Pub Date : 2025-02-27DOI: 10.1016/j.cstres.2025.02.005
Jia-Yu Wu , Bing Han , Ting Yang , Lu Zheng , Yi-Xin Guo , Jia-Yao Li , Xiao-Yu Guo , Huan-Huan Yin , Ru-Jia Xie
Endoplasmic reticulum (ER) stress-induced apoptosis plays a crucial role in various liver diseases. Hepatocytes respond to ER stress by activating the unfolded protein response and autophagy, which is essential for maintaining ER homeostasis. However, failure to restore ER balance via autophagy contributes to apoptosis. In this study, we aimed to explore the role of C/EBP homologous protein (CHOP) in regulating ER stress-induced apoptosis in rat hepatocytes. We found that CHOP downregulates autophagy, aggravating apoptosis. Our results revealed that inhibition of CHOP expression enhanced autophagy and reduced DTT-induced apoptosis in BRL-3A cells, whereas CHOP overexpression worsened apoptosis. Chromatin immunoprecipitation assays revealed that CHOP negatively regulates autophagy-related genes, such as ATG12, ATG5, and LC3. These findings suggest that CHOP modulation plays a crucial role in ER stress-induced hepatocyte apoptosis by regulating autophagy.
背景：与内质网（ER）应激相关的细胞凋亡涉及多种肝脏疾病，包括肝纤维化、非酒精性脂肪肝和肝硬化。肝细胞通过引发未折叠蛋白反应（UPR）和增强自噬来应对ER应激。自噬是维持ER正常功能的关键机制，它通过降解受损的ER片段和清除ER腔中的异常蛋白质聚集体来实现。如果不能通过自噬恢复ER平衡，就会对肝细胞造成危害，并导致与ER应激相关的细胞凋亡。最近的研究结果表明，C/EBP同源蛋白（CHOP）可通过下调自噬作用加剧ER应激相关的细胞凋亡，但其潜在机制仍难以确定。目的：研究CHOP对ER应激诱导的大鼠肝细胞凋亡的影响及其潜在的分子机制：方法：用雷帕霉素（RAP）和 3-甲基腺嘌呤预处理 BRL-3A 细胞，然后用二硫苏糖醇（DTT）处理。分别使用实时细胞分析（RTCA）和流式细胞仪检测细胞的生长率和凋亡率。ER应激相关分子水平通过Western印迹法测定。使用 CHOP、小干扰 RNA 和慢病毒载体系统转染 BRL-3A 细胞，观察 CHOP 基因沉默或过表达对自噬和细胞凋亡的影响。染色质免疫共沉淀（ChIP）被用来确认CHOP是否直接与ER应激下的ATG12、ATG5和LC3启动子区域结合：结果：ER应激相关分子在BRL-3A肝细胞中急剧上调，肝细胞凋亡增加。RAP 预处理明显降低了 DTT 诱导的 ER 应激相关分子的表达；相反，3-MA 预处理促进了 DTT 诱导的 ER 应激相关凋亡分子的水平。随着肝细胞中 CHOP 表达的减少，自噬相关分子的水平急剧上升，DTT 诱导的肝细胞凋亡也随之减少。然而，在过表达 CHOP 的细胞中却观察到了相反的趋势。通过 ChIP 检测发现，DTT 处理后，CHOP 对 BRL-3A 细胞中的 ATG12、ATG5 和 LC3 等自噬相关分子有负向调节作用：结论：CHOP在ER应激过程中的增强抑制了自噬，促进了肝细胞凋亡；然而，CHOP基因表达的减少可减轻DTT诱导的肝细胞凋亡。过表达 CHOP 会加重 DTT 诱导的肝细胞凋亡。
{"title":"CHOP aggravates hepatocyte apoptosis upon endoplasmic reticulum stress by downregulating autophagy","authors":"Jia-Yu Wu , Bing Han , Ting Yang , Lu Zheng , Yi-Xin Guo , Jia-Yao Li , Xiao-Yu Guo , Huan-Huan Yin , Ru-Jia Xie","doi":"10.1016/j.cstres.2025.02.005","DOIUrl":"10.1016/j.cstres.2025.02.005","url":null,"abstract":"<div><div>Endoplasmic reticulum (ER) stress-induced apoptosis plays a crucial role in various liver diseases. Hepatocytes respond to ER stress by activating the unfolded protein response and autophagy, which is essential for maintaining ER homeostasis. However, failure to restore ER balance via autophagy contributes to apoptosis. In this study, we aimed to explore the role of C/EBP homologous