Cellular and Molecular Life Sciences最新文献

Gut microbiota is a complex and dynamic system that plays critical roles in human health and various disease. Progressive chronic kidney disease (CKD) suggests that patients irreversibly progress to end-stage kidney disease and need renal replacement treatments, including dialysis and transplantation. Ample evidence indicates that local oxidative stress and inflammation play pivotal roles in the pathogenesis and progression of CKD and dysbiosis of gut microbiota. CKD is always accompanied by intestinal inflammation and oxidative stress, which lead to rapid systemic translocation of bacterial-derived uraemic toxins, including indoxyl sulphate, phenyl sulphate and indole-3-acetic acid, and the consequent development and aggravation of renal fibrosis. Although inflammation and oxidative stress have been extensively discussed, there is a paucity of reports on the effects of gut microbiota on renal fibrosis and gut microbiota mediation of oxidative stress and inflammation. This review provides an overview of gut microbiota on inflammation and oxidative stress in renal fibrosis, briefly discusses regulation of the gut flora using microecological preparations and natural products, such as resveratrol, curcumin and emodin as treatments for CKD, and provides a clear pathophysiological rationale for the design of promising therapeutic strategies.

Background: Aberrant glycosylation is one of the hallmarks of cancer. The profile of glycoprotein expression caused by abnormal glycosylation has been revealed, while abnormal glycogenes that may disturb the structure of glycans have not yet been identified in esophageal squamous cell carcinoma (ESCC).

Methods: Genomic alterations driven by differentially expressed glycogenes in ESCC were compared with matched normal tissues by multi-omics analysis. Immunohistochemistry, MTT, colony formation, transwell assays, subcutaneous tumor formation experiments and tail vein injection were used to study the expression and the effect on the proliferation and metastasis of the differentially expressed glycogenes POFUT1 and RPN1 in ESCC. In the alkyne fucose labeling experiment, AAL lectin affinity chromatography and immunoprecipitation were used to explore the mechanism of POFUT1 in ESCC.

Results: The expression of the POFUT1 and RPN1 glycogenes were upregulated, as determined by genomic copy number gain and proteomics analysis. The overexpression of POFUT1 or RPN1 was associated with poor prognosis in ESCC patients and affected the proliferation and metastasis of ESCC in vivo and in vitro. The overexpression of POFUT1 increased the overall fucosylation level and activated the Notch signaling pathway, which partially mediated POFUT1 induced pro-migration in ESCC. The regulation of malignant progression of ESCC by RPN1 may be related to the TNF signaling pathway, p53 signaling pathway, etc. CONCLUSIONS: Our study fills a gap in the study of abnormal glycogenes and highlights the potential role of the POFUT1/Notch axis in ESCC. Moreover, our study identifies POFUT1 and RPN1 as promising anticancer targets in ESCC.

Angiotensensin-converting enzyme-2 (ACE2) is a receptor for SARS-CoV-2, allowing the virus to enter cells. Although tumor patients infected by SARS-CoV-2 often have a worse outcome, the expression, function and clinical relevance of ACE2 in tumors has not yet been thoroughly analyzed. In this study, RNA sequencing (RNA-seq) data from tumors, adjacent tissues and whole blood samples of COVID-19 patients from genome databases and from tumor cell lines and endothelial cells infected with different SARS-CoV-2 variants or transfected with an ACE2 expression vector (ACE2^high) or mock (ACE2^low) were analyzed for the expression of ACE2 and immune response relevant molecules in silico or by qPCR, flow cytometry, Western blot and/or RNA-seq. The differential expression profiles in ACE2^high vs. ACE2^low cells correlated with available SARS-CoV-2 RNA-seq datasets. ACE2^high cells demonstrated upregulated mRNA and/or protein levels of HLA class I, programmed death ligand 1 (PD-L1), components of the antigen processing machinery (APM) and the interferon (IFN) signaling pathway compared to ACE2^low cells. Co-cultures of ACE2^high cells with peripheral blood mononuclear cells increased immune cell migration and infiltration towards ACE2^high cells, apoptosis of ACE2^high cells, release of innate immunity-related cytokines and altered NK cell-mediated cytotoxicity. Thus, ACE2 expression was associated in different model systems and upon SARS-CoV-2 infection with an altered host immunogenicity, which might influence the efficacy of immune checkpoint inhibitors. These results provide novel insights into the (patho)physiological role of ACE2 on immune response-relevant mechanisms and suggest an alternative strategy to reduce COVID-19 severity in infected tumor patients targeting the ACE2-induced IFN-PD-L1 axis.

