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Ubiquitin-like modification dependent proteasomal degradation and disease therapy. 依赖蛋白酶体降解的泛素样修饰与疾病治疗。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2024-11-01 Epub Date: 2024-06-08 DOI: 10.1016/j.molmed.2024.05.005
Tiantian Wang, Jie Jiang, Xue Zhang, Xisong Ke, Yi Qu
{"title":"Ubiquitin-like modification dependent proteasomal degradation and disease therapy.","authors":"Tiantian Wang, Jie Jiang, Xue Zhang, Xisong Ke, Yi Qu","doi":"10.1016/j.molmed.2024.05.005","DOIUrl":"10.1016/j.molmed.2024.05.005","url":null,"abstract":"<p><p>Although it is believed that ubiquitin (Ub) modification is required for protein degradation in the proteasome system (UPS), several proteins are subject to Ub-independent proteasome degradation, and in many cases ubiquitin-like (UBL) modifications, including neddylation, FAT10ylation, SUMOylation, ISGylation, and urmylation, are essential instead. In this Review, we focus on UBL-dependent proteasome degradation (UBLPD), on proteasome regulators especially shuttle factors and receptors, as well as potential competition and coordination with UPS. We propose that there is a distinct UBL-proteasome system (UBLPS) that might be underestimated in protein degradation. Finally, we investigate the association of UBLPD with muscle wasting and neurodegenerative diseases in which the proteasome is abnormally activated and impaired, respectively, and suggest strategies to modulate UBLPD for disease therapy.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"1061-1075"},"PeriodicalIF":12.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141293763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Targeting epigenetic dysregulation in autism spectrum disorders. 针对自闭症谱系障碍的表观遗传失调。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2024-11-01 Epub Date: 2024-07-05 DOI: 10.1016/j.molmed.2024.06.004
Macarena L Herrera, Juan Paraíso-Luna, Isabel Bustos-Martínez, Ángel Barco
{"title":"Targeting epigenetic dysregulation in autism spectrum disorders.","authors":"Macarena L Herrera, Juan Paraíso-Luna, Isabel Bustos-Martínez, Ángel Barco","doi":"10.1016/j.molmed.2024.06.004","DOIUrl":"10.1016/j.molmed.2024.06.004","url":null,"abstract":"<p><p>Autism spectrum disorders (ASD) comprise a range of neurodevelopmental pathologies characterized by deficits in social interaction and repetitive behaviors, collectively affecting almost 1% of the worldwide population. Deciphering the etiology of ASD has proven challenging due to the intricate interplay of genetic and environmental factors and the variety of molecular pathways affected. Epigenomic alterations have emerged as key players in ASD etiology. Their research has led to the identification of biomarkers for diagnosis and pinpointed specific gene targets for therapeutic interventions. This review examines the role of epigenetic alterations, resulting from both genetic and environmental influences, as a central causative factor in ASD, delving into its contribution to pathogenesis and treatment strategies.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"1028-1046"},"PeriodicalIF":12.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141545310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 dual role of the TSC complex in cancer. TSC 复合物在癌症中的双重作用。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2024-11-01 DOI: 10.1016/j.molmed.2024.10.009
Josephine Hartung, Christine Müller, Cornelis F Calkhoven
{"title":"The dual role of the TSC complex in cancer.","authors":"Josephine Hartung, Christine Müller, Cornelis F Calkhoven","doi":"10.1016/j.molmed.2024.10.009","DOIUrl":"https://doi.org/10.1016/j.molmed.2024.10.009","url":null,"abstract":"<p><p>The tuberous sclerosis complex (TSC1/TSC2/TBC1D7) primarily functions to inhibit the mechanistic target of rapamycin complex 1 (mTORC1), a crucial regulator of cell growth. Mutations in TSC1 or TSC2 cause tuberous sclerosis complex (TSC), a rare autosomal dominant genetic disorder marked by benign tumors in multiple organs that rarely progress to malignancy. Traditionally, TSC proteins are considered tumor suppressive due to their inhibition of mTORC1 and other mechanisms. However, more recent studies have shown that TSC proteins can also promote tumorigenesis in certain cancer types. In this review, we explore the composition and function of the TSC protein complex, the roles of its individual components in cancer biology, and potential future therapeutic targeting strategies.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 aging lipidome: exercise is medicine. 衰老的脂质体：运动就是药物。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2024-11-01 Epub Date: 2024-06-24 DOI: 10.1016/j.molmed.2024.06.006
