blotting. The sirtuin-1, beclin-1, and Atg5 genes were also studied using RT-PCR. Aβ and TPP1 localizations were observed via immunocytochemistry. CER reduced the Aβ load in HT-22 cells by inducing TPP1 expression and converting pro-TPP1 into the mature form. Furthermore, exposure to CER and fAβ<sub>1–42</sub> induced the autophagy-regulatory/related pathways in HT-22 cells and exposure to CER alone increased sirtuin-1 activity. Based on the present findings, we suggest that augmentation of TPP1 with enzyme replacement therapy may be a potential therapeutic option for the treatment of AD.</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":"142372240","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.2024.123098
Aims
Acute kidney injury (AKI) is a life-threatening condition marked by sudden kidney function loss and azotemia. While its management is limited to supportive care, the effects of hyperbaric oxygen therapy (HBO) on AKI remain a subject of conflicting animal research. This study aimed to systematically review and meta-analyze HBO's effects on renal function biomarkers serum creatinine (SCr) and blood urea nitrogen (BUN) in murine AKI models, also exploring tissue-level nephroprotection.
Main methods
The PUBMED, SciELO, and LILACS databases were searched until September 5, 2024. Effect sizes of HBO on SCr and BUN levels were expressed as standardized mean difference (SMD) alongside 95 % confidence interval (CI), calculated by random-effects model. Extracted data also included murine specie/strain, HBO parameters, AKI induction method (toxic, ischemic, others), and histological findings. Study quality and publication bias were respectively assessed using the CAMARADES checklist and Egger's test. This review adhered to PRISMA guidelines and was registered in PROSPERO (CRD42022369804).
Key findings
Data synthesis from 21 studies demonstrates that HBO effectively reduces azotemia in AKI-affected animals (SCr's SMD = −1.69, 95 % CI = −2.38 to −0.99, P < 0.001; BUN's SMD = −1.51, 95 % CI = −2.32 to −0.71, P < 0.001) while mitigating histological damage. Subgroup analyses indicate that HBO particularly benefits ischemic and other AKI types (P < 0.05). In contrast, data from toxic AKI models were inconclusive due to insufficient statistical power (P > 0.05, 1-β < 30 %).
Significance
This meta-analysis provides compelling evidence supporting the adjunctive use of HBO in AKI management.
目的：急性肾损伤（AKI）是一种以肾功能突然丧失和氮质血症为特征的危及生命的疾病。虽然对急性肾损伤的治疗仅限于支持性护理，但高压氧疗法（HBO）对急性肾损伤的影响仍是一个相互矛盾的动物研究课题。本研究旨在系统回顾和荟萃分析高压氧治疗对小鼠 AKI 模型中肾功能生物标志物血清肌酐（SCr）和血尿素氮（BUN）的影响，同时探讨组织水平的肾保护作用：主要方法：检索 PUBMED、SciELO 和 LILACS 数据库，直至 2024 年 9 月 5 日。HBO对SCr和BUN水平的影响大小以标准化平均差（SMD）和95%置信区间（CI）表示，采用随机效应模型计算。提取的数据还包括小鼠种类/品系、HBO参数、AKI诱导方法（毒性、缺血性、其他）和组织学结果。研究质量和发表偏倚分别采用CAMARADES核对表和Egger检验进行评估。本综述遵循了 PRISMA 指南，并在 PROSPERO（CRD42022369804）上进行了注册：来自 21 项研究的数据综合显示，HBO 可有效降低受 AKI 影响动物的氮质血症（SCr's SMD = -1.69, 95 % CI = -2.38 to -0.99, P 0.05, 1-β 显著性）：这项荟萃分析提供了令人信服的证据，支持在 AKI 治疗中辅助使用 HBO。
