Spatiotemporal orchestration of macrophage activation trajectories by Vγ4 T cells during skin wound healing.

Dysregulated macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes underlies impaired cutaneous wound healing. This study reveals Vγ4+ γδ T cells spatiotemporally calibrate macrophage trajectories during skin repair via sophisticated interferon-γ (IFN-γ) conditioning across multiple interconnected tissues. Locally within wound beds, infiltrating Vγ4+ γδ T cells directly potentiate M1 activation and suppress M2 polarization thereby prolonging local inflammation. In draining lymph nodes, infiltrated Vγ4+ γδ T cells expand populations of IFN-γ-competent lymphocytes which disseminate systemically and infiltrate into wound tissues, further enforcing M1 macrophages programming. Moreover, Vγ4+γδ T cells flushed into bone marrow stimulate increased IFN-γ production, which elevates the output of pro-inflammatory Ly6C+monocytes. Mobilization of these monocytes continually replenishes the M1 macrophage pool in wounds, preventing phenotypic conversion to M2 activation. Thus, multi-axis coordination of macrophage activation trajectories by trafficking Vγ4+ γδ T cells provides a sophisticated immunological mechanism regulating inflammation timing and resolution during skin repair.

Melatonin mitigates manganese-induced neural damage via modulation of gut microbiota-metabolism in mice.

Manganese (Mn), a common environmental and occupational risk factor for Parkinson's disease (PD), can cause central nervous system damage and gastrointestinal dysfunction. The melatonin has been shown to effectively improve neural damage and intestinal microbiota disturbances in animal models. This research investigated the mechanism by which exogenous melatonin prevented Mn-induced neurogenesis impairment and neural damage. Here, we established subchronic Mn-exposed mice model and melatonin supplement tests to evaluate the role of melatonin in alleviating Mn-induced neurogenesis impairment. Mn induced neurogenesis impairment and microglia overactivation, behavioral dysfunction, gut microbiota dysbiosis and serum metabolic disorder in mice. All these events were reversed with the melatonin supplement. The behavioral tests revealed that melatonin group showed approximately 30 % restoration of motor activity. According to quantitative real time polymerase chain reaction (qPCR) results, melatonin group showed remarkable restoration of the expression of dopamine neurons and neurogenesis markers, approximately 46.4 % (TH), 68.4 % (DCX in hippocampus) and 48 % (DCX in striatum), respectively. Interestingly, melatonin increased neurogenesis probably via the gut microbiota and metabolism modulation. The correlation analysis of differentially expressed genes associated with hippocampal neurogenesis indicated that Firmicutes-lipid metabolism might mediate the critical repair role of melatonin in neurogenesis in Mn-exposed mice. In conclusion, exogenous melatonin supplementation can promote neurogenesis, and restore neuron loss and neural function in Mn-exposed mice, and the multi-omics results provide new research ideas for future mechanistic studies.

Network Pharmacology and Bioinformatics Analyses Identify the Core Genes and Pyroptosis-Related Mechanisms of Nardostachys Chinensis for Atrial Fibrillation.

BACKGROUND: Nardostachys chinensis is an herbal medicine widely used in the treatment of atrial fibrillation (AF), but the mechanism is unclear. OBJECTIVE: To explore the molecular mechanism of N. chinensis against AF. METHODS: The TCMSP was used to screen the active N. chinensis compounds and their targets. Differentially expressed genes (DEGs) for AF were identified using open-access databases. Using Venn diagrams, the cross-targets of N. chinensis, pyroptosis, and AF were obtained. The genes underwent molecular docking as well as gene set enrichment analysis (GSEA). A nomogram based on candidate genes was constructed and evaluated with the clinical impact curve. After that, the immune infiltration of the dataset was analyzed by single sample GSEA (ssGSEA). Finally, microRNAs (miRNAs) and transcription factors (TFs) were predicted based on candidate genes. RESULTS: Tumor necrosis factor (TNF) and caspase-8 (CASP8) were obtained as candidate genes by taking the intersection of DEGs, targets of N. chinensis, and pyroptosis-related genes. Tolllike receptor (TLR) and peroxisome proliferator-activated receptor (PPAR) signaling pathways were linked to candidate genes. Additionally, immune cell infiltration analysis revealed that CASP8 was associated with natural killer T cells, natural killer cells, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSC), macrophages, CD8 T cells, and CD4 T cells. Finally, miR-34a-5p and several TFs were found to regulate the expression of CASP8 and TNF. CONCLUSION: CASP8 and TNF are potential targets of N. chinensis intervention in pyroptosisrelated AF, and the TLR/NLRP3 signaling pathway may be associated with this process.

The value of preoperative neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and red blood cell distribution width in predicting positive surgical margin after laparoscopic radical prostatectomy.

