Giulia Fasano, Stefania Petrini, Valeria Bonavolontà, Graziamaria Paradisi, Catia Pedalino, Marco Tartaglia, Antonella Lauri
BACKGROUND: RASopathies are genetic syndromes affecting development and having variable cancer predisposition. These disorders are clinically related and are caused by germline mutations affecting key players and regulators of the RAS-MAPK signaling pathway generally leading to an upregulated ERK activity. Gain-of-function (GOF) mutations in PTPN11, encoding SHP2, a cytosolic protein tyrosine phosphatase positively controlling RAS function, underlie approximately 50% of Noonan syndromes (NS), the most common RASopathy...
April 9, 2024: Molecular Medicine
Dipabarna Bhattacharya, Jason Theodoropoulos, Katariina Nurmi, Timo Juutilainen, Kari K Eklund, Riitta Koivuniemi, Tiina Kelkka, Satu Mustjoki, Tapio Lönnberg
BACKGROUND: Immune-mediated arthritis is a group of autoinflammatory diseases, where the patient's own immune system attacks and destroys synovial joints. Sustained remission is not always achieved with available immunosuppressive treatments, warranting more detailed studies of T cell responses that perpetuate synovial inflammation in treatment-refractory patients. METHODS: In this study, we investigated CD4 + and CD8 + T lymphocytes from the synovial tissue and peripheral blood of patients with treatment-resistant immune-mediated arthritis using paired single-cell RNA and TCR-sequencing...
April 9, 2024: Molecular Medicine
Tairan Wang, Yan Jin, Mengyao Wang, Boya Chen, Jinyu Sun, Jiaying Zhang, Hui Yang, Xinyao Deng, Xingyue Cao, Lidong Wang, Yuanyuan Tang
Effective therapeutic targets and early diagnosis are major challenges in the treatment of gastrointestinal tract (GIT) cancers. SALL4 is a well-known transcription factor that is involved in organogenesis during embryonic development. Previous studies have revealed that SALL4 regulates cell proliferation, survival, and migration and maintains stem cell function in mature cells. Additionally, SALL4 overexpression is associated with tumorigenesis. Despite its characterization as a biomarker in various cancers, the role of SALL4 in GIT cancers and the underlying mechanisms are unclear...
April 8, 2024: Molecular Medicine
Dane A Thompson, Tea Tsaava, Arvind Rishi, Sam J George, Tyler D Hepler, Daniel Hide, Valentin A Pavlov, Michael Brines, Sangeeta S Chavan, Kevin J Tracey
No abstract text is available yet for this article.
April 3, 2024: Molecular Medicine
Jianlin Shen, Yujian Lan, Ziyu Ji, Huan Liu
BACKGROUND: Intervertebral disc degeneration (IVDD) is one of the etiologic factors of degenerative spinal diseases, which can lead to a variety of pathological spinal conditions such as disc herniation, spinal stenosis, and scoliosis. IVDD is a leading cause of lower back pain, the prevalence of which increases with age. Recently, Sirtuins/SIRTs and their related activators have received attention for their activity in the treatment of IVDD. In this paper, a comprehensive systematic review of the literature on the role of SIRTs and their activators on IVDD in recent years is presented...
March 29, 2024: Molecular Medicine
Joshua Bloom, Georgios Pantouris, Mingzhu He, Bayan Aljabari, Lopa Mishra, Ramu Manjula, Andrew Parkins, Elias J Lolis, Yousef Al-Abed
BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in multiple inflammatory and non-inflammatory diseases, including liver injury induced by acetaminophen (APAP) overdose. Multiple small molecule inhibitors of MIF have been described, including the clinically available anti-rheumatic drug T-614 (iguratimod); however, this drug's mode of inhibition has not been fully investigated. METHODS: We conducted in vitro testing including kinetic analysis and protein crystallography to elucidate the interactions between MIF and T-614...
March 27, 2024: Molecular Medicine
Yi-Yi Wang, Guo-Qiang Zhu, Kun Xia, Hong-Bo Zeng, Yun-Hui He, Hui Xie, Zhen-Xing Wang, Ran Xu
BACKGROUND: Benign prostatic hyperplasia (BPH) is a prevalent disease affecting elderly men, with chronic inflammation being a critical factor in its development. Omentin-1, also known as intelectin-1 (ITLN-1), is an anti-inflammatory protein primarily found in the epithelial cells of the small intestine. This study aimed to investigate the potential of ITLN-1 in mitigating BPH by modulating local inflammation in the prostate gland. METHODS: Our investigation involved two in vivo experimental models...