Since the late 20th century, researchers have known that caspases are a pillar of cell death, particularly apoptosis. However, recent advances in cell biology have unraveled the multiple roles of caspases. These enzymes have an unconventional role in cell proliferation, differentiation, and invasion. As a result, caspase deregulation can fuel the fire of cancer, incite flames of inflammation, flare neurodegenerative disorders, and exacerbate skin pathologies. Several therapeutic approaches toward caspase inhibition have been investigated, but can caspase inhibitors harness the maladaptive effect of these proteases without causing significant side effects? A few studies have exploited caspase induction for cancer or adoptive cell therapies. Here, we provide a compelling picture of caspases, starting with their evolution, their polytomous roles beyond cell death, the flaws of their deregulation, and the merits of targeting them for therapeutic implications. Furthermore, we provide a deeper understanding of the evolution of caspase-related research up to the current era, pinpointing the role of caspases in cell survival and aiding in the development of effective caspase-targeted therapies.

Elevated neutrophil counts in broncho-alveolar lavage (BAL) fluids of lung transplant (LTx) patients with chronic lung allograft dysfunction (CLAD) are associated with disease pathology. However, phenotypical characteristics of these cells remained largely unknown. Moreover, despite enhanced levels of the most potent human neutrophil-attracting chemokine CXCL8 in BAL fluid, no discrimination had been made between natural NH₂-terminally truncated CXCL8 proteoforms, which exhibit up to 30-fold differences in biological activity. Therefore, we aimed to characterize the neutrophil maturation and activation state, as well as proteolytic activation of CXCL8, in BAL fluids and peripheral blood of LTx patients with CLAD or infection and stable LTx recipients. Flow cytometry and microscopy revealed a high diversity in neutrophil maturity in blood and BAL fluid, ranging from immature band to hypersegmented aged cells. In contrast, the activation phenotype of neutrophils in BAL fluid was remarkably homogeneous. The highly potentiated NH₂-terminally truncated proteoforms CXCL8(6-77), CXCL8(8-77) and CXCL8(9-77), but also the partially inactivated CXCL8(10-77), were detected in BAL fluids of CLAD and infected LTx patients, as well as in COVID-19 and influenza patient cohorts by tandem mass spectrometry. Moreover, the most potent proteoform CXCL8(9-77) specifically correlated with the neutrophil counts in the LTx BAL fluids. Finally, rapid proteolysis of CXCL8 in BAL fluids could be inhibited by a combination of serine and metalloprotease inhibitors. In conclusion, proteolytic activation of CXCL8 promotes neutrophilic inflammation in LTx patients. Therefore, application of protease inhibitors may hold pharmacological promise for reducing excessive neutrophil-mediated inflammation and collateral tissue damage in the lungs.

X-Linked myotubular myopathy (XLMTM) is characterized by severe skeletal muscle weakness and reduced life expectancy. The pathomechanism and the impact of non-muscular defects affecting survival, such as liver dysfunction, are poorly understood. Here, we investigated organ-specific effects of XLMTM using the Mtm1^-/y mouse model. We performed RNA-sequencing to identify a common mechanism in different skeletal muscles, and to explore potential phenotypes and compensatory mechanisms in the heart and the liver. The cardiac and hepatic function and structural integrity were assessed both in vivo and in vitro. Our findings revealed no defects in liver function or morphology. A disease signature common to several skeletal muscles highlighted dysregulation of muscle development, inflammation, cell adhesion and oxidative phosphorylation as key pathomechanisms. The heart displayed only mild functional alterations without obvious structural defects. Transcriptomic analyses revealed an opposite dysregulation of mitochondrial function, cell adhesion and beta integrin trafficking pathways in cardiac muscle compared to skeletal muscles. Despite this dysregulation, biochemical and cellular experiments demonstrated that these pathways were strongly affected in skeletal muscle and normal in cardiac muscle. Moreover, biomarkers reflecting the molecular activity of MTM1, such as PtdIns3P and dynamin 2 levels, were increased in the skeletal muscles but not in cardiac muscle. Overall, these data suggest a compensatory mechanism preserving cardiac function, pointing to potential therapeutic targets to cure the severe skeletal muscle defects in XLMTM.