protein (CHOP) in regulating ER stress-induced apoptosis in rat hepatocytes. We found that CHOP downregulates autophagy, aggravating apoptosis. Our results revealed that inhibition of CHOP expression enhanced autophagy and reduced DTT-induced apoptosis in BRL-3A cells, whereas CHOP overexpression worsened apoptosis. Chromatin immunoprecipitation assays revealed that CHOP negatively regulates autophagy-related genes, such as ATG12, ATG5, and LC3. These findings suggest that CHOP modulation plays a crucial role in ER stress-induced hepatocyte apoptosis by regulating autophagy.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 3","pages":"Pages 109-118"},"PeriodicalIF":3.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-19DOI: 10.1016/j.cstres.2025.02.003
Xin-Feng Jiao , Yue Gao , Ran Ni , Wen-Ya Zhao , Can Zhao , Xiang Lu , Hai-Feng Zhang , Wei Gao , Lan Luo
Sarcopenia is a geriatric syndrome characterized by progressive loss of muscle mass and function. Heat shock protein (HSP) A12B is essential for angiogenesis and endothelial function. However, the association of HSPA12B levels with sarcopenia remains unclear. A total of 936 community-dwelling elderly people were recruited, and serum HSPA12B was measured by enzyme-linked immunosorbent assay. Appendicular skeletal muscle mass index (ASMI), grip strength, and gait speed were taken to assess sarcopenia. We found that serum HSPA12B levels in patients with sarcopenia (median [interquartile range] = 182.15 [137.58–225.86] ng/mL) were lower than those in elderly people without sarcopenia (228.96 [193.03–292.93] ng/mL, P < 0.001). Receiver operating characteristic curve analysis indicated that the optimal cut-off value of serum HSPA12B level for predicting sarcopenia was 185.50 ng/mL, with a sensitivity of 52.6% and a specificity of 80.8% (area under curve = 0.742, 95% confidence interval [CI] = 0.711–0.772, P < 0.001). Moreover, serum HSPA12B concentration was positively correlated with ASMI (r = 0.354, P < 0.001), grip strength (r = 0.381, P < 0.001), and gait speed (r = 0.169, P < 0.001). Multivariate logistic regression analysis showed that decreased serum HSPA12B levels (<185.50 ng/mL) were a risk factor for increased risk of sarcopenia (adjusted odds ratio = 4.335, 95% CI = 3.136–5.993, P < 0.001). In addition, serum HSPA12B level was also positively correlated with serum levels of angiogenesis markers, vascular endothelial growth factor (r = 0.080, P = 0.014), and angiopoietin-1 (r = 0.108, P = 0.001). In summary, our results indicate that low serum HSPA12B level is associated with an increased risk of sarcopenia in the elderly, suggesting a potential role of HSPA12B in the development of sarcopenia.