{"title":"Nephroprotective effects of hyperbaric oxygen therapy in murine models of acute kidney injury: A systematic review and meta-analysis","authors":"","doi":"10.1016/j.lfs.2024.123098","DOIUrl":"10.1016/j.lfs.2024.123098","url":null,"abstract":"<div><h3>Aims</h3><div>Acute kidney injury (AKI) is a life-threatening condition marked by sudden kidney function loss and azotemia. While its management is limited to supportive care, the effects of hyperbaric oxygen therapy (HBO) on AKI remain a subject of conflicting animal research. This study aimed to systematically review and meta-analyze HBO's effects on renal function biomarkers serum creatinine (SCr) and blood urea nitrogen (BUN) in murine AKI models, also exploring tissue-level nephroprotection.</div></div><div><h3>Main methods</h3><div>The PUBMED, SciELO, and LILACS databases were searched until September 5, 2024. Effect sizes of HBO on SCr and BUN levels were expressed as standardized mean difference (SMD) alongside 95 % confidence interval (CI), calculated by random-effects model. Extracted data also included murine specie/strain, HBO parameters, AKI induction method (toxic, ischemic, others), and histological findings. Study quality and publication bias were respectively assessed using the CAMARADES checklist and Egger's test. This review adhered to PRISMA guidelines and was registered in PROSPERO (CRD42022369804).</div></div><div><h3>Key findings</h3><div>Data synthesis from 21 studies demonstrates that HBO effectively reduces azotemia in AKI-affected animals (SCr's SMD = −1.69, 95 % CI = −2.38 to −0.99, <em>P</em> < 0.001; BUN's SMD = −1.51, 95 % CI = −2.32 to −0.71, P < 0.001) while mitigating histological damage. Subgroup analyses indicate that HBO particularly benefits ischemic and other AKI types (<em>P</em> < 0.05). In contrast, data from toxic AKI models were inconclusive due to insufficient statistical power (<em>P</em> > 0.05, 1-β < 30 %).</div></div><div><h3>Significance</h3><div>This meta-analysis provides compelling evidence supporting the adjunctive use of HBO in AKI management.</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":"142372245","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.2024.123091
Aims
Accumulating evidence indicates the involvement of TRESK potassium channels in migraine, however, effects of TRESK activation on migraine-related mechanisms remain unclear. We explored effects of TRESK channel modulation on migraine-related behavioral and molecular markers in in-vivo and ex-vivo rat models of migraine.
Main methods
The selective TRESK activator cloxyquin at different doses, the TRESK inhibitor A2764, and the migraine drug sumatriptan were tested alone or in different combinations in nitroglycerin (NTG)-induced in-vivo model, and in ex-vivo meningeal, trigeminal ganglion and brainstem preparations in which CGRP release was induced by capsaicin. Mechanical allodynia, CGRP and c-fos levels in trigeminovascular structures and meningeal mast cells were evaluated.
Key findings
Cloxyquin attenuated NTG-induced mechanical allodynia, brainstem c-fos and CGRP levels, trigeminal ganglion CGRP levels and meningeal mast cell degranulation and number, in-vivo. It also diminished capsaicin-induced CGRP release from ex-vivo meningeal, trigeminal ganglion and brainstem preparations. Specific TRESK inhibitor A2764 abolished all effects of cloxyquin in in-vivo and ex-vivo. Combining cloxyquin and sumatriptan exerted a synergistic effect ex-vivo, but not in-vivo.
Significance
Our findings provide the experimental evidence for the anti-migraine effect of TRESK activation in migraine-like conditions. The modulation of TRESK channels may therefore be an attractive alternative strategy to relieve migraine pain.