Abel Plaza-Florido, Inmaculada Pérez-Prieto, Alejandro Lucia
{"title":"The aging lipidome: exercise is medicine.","authors":"Abel Plaza-Florido, Inmaculada Pérez-Prieto, Alejandro Lucia","doi":"10.1016/j.molmed.2024.06.006","DOIUrl":"10.1016/j.molmed.2024.06.006","url":null,"abstract":"<p><p>The molecular mechanisms behind the potential 'anti-aging' effects of exercise remain to be elucidated. Janssens et al. studied the lipidome of different mouse tissues and human skeletal muscle. They identified an evolutionary conserved 'lipid aging' signature, characterized by bis(monoacylglycero)phosphate accumulation, which, at the muscle level, can be attenuated by exercise.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"1001-1003"},"PeriodicalIF":12.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141451599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Cognitive impairment in people living with HIV: mechanisms, controversies, and future perspectives. 艾滋病病毒感染者的认知障碍：机制、争议和未来展望。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2024-11-01 Epub Date: 2024-07-01 DOI: 10.1016/j.molmed.2024.06.005
Charalampos D Moschopoulos, Kate Alford, Anastasia Antoniadou, Jaime H Vera
{"title":"Cognitive impairment in people living with HIV: mechanisms, controversies, and future perspectives.","authors":"Charalampos D Moschopoulos, Kate Alford, Anastasia Antoniadou, Jaime H Vera","doi":"10.1016/j.molmed.2024.06.005","DOIUrl":"10.1016/j.molmed.2024.06.005","url":null,"abstract":"<p><p>Despite the dramatic decrease in HIV-associated neurocognitive impairment (NCI) in the combined antiretroviral treatment (cART) era, subtler neuropsychological complications remain prevalent. In this review, we discuss the changing pathophysiology of HIV-associated NCI, considering recent evidence of HIV neuropathogenesis, and the pivotal role of cART. Furthermore, we address the multifactorial nature of NCI in people living with HIV, including legacy and ongoing insults to the brain, as well as host-specific factors. We also summarize the ongoing debate about the refinement of diagnostic criteria, exploring the strengths and limitations of these recent approaches. Finally, we present current research in NCI management in people living with HIV and highlight the need for using both pharmacological and nonpharmacological pathways toward a holistic approach.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"1076-1089"},"PeriodicalIF":12.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141493537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Amyloid and collagen templates in aortic valve calcification. 主动脉瓣钙化中的淀粉样蛋白和胶原蛋白模板。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2024-11-01 Epub Date: 2024-06-05 DOI: 10.1016/j.molmed.2024.04.015
Shobini Jayaraman, Navneet Narula, Jagat Narula, Olga Gursky
{"title":"Amyloid and collagen templates in aortic valve calcification.","authors":"Shobini Jayaraman, Navneet Narula, Jagat Narula, Olga Gursky","doi":"10.1016/j.molmed.2024.04.015","DOIUrl":"10.1016/j.molmed.2024.04.015","url":null,"abstract":"<p><p>Calcific aortic valve disease (CAVD) is a widely prevalent heart disorder in need of pharmacological interventions. Calcified areas in aortic valves often contain amyloid fibrils that promote calcification in vitro. This opinion paper suggests that amyloid contributes to CAVD development; amyloid-assisted nucleation can accelerate hydroxyapatite deposition onto collagen matrix. Notably, acidic arrays in amyloid match calcium-calcium spacing in the amorphous hydroxyapatite precursor, while oscillating hemodynamic perturbations promote amyloid deposition in the valve. Lipoprotein(a), a genetic risk factor for CAVD, augments calcification via several mechanisms, wherein hydrolysis of oxidized phospholipids (oxPLs) by Lp(a)-associated enzymes helps generate orthophosphate, and apolipoprotein(a) blocks plasmin-induced fibril degradation. Current studies of amyloid-calcium-collagen interactions in solution and in fibrillar complexes allow deeper insight into the role of amyloid in calcification.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"1010-1019"},"PeriodicalIF":12.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141284818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Unraveling host genetics and microbiome genome crosstalk: a novel therapeutic approach. 揭示宿主遗传学和微生物组基因组串扰：一种新的治疗方法。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2024-11-01 Epub Date: 2024-06-27 DOI: 10.1016/j.molmed.2024.06.007