{"title":"Low serum HSPA12B levels are associated with an increased risk of sarcopenia in a Chinese population of older adults","authors":"Xin-Feng Jiao , Yue Gao , Ran Ni , Wen-Ya Zhao , Can Zhao , Xiang Lu , Hai-Feng Zhang , Wei Gao , Lan Luo","doi":"10.1016/j.cstres.2025.02.003","DOIUrl":"10.1016/j.cstres.2025.02.003","url":null,"abstract":"<div><div>Sarcopenia is a geriatric syndrome characterized by progressive loss of muscle mass and function. Heat shock protein (HSP) A12B is essential for angiogenesis and endothelial function. However, the association of HSPA12B levels with sarcopenia remains unclear. A total of 936 community-dwelling elderly people were recruited, and serum HSPA12B was measured by enzyme-linked immunosorbent assay. Appendicular skeletal muscle mass index (ASMI), grip strength, and gait speed were taken to assess sarcopenia. We found that serum HSPA12B levels in patients with sarcopenia (median [interquartile range] = 182.15 [137.58–225.86] ng/mL) were lower than those in elderly people without sarcopenia (228.96 [193.03–292.93] ng/mL, <em>P</em> < 0.001). Receiver operating characteristic curve analysis indicated that the optimal cut-off value of serum HSPA12B level for predicting sarcopenia was 185.50 ng/mL, with a sensitivity of 52.6% and a specificity of 80.8% (area under curve = 0.742, 95% confidence interval [CI] = 0.711–0.772, <em>P</em> < 0.001). Moreover, serum HSPA12B concentration was positively correlated with ASMI (<em>r</em> = 0.354, <em>P</em> < 0.001), grip strength (<em>r</em> = 0.381, <em>P</em> < 0.001), and gait speed (<em>r</em> = 0.169, <em>P</em> < 0.001). Multivariate logistic regression analysis showed that decreased serum HSPA12B levels (<185.50 ng/mL) were a risk factor for increased risk of sarcopenia (adjusted odds ratio = 4.335, 95% CI = 3.136–5.993, <em>P</em> < 0.001). In addition, serum HSPA12B level was also positively correlated with serum levels of angiogenesis markers, vascular endothelial growth factor (<em>r</em> = 0.080, <em>P</em> = 0.014), and angiopoietin-1 (<em>r</em> = 0.108, <em>P</em> = 0.001). In summary, our results indicate that low serum HSPA12B level is associated with an increased risk of sarcopenia in the elderly, suggesting a potential role of HSPA12B in the development of sarcopenia.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 2","pages":"Pages 100-108"},"PeriodicalIF":3.3,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Atopic dermatitis (AD) is prone to exacerbations in response to various triggering factors and flare-ups after remission. We searched for molecules associated with relapse/exacerbation of AD among molecules with altered gene expression in the skin of patients with AD. Microarray analyses were performed on lesional and nonlesional skin of adolescent or adult patients with recalcitrant AD and healthy controls. Five chaperones involved in intracellular stress responses, namely heat shock protein family A (Hsp70) member 9 (HSPA9), heat shock protein 90 beta family member 1 (HSP90B1), calnexin (CANX), malectin (MLEC; endoplasmic reticulum-associated degradation), and heat shock protein family D (Hsp60) member 1 (HSPD1), were consistently upregulated in involved and uninvolved skin of patients with AD. Damage-associated molecular patterns were upregulated in involved skin. KLF transcription factor 2 (KLF2) was decreased in involved skin and exhibited a decreasing trend in uninvolved skin of patients with AD. CD4(+)/CD8(+) double-positive cells (1.4% of T cells) were detected in lesions with declined KLF2 levels. WNT inhibitory factor 1 (WIF1) was downregulated in involved skin. Prolactin-induced protein was upregulated in only uninvolved skin of patients with AD. We found increased intracellular stress responses and decreased expression of KLF2 in the skin of patients with AD. Multifactorial genetic diseases, such as asthma, inflammatory bowel disease, type 2 diabetes, and rheumatoid arthritis, are associated with intracellular stress. Intracellular abnormalities may also be responsible for AD. Further research on AD may incorporate enhanced intracellular stress response and the decreased expression of KLF2 into the mechanism underlying AD.