The thalamic reticular nucleus (TRN) is an anatomical and functional hub that modulates the flow of information between the cerebral cortex and thalamus, and its dysfunction has been linked to sensory disturbance and multiple behavioral disorders. Therefore, understanding how TRN neurons differentiate and establish connectivity is crucial to clarify the basics of TRN functions. Here, we showed that the regulatory cascade of the transcription factors Ascl1 and Isl1 promotes the fate of TRN neurons and concomitantly represses the fate of non-TRN prethalamic neurons. Furthermore, we found that this cascade is necessary for the correct development of the two main axonal connections, thalamo-cortical projections and prethalamo-thalamic projections. Notably, the disruption of prethalamo-thalamic axons can cause the pathfinding defects of thalamo-cortical axons in the thalamus. Finally, forced Isl1 expression can rescue disruption of cell fate specification and prethalamo-thalamic projections in in vitro primary cultures of Ascl1-deficient TRN neurons, indicating that Isl1 is an essential mediator of Ascl1 function in TRN development. Together, our findings provide insights into the molecular mechanisms for TRN neuron differentiation and circuit formation.

Neurodegenerative disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) affect millions of people worldwide. Curative treatment for these neurodegenerative disorders is still lacking and therefore a further understanding of their cause and progression is urgently needed. Extracellular vesicles (EVs) are nanosized vesicles loaded with cargo, such as proteins and miRNAs, that are released by cells and play an important role in intercellular communication. Intercellular communication through EVs can contribute to the spread of pathological proteins, such as amyloid-beta and tau, or cause pathogenesis through other mechanisms. In addition, EVs may serve as potential biomarkers for diagnosis and for monitoring disease progression. In this review, we summarize and discuss recent advances in our understanding of the role of EVs in AD, ALS an PD with an emphasis on dysregulated cargo in each disease. We highlight shared dysregulated cargo between these diseases, discuss underlying pathways, and outline future implications for therapeutic strategies.

MTSS1 is a ubiquitously expressed intracellular protein known mainly for its involvement in basic cellular processes, such as the regulation of actin organization and membrane architecture. MTSS1 has attracted much attention for its role as a tumor suppressor, being absent or expressed at reduced levels in advanced and metastasizing cancers. Occasionally, MTSS1 is, instead, upregulated in metastasis and, in some cases, even in primary tumors. In addition to these well-established functions of MTSS1 linked to its I-BAR- and WH2-domains, the protein is involved in modulating cell-cell contacts, cell differentiation, lipid metabolism, and vesicle formation and acts as a scaffolding protein for several E3 ubiquitin ligases. MTSS1 is classified as a housekeeping protein and is never mutated despite the several pathologic phenotypes linked to its dysregulation. Despite MTSS1's involvement in fundamental signaling pathways, MTSS1 gene ablation is not ubiquitously lethal, although it affects embryonic development. Due to MTSS1´s involvement in many seemingly disparate processes, with many cases lacking mechanistic explanations, we found it timely to review the recent data on MTSS1's role at the cellular level, as well as in health and disease, to direct further studies on this interesting multifunctional protein.

The accumulation of reactive oxygen species (ROS) significantly contributes to intervertebral disc degeneration (IDD), but the mechanisms behind this phenomenon remain unclear. This study revealed elevated ROS levels in the intervertebral discs (IVDs) of aged mice compared to those of younger mice. The local application of hydrogen peroxide (H₂O₂) near lumbar discs also induced ROS accumulation and IDD. Isobaric tags for relative and absolute quantitation (iTRAQ) analysis of discs from aged and H₂O₂-injected mice showed increased levels of YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) and matrix metallopeptidase 1/3/7/9 (MMP1/3/7/9), along with decreased levels of forkhead box O3 (FOXO3) and TIMP1 (tissue inhibitor of metalloproteinases 1). Our experiments indicated that in nucleus pulposus (NP) cells and young mouse IVDs that were not exposed to ROS, FOXO3 recruited histone acetyltransferase CBP (CREB binding protein) and mediator complex subunit 1 (Med1) to activate TIMP1 expression, which inhibited MMP activity and prevented disc degeneration. However, ROS exposure activated YTHDF2 and promoted the degradation of m⁶A-modified FOXO3 mRNA, impairing FOXO3's ability to activate TIMP1. This degradation exacerbated MMP activity and contributed to the degradation of the IVD extracellular matrix. Notably, administration of the YTHDF2 inhibitor DC-Y13-27 in older and H₂O₂-treated mice significantly enhanced FOXO3 and TIMP1 expression, reduced MMP activity, and mitigated IVD degeneration. Together, this study uncovers a novel ROS-regulated pathway in IDD, centered on the YTHDF2/FOXO3/TIMP1/MMPs axis, suggesting that targeting YTHDF2 may represent a promising therapeutic strategy for combating the progression of IDD.