Qian Zhang, Dennis Schwarz, Yumei Cheng, Yahya Sohrabi
{"title":"Unraveling host genetics and microbiome genome crosstalk: a novel therapeutic approach.","authors":"Qian Zhang, Dennis Schwarz, Yumei Cheng, Yahya Sohrabi","doi":"10.1016/j.molmed.2024.06.007","DOIUrl":"10.1016/j.molmed.2024.06.007","url":null,"abstract":"<p><p>The ability of the gut microbiome to adapt to a new environment and utilize a new metabolite or dietary compound by inducing structural variations (SVs) in the genome has an important role in human health. Here, we discuss recent data on host genetic regulation of SV induction and its use as a new therapeutic approach.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"1007-1009"},"PeriodicalIF":12.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Virus as the cause of type 1 diabetes. 病毒是 1 型糖尿病的病因。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2024-11-01 Epub Date: 2024-07-13 DOI: 10.1016/j.molmed.2024.06.011
Knut Dahl-Jørgensen
{"title":"Virus as the cause of type 1 diabetes.","authors":"Knut Dahl-Jørgensen","doi":"10.1016/j.molmed.2024.06.011","DOIUrl":"10.1016/j.molmed.2024.06.011","url":null,"abstract":"<p><p>Type 1 diabetes (T1D), a severe disease requiring intensive insulin treatment, carries an increased risk for complications and reduced lifespan. Certain viruses have been implicated in T1D's etiology, with 'live', replicating enteroviruses (EVs) recently found in the pancreas at diagnosis. This discovery prompted a trial to slow down disease progression using antiviral drugs. A 6-month treatment combining pleconaril and ribavirin in new-onset T1D patients preserved residual insulin production after 1 year, unlike placebo. The results support the theory that viruses may cause T1D in genetically susceptible individuals. A low-grade, persistent viral infection may initiate a cascade of pathogenic mechanisms initially involving the innate immune system, inducing β-cell stress and neoantigen release, leading to autoimmunity, and eventually the destruction of insulin-producing β-cells.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":"1020-1027"},"PeriodicalIF":12.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141604195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Fc-optimized checkpoint antibodies for cancer immunotherapy. 用于癌症免疫疗法的 Fc 优化检查点抗体。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2024-11-01 DOI: 10.1016/j.molmed.2024.10.008
Rony Dahan, Alan J Korman
{"title":"Fc-optimized checkpoint antibodies for cancer immunotherapy.","authors":"Rony Dahan, Alan J Korman","doi":"10.1016/j.molmed.2024.10.008","DOIUrl":"https://doi.org/10.1016/j.molmed.2024.10.008","url":null,"abstract":"<p><p>The development of checkpoint antibodies for cancer therapy has been guided by the principle of blocking T cell inhibitory signals. Recognition of the role of the Fc domain in therapeutic activities, through the depletion of immunosuppressive populations and myeloid cell activation, prompts a shift toward the development of optimized Fc-engineered checkpoint antibodies.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Promoting proteostasis by cAMP/PKA and cGMP/PKG. 通过 cAMP/PKA 和 cGMP/PKG 促进蛋白稳态。
IF 12.8 1区 医学
Trends in molecular medicine Pub Date : 2024-10-29 DOI: 10.1016/j.molmed.2024.10.006
Md Salim Ahammed, Xuejun Wang
{"title":"Promoting proteostasis by cAMP/PKA and cGMP/PKG.","authors":"Md Salim Ahammed, Xuejun Wang","doi":"10.1016/j.molmed.2024.10.006","DOIUrl":"10.1016/j.molmed.2024.10.006","url":null,"abstract":"<p><p>Proteasome functional insufficiency (PFI) is implicated in neurodegeneration and heart failure, where aberrant protein aggregation is common and impairs the ubiquitin (Ub)-proteasome system (UPS), exacerbating increased proteotoxic stress (IPTS) and creating a vicious circle. Breaking this circle represents a key to treating these diseases. Protein kinase (PK)-A and PKG can activate the proteasome and promote proteasomal degradation of misfolded proteins. PKA does so by phosphorylating Ser14-RPN6/PSMD11, but how PKG activates the proteasome remains unknown. Emerging evidence supports a strategy to treat diseases with IPTS by augmenting cAMP/PKA and cGMP/PKG. Conceivably, targeted activation of PKA and PKG at proteasome nanodomains would minimize the undesired effects from their actions on other targets. In this review, we discuss PKA and PKG regulation of proteostasis via the UPS.</p>","PeriodicalId":23263,"journal":{"name":"Trends in molecular medicine","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
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