{"title":"Increased intracellular stress responses and decreased KLF2 in adult patients with atopic dermatitis","authors":"Shuji Sugiura , Hiderou Yoshida , Hisashi Sugiura , Masami Uehara , Yasuo Sugiura , Yoshihiro Maruo , Yuji Hayashi , Takefumi Yamamoto , Takeshi Kato , Noriki Fujimoto , Jun Udagawa","doi":"10.1016/j.cstres.2025.02.001","DOIUrl":"10.1016/j.cstres.2025.02.001","url":null,"abstract":"<div><div>Atopic dermatitis (AD) is prone to exacerbations in response to various triggering factors and flare-ups after remission. We searched for molecules associated with relapse/exacerbation of AD among molecules with altered gene expression in the skin of patients with AD. Microarray analyses were performed on lesional and nonlesional skin of adolescent or adult patients with recalcitrant AD and healthy controls. Five chaperones involved in intracellular stress responses, namely heat shock protein family A (Hsp70) member 9 (<em>HSPA9</em>), heat shock protein 90 beta family member 1 (<em>HSP90B1</em>), calnexin (<em>CANX</em>), malectin (<em>MLEC</em>; endoplasmic reticulum-associated degradation), and heat shock protein family D (Hsp60) member 1 (<em>HSPD1</em>), were consistently upregulated in involved and uninvolved skin of patients with AD. Damage-associated molecular patterns were upregulated in involved skin. KLF transcription factor 2 (<em>KLF2</em>) was decreased in involved skin and exhibited a decreasing trend in uninvolved skin of patients with AD. CD4(+)/CD8(+) double-positive cells (1.4% of T cells) were detected in lesions with declined KLF2 levels. WNT inhibitory factor 1 (WIF1) was downregulated in involved skin. Prolactin-induced protein was upregulated in only uninvolved skin of patients with AD. We found increased intracellular stress responses and decreased expression of KLF2 in the skin of patients with AD. Multifactorial genetic diseases, such as asthma, inflammatory bowel disease, type 2 diabetes, and rheumatoid arthritis, are associated with intracellular stress. Intracellular abnormalities may also be responsible for AD. Further research on AD may incorporate enhanced intracellular stress response and the decreased expression of KLF2 into the mechanism underlying AD.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 2","pages":"Pages 84-99"},"PeriodicalIF":3.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-09DOI: 10.1016/j.cstres.2025.02.002
Jill L. Johnson
The FK506-binding protein 51 (FKBP51) is an important regulator of glucocorticoid receptor activity and an Hsp90 cochaperone. FKBP51 has previously been identified as a drug target due to its roles in stress-related disorders and pain tolerance. Two recent publications in Cell Stress and Chaperones further explore FKBP51 functions. To understand whether FKBP51 plays a role in sleep disturbances linked to stress disorders, one study examined the role of FKBP51 in regulating the circadian rhythm. Broadening the range of Hsp90 cochaperone function, the other article summarized the role of multiple cochaperones in Alzheimer’s disease, discussing how cochaperones affect both Aβ and tau. They emphasize the role of FKBP51 in promoting tau pathogenesis and discuss the small molecule LA1011, which binds Hsp90 and competes with Hsp90-FKBP51 interaction. Further studies with LA1011 may lead to new treatments for Alzheimer’s disease and will help clarify the contributions of FKBP51 to human disorders.
fk506结合蛋白51 （FKBP51）是糖皮质激素受体活性的重要调节因子和Hsp90的合作伙伴。由于FKBP51在压力相关疾病和疼痛耐受性中的作用，它先前已被确定为药物靶点。最近发表在Cell Stress and Chaperones上的两篇文章进一步探讨了FKBP51的功能。为了了解FKBP51是否在与应激障碍相关的睡眠障碍中发挥作用，Gebru等人研究了FKBP51在调节昼夜节律中的作用。Jeanne等拓宽了Hsp90 cochaperone功能的范围，总结了多种cochaperone在阿尔茨海默病中的作用，讨论了cochaperone如何同时影响Aβ和tau。他们强调FKBP51在促进tau发病机制中的作用，并讨论了结合Hsp90并与Hsp90-FKBP51相互作用竞争的小分子LA1011。对LA1011的进一步研究可能会导致阿尔茨海默病的新治疗方法，并将有助于阐明FKBP51对人类疾病的贡献。
{"title":"FKBP51 functions in the regulation of circadian rhythm and Alzheimer's disease","authors":"Jill L. Johnson","doi":"10.1016/j.cstres.2025.02.002","DOIUrl":"10.1016/j.cstres.2025.02.002","url":null,"abstract":"<div><div>The FK506-binding protein 51 (FKBP51) is an important regulator of glucocorticoid receptor activity and an Hsp90 cochaperone. FKBP51 has previously been identified as a drug target due to its roles in stress-related disorders and pain tolerance. Two recent publications in Cell Stress and Chaperones further explore FKBP51 functions. To understand whether FKBP51 plays a role in sleep disturbances linked to stress disorders, one study examined the role of FKBP51 in regulating the circadian rhythm. Broadening the range of Hsp90 cochaperone function, the other article summarized the role of multiple cochaperones in Alzheimer’s disease, discussing how cochaperones affect both Aβ and tau. They emphasize the role of FKBP51 in promoting tau pathogenesis and discuss the small molecule LA1011, which binds Hsp90 and competes with Hsp90-FKBP51 interaction. Further studies with LA1011 may lead to new treatments for Alzheimer’s disease and will help clarify the contributions of FKBP51 to human disorders.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 2","pages":"Pages 81-83"},"PeriodicalIF":3.3,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.cstres.2024.11.007
