Latest ArticlesDegenerative musculoskeletal diseases are structural and functional failures of the musculoskeletal system, including osteoarthritis, osteoporosis, intervertebral disc degeneration (IVDD), and sarcopenia. As the global population ages, degenerative musculoskeletal diseases are becoming more prevalent. However, the pathogenesis of degenerative musculoskeletal diseases is not fully understood. Previous studies have revealed that endoplasmic reticulum (ER) stress is a stress response that occurs when impairment of the protein folding capacity of the ER leads to the accumulation of misfolded or unfolded proteins in the ER, contributing to degenerative musculoskeletal diseases. By affecting cartilage degeneration, synovitis, meniscal lesion, subchondral bone remodeling of osteoarthritis, bone remodeling and angiogenesis of osteoporosis, nucleus pulposus degeneration, annulus fibrosus rupture, cartilaginous endplate degeneration of IVDD, and sarcopenia, ER stress is involved in the pathogenesis of degenerative musculoskeletal diseases. Preclinical studies have found that regulation of ER stress can delay the progression of multiple degenerative musculoskeletal diseases. These pilot studies provide foundations for further evaluation of the feasibility, efficacy, and safety of ER stress modulators in the treatment of musculoskeletal degenerative diseases in clinical trials. In this review, we have integrated up-to-date research findings of ER stress into the pathogenesis of degenerative musculoskeletal diseases. In a future perspective, we have also discussed possible directions of ER stress in the investigation of degenerative musculoskeletal disease, potential therapeutic strategies for degenerative musculoskeletal diseases using ER stress modulators, as well as underlying challenges and obstacles in bench-to-beside research.
The essential roles of platelets in thrombosis have been well recognized. Unexpectedly, thrombosis is prevalent during thrombocytopenia induced by cytotoxicity of biological, physical and chemical origins, which could be suffered by military personnel and civilians during chemical, biological, radioactive, and nuclear events. Especially, thrombosis is considered a major cause of mortality from radiation injury-induced thrombocytopenia, while the underlying pathogenic mechanism remains elusive.
A mouse model of radiation injury-induced thrombocytopenia was built by exposing mice to a sublethal dose of ionizing radiation (IR). The phenotypic and functional changes of platelets and megakaryocytes (MKs) were determined by a comprehensive set of in vitro and in vivo assays, including flow cytometry, flow chamber, histopathology, Western blotting, and chromatin immunoprecipitation, in combination with transcriptomic analysis. The molecular mechanism was investigated both in vitro and in vivo, and was consolidated using MK-specific knockout mice. The translational potential was evaluated using a human MK cell line and several pharmacological inhibitors.
In contrast to primitive MKs, mature MKs (mMKs) are intrinsically programmed to be apoptosis-resistant through reprogramming the Bcl-xL-BAX/BAK axis. Interestingly, mMKs undergo minority mitochondrial outer membrane permeabilization (MOMP) post IR, resulting in the activation of the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway via the release of mitochondrial DNA. The subsequent interferon-β (IFN-β) response in mMKs upregulates a GTPase guanylate-binding protein 2 (GBP2) to produce large and hyperreactive platelets that favor thrombosis. Further, we unmask that autophagy restrains minority MOMP in mMKs post IR.
Our study identifies that megakaryocytic mitochondria-cGAS/STING-IFN-β-GBP2 axis serves as a fundamental checkpoint that instructs the size and function of platelets upon radiation injury and can be harnessed to treat platelet pathologies.
Diabetic cardiomyopathy (DCM) causes the myocardium to rely on fatty acid β-oxidation for energy. The accumulation of intracellular lipids and fatty acids in the myocardium usually results in lipotoxicity, which impairs myocardial function. Adipsin may play an important protective role in the pathogenesis of DCM. The aim of this study is to investigate the regulatory effect of Adipsin on DCM lipotoxicity and its molecular mechanism.
A high-fat diet (HFD)-induced type 2 diabetes mellitus model was constructed in mice with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg). Liquid chromatography-tandem mass spectrometry (LC–MS/MS), glutathione-S-transferase (GST) pull-down technique, Co-immunoprecipitation (Co-IP) and immunofluorescence colocalization analyses were used to investigate the molecules which can directly interact with Adipsin. The immunocolloidal gold method was also used to detect the interaction between Adipsin and its downstream modulator.
The expression of Adipsin was significantly downregulated in the HFD-induced DCM model (P<0.05). Adipose tissue-specific overexpression of Adipsin significantly improved cardiac function and alleviated cardiac remodeling in DCM (P<0.05). Adipsin overexpression also alleviated mitochondrial oxidative phosphorylation function in diabetic stress (P<0.05). LC–MS/MS analysis, GST pull-down technique and Co-IP studies revealed that interleukin-1 receptor-associated kinase-like 2 (Irak2) was a downstream regulator of Adipsin. Immunofluorescence analysis also revealed that Adipsin was co-localized with Irak2 in cardiomyocytes. Immunocolloidal gold electron microscopy and Western blotting analysis indicated that Adipsin inhibited the mitochondrial translocation of Irak2 in DCM, thus dampening the interaction between Irak2 and prohibitin (Phb)-optic atrophy protein 1 (Opa1) on mitochondria and improving the structural integrity and function of mitochondria (P<0.05). Interestingly, in the presence of Irak2 knockdown, Adipsin overexpression did not further alleviate myocardial mitochondrial destruction and cardiac dysfunction, suggesting a downstream role of Irak2 in Adipsin-induced responses (P<0.05). Consistent with these findings, overexpression of Adipsin after Irak2 knockdown did not further reduce the accumulation of lipids and their metabolites in the cardiac myocardium, nor did it enhance the oxidation capacity of cardiomyocytes expose to palmitate (PA) (P<0.05). These results indicated that Irak2 may be a downstream regulator of Adipsin.