March 22, 2024: Molecular Medicine
Jishamol Thazhathveettil, Ashok Kumar Kumawat, Isak Demirel, Allan Sirsjö, Geena Varghese Paramel
BACKGROUND: The formation and accumulation of cholesterol crystals (CC) at the lesion site is a hallmark of atherosclerosis. Although studies have shown the importance of vascular smooth muscle cells (VSMCs) in the disease atherosclerosis, little is known about the molecular mechanism behind the uptake of CC in VSMCs and their role in modulating immune response. METHODS: Human aortic smooth muscle cells were cultured and treated with CC. CC uptake and CC mediated signaling pathway and protein induction were studied using flow cytometry, confocal microscopy, western blot and Olink proteomics...
March 22, 2024: Molecular Medicine
Siqi Yuan, Dan She, Shangming Jiang, Nan Deng, Jiayi Peng, Ling Ma
The accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER), due to genetic determinants and extrinsic environmental factors, leads to endoplasmic reticulum stress (ER stress). As ER stress ensues, the unfolded protein response (UPR), comprising three signaling pathways-inositol-requiring enzyme 1, protein kinase R-like endoplasmic reticulum kinase, and activating transcription factor 6 promptly activates to enhance the ER's protein-folding capacity and restore ER homeostasis. However, prolonged ER stress levels propels the UPR towards cellular demise and the subsequent inflammatory cascade, contributing to the development of human diseases, including cancer, neurodegenerative disorders, and diabetes...
March 20, 2024: Molecular Medicine
Weijie Liang, Ruibin Wei, Xingxing Zhu, Jinliang Li, Aiwen Lin, Jun Chen, Wen Wu, Qiang Jie
BACKGROUND: Macrophage-derived extracellular vesicle (macrophage-EV) is highly studied for its regulatory role in atherosclerosis (AS). Our current study tried to elucidate the possible role of macrophage-EV loaded with small interfering RNA against high-mobility group box 1 (siHMGB1) affecting atherosclerotic plaque formation. METHODS: In silico analysis was performed to find critical factors in mouse atherosclerotic plaque formation. EVs secreted by RAW 264.7 cells were collected by ultracentrifugation and characterized, followed by the preparation of macrophage-EV-loaded siHMGB1 (macrophage-EV/siHMGB1)...
March 16, 2024: Molecular Medicine
Xin Xie, Xiaomin Zhang, Songze Li, Wei Du
OBJECTIVE: Anesthetics have been linked to cognitive alterations, particularly in the elderly. The current research delineates how Fibroblast Growth Factor 2 (Fgf2) modulates tau protein phosphorylation, contributing to cognitive impairments in aged rats upon sevoflurane administration. METHODS: Rats aged 3, 12, and 18 months were subjected to a 2.5% sevoflurane exposure to form a neurotoxicity model. Cognitive performance was gauged, and the GEO database was employed to identify differentially expressed genes (DEGs) in the 18-month-old cohort post sevoflurane exposure...
March 16, 2024: Molecular Medicine
Peter J Hotez
My scientific life in translational medicine runs in two parallel, yet often converging paths. The first, is four-decade-long commitment to develop new vaccines for parasitic and neglected tropical diseases, as well as pandemic threats. This includes a vaccine for human hookworm infection that I began as an MD-PhD student in New York City in the 1980s, and a new low-cost COVID vaccine that reached almost 100 million people in low- and middle-income countries. Alongside this life in scientific research, is one in public engagement for vaccine and neglected disease diplomacy to ensure that people who live in extreme poverty can benefit from access to biomedical innovations...
March 15, 2024: Molecular Medicine
Franziska Hoschek, Julia Natan, Maximilian Wagner, Kirupa Sathasivam, Alshaimaa Abdelmoez, Björn von Einem, Gillian P Bates, G Bernhard Landwehrmeyer, Andreas Neueder
BACKGROUND: The disease-causing mutation in Huntington disease (HD) is a CAG trinucleotide expansion in the huntingtin (HTT) gene. The mutated CAG tract results in the production of a small RNA, HTT1a, coding for only exon 1 of HTT. HTT1a is generated by a block in the splicing reaction of HTT exon 1 to exon 2 followed by cleavage in intron 1 and polyadenylation. Translation of HTT1a leads to the expression of the highly toxic HTT exon 1 protein fragment. We have previously shown that the levels of HTT1a expression in mouse models of HD is dependent on the CAG repeat length...
March 8, 2024: Molecular Medicine
Bo Wang, Sheng Zhu, Miao Guo, Run-Dong Ma, Ya-Ling Tang, Ya-Xiong Nie, Hong-Feng Gu
BACKGROUND: Neuronal ferroptosis plays a critical role in the pathogenesis of cognitive deficits. The present study explored whether artemisinin protected type 2 diabetes mellitus (T2DM) mice from cognitive impairments by attenuating neuronal ferroptosis in the hippocampal CA1 region. METHODS: STZ-induced T2DM mice were treated with artemisinin (40 mg/kg, i.p.), or cotreated with artemisinin and Nrf2 inhibitor MEL385 or ferroptosis inducer erastin for 4 weeks. Cognitive performance was determined by the Morris water maze and Y maze tests...