Anastasiia Vasetska , Eva-Maria Packeiser , Hanna Körber , Selim Aslan , Serhan Ay , Murat Findik , Firdevs Binli , Murat Selçuk , Christelle Speiser-Fontaine , Sandra Goericke-Pesch
Slow-release gonadotropin-releasing hormone (GnRH) agonist implants are frequently used for contraception in male dogs. Although the effects are fully reversible, there is still concern about the safety of the implant’s mode of action. Addressing this, we investigated cellular stress and androgen receptor (AR) signaling during downregulation and recovery. Testicular tissues were sampled from dogs castrated at different time points after GnRH implant removal and compared with untreated controls. AR, hypoxia-inducible factor 1 (HIF1A), heat shock proteins heat shock protein 72 (HSP72), heat shock protein 73 (heat shock cognate, HSPA8) (HSP73), heat shock protein A2 (HSPA2), heat shock protein 90 alpha (inducible isoform) (HSP90AA1), and heat shock protein 90 beta (constitutive isoform) (HSP90AB1) were investigated by quantitative real-time polymerase chain reaction and AR, HSP72, HSP73, and HSP90 immunohistochemically. While AR, HIF1A, and HSP70 were upregulated at gene expression level, HSPA8, HSPA2, and HSP90AA1 expression were downregulated during spermatogenic arrest; HSP90AB1 expression did not change. Immunohistochemistry verified AR-expression in Sertoli, peritubular, and Leydig cells, occasionally also in spermatogonia. Stress-inducible HSP72 was occasionally detected, while constitutive HSP73 and HSP90 were abundantly expressed by germ cells. Our results were similar to studies on seasonal breeders such as pine voles, geese, fish, and soft-shelled turtles. Accordingly, GnRH implants did not impose additional cellular stress on testicular cells when compared with natural recrudescence. Since comparative data on HIF1α are scarce, we cannot draw conclusions about hypoxic conditions.
{"title":"Molecular response of canine testis to GnRH agonist: Insights into AR, HIF-1α, and HSPs expression during arrest and recovery of spermatogenesis","authors":"Anastasiia Vasetska , Eva-Maria Packeiser , Hanna Körber , Selim Aslan , Serhan Ay , Murat Findik , Firdevs Binli , Murat Selçuk , Christelle Speiser-Fontaine , Sandra Goericke-Pesch","doi":"10.1016/j.cstres.2024.11.007","DOIUrl":"10.1016/j.cstres.2024.11.007","url":null,"abstract":"<div><div>Slow-release gonadotropin-releasing hormone (GnRH) agonist implants are frequently used for contraception in male dogs. Although the effects are fully reversible, there is still concern about the safety of the implant’s mode of action. Addressing this, we investigated cellular stress and androgen receptor (AR) signaling during downregulation and recovery. Testicular tissues were sampled from dogs castrated at different time points after GnRH implant removal and compared with untreated controls. <em>AR</em>, hypoxia-inducible factor 1 (<em>HIF1A</em>), heat shock proteins heat shock protein 72 (<em>HSP72</em>), heat shock protein 73 (heat shock cognate, HSPA8) (<em>HSP73</em>), heat shock protein A2 (<em>HSPA2</em>), heat shock protein 90 alpha (inducible isoform) (<em>HSP90AA1</em>), and heat shock protein 90 beta (constitutive isoform) (<em>HSP90AB1</em>) were investigated by quantitative real-time polymerase chain reaction and AR, HSP72, HSP73, and HSP90 immunohistochemically. While <em>AR</em>, <em>HIF1A</em>, and <em>HSP70</em> were upregulated at gene expression level, <em>HSPA8</em>, <em>HSPA2</em>, and <em>HSP90AA1</em> expression were downregulated during spermatogenic arrest; <em>HSP90AB1</em> expression did not change. Immunohistochemistry verified AR-expression in Sertoli, peritubular, and Leydig cells, occasionally also in spermatogonia. Stress-inducible HSP72 was occasionally detected, while constitutive HSP73 and HSP90 were abundantly expressed by germ cells. Our results were similar to studies on seasonal breeders such as pine voles, geese, fish, and soft-shelled turtles. Accordingly, GnRH implants did not impose additional cellular stress on testicular cells when compared with natural recrudescence. Since comparative data on HIF1α are scarce, we cannot draw conclusions about hypoxic conditions.