Adipsin improves fatty acid β-oxidation and alleviates mitochondrial injury in DCM. The mechanism is related to Irak2 interaction and inhibition of Irak2 mitochondrial translocation.
Cell metabolism plays a pivotal role in tumor progression, and targeting cancer metabolism might effectively kill cancer cells. We aimed to investigate the role of hexokinases in prostate cancer (PCa) and identify a crucial target for PCa treatment.
The Cancer Genome Atlas (TCGA) database, online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase (ADPGK) in PCa. The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo. Quantitative proteomics, metabolomics, and extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) tests were performed to evaluate the impact of ADPGK on PCa metabolism. The underlying mechanisms were explored through ADPGK overexpression and knockdown, co-immunoprecipitation (Co-IP), ECAR analysis and cell counting kit-8 (CCK-8) assays.
ADPGK was the only glucokinase that was both upregulated and predicted worse overall survival (OS) in prostate adenocarcinoma (PRAD). Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs. non-PCa tissues. High ADPGK expression indicates worse survival outcomes, and ADPGK serves as an independent factor of biochemical recurrence. In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration, and ADPGK inhibition suppressed malignant phenotypes. Metabolomics, proteomics, and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa. Mechanistically, ADPGK binds aldolase C (ALDOC) to promote glycolysis via AMP-activated protein kinase (AMPK) phosphorylation. ALDOC was positively correlated with ADPGK, and high ALDOC expression was associated with worse survival outcomes in PCa.
In summary, ADPGK is a driving factor in PCa progression, and its high expression contributes to a poor prognosis in PCa patients. ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling, suggesting that ADPGK might be an effective target and marker for PCa treatment and prognosis evaluation.
As the body’s integumentary system, the skin is vulnerable to injuries. The subsequent wound healing processes aim to restore dermal and epidermal integrity and functionality. To this end, multiple tissue-resident cells and recruited immune cells cooperate to efficiently repair the injured tissue. Such temporally- and spatially-coordinated interplay necessitates tight regulation to prevent collateral damage such as overshooting immune responses and excessive inflammation. In this context, regulatory T cells (Tregs) hold a key role in balancing immune homeostasis and mediating cutaneous wound healing. A comprehensive understanding of Tregs’ multifaceted field of activity may help decipher wound pathologies and, ultimately, establish new treatment modalities. Herein, we review the role of Tregs in orchestrating the regeneration of skin adnexa and catalyzing healthy wound repair. Further, we discuss how Tregs operate during fibrosis, keloidosis, and scarring.
Advances in chimeric antigen receptor (CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies. However, progress is still hindered as clinical benefit is only available for a fraction of patients. A lack of understanding of CAR-T cell behaviors in vivo at the single-cell level impedes their more extensive application in clinical practice. Mounting evidence suggests that single-cell sequencing techniques can help perfect the receptor design, guide gene-based T cell modification, and optimize the CAR-T manufacturing conditions, and all of them are essential for long-term immunosurveillance and more favorable clinical outcomes. The information generated by employing these methods also potentially informs our understanding of the numerous complex factors that dictate therapeutic efficacy and toxicities. In this review, we discuss the reasons why CAR-T immunotherapy fails in clinical practice and what this field has learned since the milestone of single-cell sequencing technologies. We further outline recent advances in the application of single-cell analyses in CAR-T immunotherapy. Specifically, we provide an overview of single-cell studies focusing on target antigens, CAR-transgene integration, and preclinical research and clinical applications, and then discuss how it will affect the future of CAR-T cell therapy.
Regulation of gut microbiota and its impact on human health is the theme of intensive research. The incidence and prevalence of atrial fibrillation (AF) are continuously escalating as the global population ages and chronic disease survival rates increase; however, the mechanisms are not entirely clarified. It is gaining awareness that alterations in the assembly, structure, and dynamics of gut microbiota are intimately engaged in the AF progression. Owing to advancements in next-generation sequencing technologies and computational strategies, researchers can explore novel linkages with the genomes, transcriptomes, proteomes, and metabolomes through parallel meta-omics approaches, rendering a panoramic view of the culture-independent microbial investigation. In this review, we summarized the evidence for a bidirectional correlation between AF and the gut microbiome. Furthermore, we proposed the concept of "gut-immune-heart" axis and addressed the direct and indirect causal roots between the gut microbiome and AF. The intricate relationship was unveiled to generate innovative microbiota-based preventive and therapeutic interventions, which shed light on a definite direction for future experiments.
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