March 7, 2024: Molecular Medicine
Hengru Guo, Ying Xin, Saifei Wang, Xiaoning Zhang, Yanqi Ren, Bo Qiao, Hongjiang Li, Jing Wu, Xiao Hao, Lijun Xu, Yushan Yan, Haohao Zhang
BACKGROUND: Imbalance in energy regulation is a major cause of insulin resistance and diabetes. Melanocortin-4 receptor (MC4R) signaling at specific sites in the central nervous system has synergistic but non-overlapping functions. However, the mechanism by which MC4R in the arcuate nucleus (ARC) region regulates energy balance and insulin resistance remains unclear. METHODS: The MC4Rflox/flox mice with proopiomelanocortin (POMC) -Cre mice were crossed to generate the POMC-MC4Rflox/+ mice...
March 6, 2024: Molecular Medicine
Anna Marie Buchanan, Sergio Mena, Iman Choukari, Aditya Vasa, Jesseca N Crawford, Jim Fadel, Nick Maxwell, Lawrence Reagan, Allie Cruikshank, Janet Best, H Fred Nijhout, Michael Reed, Parastoo Hashemi
BACKGROUND: Loss of dopaminergic neurons underlies the motor symptoms of Parkinson's disease (PD). However stereotypical PD symptoms only manifest after approximately 80% of dopamine neurons have died making dopamine-related motor phenotypes unreliable markers of the earlier stages of the disease. There are other non-motor symptoms, such as depression, that may present decades before motor symptoms. METHODS: Because serotonin is implicated in depression, here we use niche, fast electrochemistry paired with mathematical modelling and machine learning to, for the first time, robustly evaluate serotonin neurochemistry in vivo in real time in a toxicological model of Parkinsonism, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)...
March 1, 2024: Molecular Medicine
Zhiwen Zhang, Quan Guo, Chao Ma, Zhenzhou Zhao, Qingbo Shi, Haosen Yu, Lixin Rao, Muwei Li
BACKGROUND: Endothelial-to-Mesenchymal Transformation (EndMT) plays key roles in endothelial dysfunction during the pathological progression of atherosclerosis; however, its detailed mechanism remains unclear. Herein, we explored the biological function and mechanisms of upstream stimulating factor 1 (USF1) in EndMT during atherosclerosis. METHODS: The in vivo and in vitro atherosclerotic models were established in high fat diet-fed ApoE-/- mice and ox-LDL-exposed human umbilical vein endothelial cells (HUVECs)...
February 29, 2024: Molecular Medicine
Wei Wang, Rongli Xu, Ping He, Yuqing Xiong, Haomiao Zhao, Xuewei Fu, Jie Lin, Lijiao Ye
BACKGROUND: Sepsis is a systemic inflammatory response which is frequently associated with acute lung injury (ALI). Activating transcription factor 3 (ATF3) promotes M2 polarization, however, the biological effects of ATF3 on macrophage polarization in sepsis remain undefined. METHODS: LPS-stimulated macrophages and a mouse model of cecal ligation and puncture (CLP)-induced sepsis were generated as in vitro and in vivo models, respectively. qRT-PCR and western blot were used to detect the expression of ATF3, ILF3, NEAT1 and other markers...
February 23, 2024: Molecular Medicine
Liang Ding, Zheng Yang, Baier Sun
BACKGROUND: The escalating challenge of Carbapenem-resistant Klebsiella pneumoniae (CRKP) in hospital-acquired pneumonia (HAP) is closely linked to the blaNDM-1 gene. This study explores the regulatory mechanisms of blaNDM-1 expression and aims to enhance antibacterial tactics to counteract the spread and infection of resistant bacteria. METHODS: KP and CRKP strains were isolated from HAP patients' blood samples. Transcriptomic sequencing (RNA-seq) identified significant upregulation of blaNDM-1 gene expression in CRKP strains...
February 23, 2024: Molecular Medicine
Lini Fang, Yang Tao, Guoying Che, Yongzi Yun, Min Ren, Yujie Liu
BACKGROUND: Reperfusion is the most effective strategy for myocardial infarct, but induces additional injury. WD repeat and SOCS box containing protein 1 (WSB1) plays a protective role in ischemic cells. This study aims to investigate the effects of WSB1 on myocardial ischemia-reperfusion (IR) injury. METHODS: The myocardial IR was induced by left anterior descending (LAD) ligation for 45 min and subsequent reperfusion. The overexpression of WSB1 was mediated by tail vein injection of AAV9 loaded with WSB1 encoding sequence two weeks before IR surgery...
February 23, 2024: Molecular Medicine
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