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 1","pages":"Pages 9-21"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11719361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Malaria caused by Plasmodium spp., is a major public health issue in sub-Saharan Africa. The fight against malaria has stalled due to increasing resistance to treatments and insecticides. There is an urgent need to focus on new therapeutic targets to combat malaria effectively. This study aimed to measure the secreted heat shock protein gp96 levels in both malaria patients and controls. Indeed, gp96 plays a crucial role in parasite survival within the host and in establishing a successful infection. Therefore, gp96 could be a promising target for antimalarial drugs. In our study, we included 60 malaria patients, 30 with severe malaria (SM) and 30 with uncomplicated malaria (UM). Additionally, 28 controls were included. Using the ELISA method, we measured gp96 levels in the participants' blood samples. We then used the Mann–Whitney or analyse of variance tests to calculate descriptive statistics and determined the correlation between gp96 level and parasitemia using Spearman's rank correlation test. The study found that gp96 levels in the plasma significantly increased in malaria patients (23.86 ng/mL) compared to control (5.88 ng/mL), with a P < 0.0001. Interestingly, there was a significant difference between SM (27.56 ng/mL) and UM (13.9 ng/mL), with a P-value of 0.001. These findings are accompanied by significantly higher parasitemia and elevated proinflammatory cytokines such as IL-17A and IL-1β levels in SM patients compared to UM and controls. Furthermore, there was no significant positive correlation between gp96 levels and parasitemia/proinflammatory cytokines. Our research has revealed, for the first time, that individuals with SM have significantly higher levels of gp96 in the context of high parasitemia and proinflammatory cytokines. Our preliminary results will be taken further to evaluate gp96 as a valuable biomarker for the diagnosis of SM and a potential target for antimalarial drug discovery.
{"title":"Secreted extracellular heat shock protein gp96 and inflammatory cytokines are markers of severe malaria outcome","authors":"Fatou Thiam , Djibaba Djoumoi , Mame Ndew Mbaye , Aminata Fall , Abou Abdallah Malick Diouara , Mamadou Diop , Cheikh Momar Nguer , Babacar Mbengue , Gora Diop , Evelyne Kohli , Alioune Dieye","doi":"10.1016/j.cstres.2024.12.004","DOIUrl":"10.1016/j.cstres.2024.12.004","url":null,"abstract":"<div><div>Malaria caused by <em>Plasmodium spp.</em>, is a major public health issue in sub-Saharan Africa. The fight against malaria has stalled due to increasing resistance to treatments and insecticides. There is an urgent need to focus on new therapeutic targets to combat malaria effectively. This study aimed to measure the secreted heat shock protein gp96 levels in both malaria patients and controls. Indeed, gp96 plays a crucial role in parasite survival within the host and in establishing a successful infection. Therefore, gp96 could be a promising target for antimalarial drugs. In our study, we included 60 malaria patients, 30 with severe malaria (SM) and 30 with uncomplicated malaria (UM). Additionally, 28 controls were included. Using the ELISA method, we measured gp96 levels in the participants' blood samples. We then used the Mann–Whitney or analyse of variance tests to calculate descriptive statistics and determined the correlation between gp96 level and parasitemia using Spearman's rank correlation test. The study found that gp96 levels in the plasma significantly increased in malaria patients (23.86 ng/mL) compared to control (5.88 ng/mL), with a <em>P</em> < 0.0001. Interestingly, there was a significant difference between SM (27.56 ng/mL) and UM (13.9 ng/mL), with a <em>P</em>-value of 0.001. These findings are accompanied by significantly higher parasitemia and elevated proinflammatory cytokines such as IL-17A and IL-1β levels in SM patients compared to UM and controls. Furthermore, there was no significant positive correlation between gp96 levels and parasitemia/proinflammatory cytokines. Our research has revealed, for the first time, that individuals with SM have significantly higher levels of gp96 in the context of high parasitemia and proinflammatory cytokines. Our preliminary results will be taken further to evaluate gp96 as a valuable biomarker for the diagnosis of SM and a potential target for antimalarial drug discovery.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 1","pages":"Pages 48-56"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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