{"title":"TRESK channel activation ameliorates migraine-like pain via modulation of CGRP release from the trigeminovascular system and meningeal mast cells in experimental migraine models","authors":"","doi":"10.1016/j.lfs.2024.123091","DOIUrl":"10.1016/j.lfs.2024.123091","url":null,"abstract":"<div><h3>Aims</h3><div>Accumulating evidence indicates the involvement of TRESK potassium channels in migraine, however, effects of TRESK activation on migraine-related mechanisms remain unclear. We explored effects of TRESK channel modulation on migraine-related behavioral and molecular markers in in-vivo and ex-vivo rat models of migraine.</div></div><div><h3>Main methods</h3><div>The selective TRESK activator cloxyquin at different doses, the TRESK inhibitor A2764, and the migraine drug sumatriptan were tested alone or in different combinations in nitroglycerin (NTG)-induced in-vivo model, and in ex-vivo meningeal, trigeminal ganglion and brainstem preparations in which CGRP release was induced by capsaicin. Mechanical allodynia, CGRP and c-fos levels in trigeminovascular structures and meningeal mast cells were evaluated.</div></div><div><h3>Key findings</h3><div>Cloxyquin attenuated NTG-induced mechanical allodynia, brainstem c-fos and CGRP levels, trigeminal ganglion CGRP levels and meningeal mast cell degranulation and number, in-vivo. It also diminished capsaicin-induced CGRP release from ex-vivo meningeal, trigeminal ganglion and brainstem preparations. Specific TRESK inhibitor A2764 abolished all effects of cloxyquin in in-vivo and ex-vivo. Combining cloxyquin and sumatriptan exerted a synergistic effect ex-vivo, but not in-vivo.</div></div><div><h3>Significance</h3><div>Our findings provide the experimental evidence for the anti-migraine effect of TRESK activation in migraine-like conditions. The modulation of TRESK channels may therefore be an attractive alternative strategy to relieve migraine pain.</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":"142372247","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.2024.123089
Glioblastoma multiforme (GBM), also known as grade IV astrocytoma, is the most common and deadly brain tumour. It has a poor prognosis and a low survival rate. GBM cells' immunological escape mechanism helps them resist advanced multimodal therapy. In physiological homeostasis, brain astrocytes and microglia suppress infections and clear the potential pathogen from the system. However, in severe pathological conditions like cancer, the immune response fails to eliminate mutated and rapidly over-proliferating GBM cells. The malignant cells' interactions with immune cells and the neoplasm's immunosuppressive environment enable the avoidance and their clearance. Immunotherapy efficiently addresses these difficulties, as shown by sufficient evidence. This review discusses how GBM cells inhibit and elude the immune system. These include MHC molecule expression alteration and PD-L1 and CTLA-4 immune checkpoint overexpression. Without co-stimulation, these changes induce effector T-cell tolerance and anergy. The review also covers how MDSCs, TAMs, Herpes Virus Entry Mediators, and Human cytomegalovirus protein decrease the effector immune response against glioblastoma. The latter part discusses various therapies that are available in the market or under clinical trials which revolves around combating resistance against the available multimodal therapies. The recent trends indicate that there are various monoclonal antibodies and peptide-based vaccines that can be utilized to overcome the immune evasion technique harbored by GBM cells.
A strategic development of Immunotherapy considering these hallmarks of immune evasion may help in designing a therapy that may prove to be effective in killing the GBM cells thereby, improving the overall survival of GBM-affected patients.
{"title":"Immunological challenges and opportunities in glioblastoma multiforme: A comprehensive view from immune system lens","authors":"","doi":"10.1016/j.lfs.2024.123089","DOIUrl":"10.1016/j.lfs.2024.123089","url":null,"abstract":"<div><div>Glioblastoma multiforme (GBM), also known as grade IV astrocytoma, is the most common and deadly brain tumour. It has a poor prognosis and a low survival rate. GBM cells' immunological escape mechanism helps them resist advanced multimodal therapy. In physiological homeostasis, brain astrocytes and microglia suppress infections and clear the potential pathogen from the system. However, in severe pathological conditions like cancer, the immune response fails to eliminate mutated and rapidly over-proliferating GBM cells. The malignant cells' interactions with immune cells and the neoplasm's immunosuppressive environment enable the avoidance and their clearance. Immunotherapy efficiently addresses these difficulties, as shown by sufficient evidence. This review discusses how GBM cells inhibit and elude the immune system. These include MHC molecule expression alteration and PD-L1 and CTLA-4 immune checkpoint overexpression. Without co-stimulation, these changes induce effector T-cell tolerance and anergy. The review also covers how MDSCs, TAMs, Herpes Virus Entry Mediators, and Human cytomegalovirus protein decrease the effector immune response against glioblastoma. The latter part discusses various therapies that are available in the market or under clinical trials which revolves around combating resistance against the available multimodal therapies. The recent trends indicate that there are various monoclonal antibodies and peptide-based vaccines that can be utilized to overcome the immune evasion technique harbored by GBM cells.</div><div>A strategic development of Immunotherapy considering these hallmarks of immune evasion may help in designing a therapy that may prove to be effective in killing the GBM cells thereby, improving the overall survival of GBM-affected patients.</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":"142372244","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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