BACKGROUND: Prostate cancer (PCa) is one of the most common malignant tumors in men, and laparoscopic radical prostatectomy (LRP) is commonly used to treat localized and advanced PCa. Positive surgical margin (PSM) is one of the most frequent problems faced by surgeons. AIMS: This study aimed to explore the value of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and red blood cell distribution width (RDW) in predicting PSM after LRP. METHODS AND RESULTS: Three hundred and twenty patients with PCa were admitted and underwent LRP in Beijing Chaoyang Hospital from January 2017 to June 2023. Patients were randomly divided into a training set (225 cases) and a validation set (95 cases) in a 7:3 ratio. NLR, PLR, and RDW were significantly higher in the PSM group than in the negative surgical margins (NSM) group. In addition, the NLR, PLR, and RDW values correlated with clinical T stage, Gleason score, and seminal vesicle invasion in the PSM group. In training set, ROC curve analysis revealed that the optimal cutoff values of NLR, PLR, and RDW for predicting postoperative PSM in PCa were 2.31, 115.40, and 12.85%, respectively. Multivariate Logistic regression analysis showed NLR and RDW were the clinical independent predictors. The area under the curve (AUC, 0.770, 95% CI 0.709-0.831) for postoperative PSM was the highest when a combination of the three parameters was used, with sensitivity and specificity of 62.5% and 85.2%, respectively. In validation set, the AUC values for NLR, PLR, RDW and the three markers combined were 0.708, 0.675, 0.723, and 0.780, respectively. Correlation analysis showed that in the PSM group, NLR was positively correlated with PLR and RDW, and PLR was positively correlated with RDW. By contrast, in the NSM group, a positive association was only found between NLR and PLR. CONCLUSIONS: Higher preoperative NLR, PLR, and RDW values were associated with postoperative PSM. Additionally, the three markers combined may be useful to predict PSM.

Single-cell transcriptomics analysis of zebrafish brain reveals adverse effects of manganese on neurogenesis.

Manganese (Mn) is considered as an important environmental risk factor for Parkinson's disease. Excessive exposure to Mn can damage various neural cells and affect the neurogenesis, resulting in neurological dysfunction. However, the specific mechanisms of Mn exposure affecting neurogenesis have not been well understood, including compositional changes and heterogeneity of various neural cells. Zebrafish have been successfully used as a neurotoxicity model due to its homology with mammals in several key regions of the brain, as well as its advantages such as small size. We performed single-cell RNA sequencing of zebrafish brains from normal and Mn-exposed groups. Our results suggested that low levels of Mn exposure activated neurogenesis in the zebrafish brain, including promoting the proliferation of neural progenitor cells and differentiation to newborn neurons and oligodendrocytes, while high levels of Mn exposure inhibited neurogenesis and neural function. Mn could affect neurogenesis through specific molecular pathways. In addition, Mn regulated intercellular communication and affected cellular communication in neural cells through specific signaling pathways. Taken together, our study elucidates the cellular composition of the zebrafish brain and adds to the understanding of the mechanisms involved in Mn-induced neurogenesis damage.

Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy.

Emerging evidence indicates that cancer cells can mimic characteristics of embryonic development, promoting their development and progression. Cancer cells share features with embryonic development, characterized by robust proliferation and differentiation regulated by signaling pathways such as Wnt, Notch, hedgehog, and Hippo signaling. In certain phase, these cells also mimic embryonic diapause and fertilized egg implantation to evade treatments or immune elimination and promote metastasis. Additionally, the upregulation of ATP-binding cassette (ABC) transporters, including multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and breast cancer-resistant protein (BCRP), in drug-resistant cancer cells, analogous to their role in placental development, may facilitate chemotherapy efflux, further resulting in treatment resistance. In this review, we concentrate on the underlying mechanisms that contribute to tumor development and progression from the perspective of embryonic development, encompassing the dysregulation of developmental signaling pathways, the emergence of dormant cancer cells, immune microenvironment remodeling, and the hyperactivation of ABC transporters. Furthermore, we synthesize and emphasize the connections between cancer hallmarks and embryonic development, offering novel insights for the development of innovative cancer treatment strategies.

Laboratory Evaluation of a Low-Damage Authigenic Mud Acid System for Bai-823 Well Block.

Aiming at the problem of single and poor adaptability of Bai-823 plugging removal system, an authigenic mud acid system using methyl formate, ammonium chloride, and ammonium fluoride as raw materials is proposed, which can adapt to the temperature of 60-80 °C of the target reservoir and sandstone lithology. The acid-generating capacity of the authigenic acid system at different temperatures was evaluated. The results showed that the H+ concentration remained at 3.35 mol/L after 180 min at 80 °C, which indicated that authigenic acid could generate acid continuously and thus be competent for acidizing and plugging removal of further wells. The corrosion rate of authigenic acid to N80 steel was further investigated. When 2 wt % SA1-3B corrosion inhibitor was used, the corrosion rate was only 0.15 g/(m2·h). At the same time, the corrosion capacities of authigenic acid to rock core and scale samples were studied, which were 19.38 and 93.81%, respectively, indicating that the authigenic acid system realized pipeline and reservoir friendliness when it was able to effectively remove plugging. Finally, a core displacement experiment was carried out to simulate reservoir acidizing for plugging removal. The results showed that the core permeability increased from 1.00 to 1.63 after acidizing modification with authigenic acid. All of the above studies show that a kind of authigenic mud acid has been successfully prepared, and a new idea for the authigenic acid system has been proposed.

The association of serum neurofilament light chains with early symptoms related to Parkinson's disease: A cross-sectional study.

Neurofilament light chains (NfL), released with neural axon injury, is considered as a potential biomarker for Parkinson's disease (PD). The relationship between NfL and PD has been studied mainly in diagnosed patients. Few large-scale studies analyze the association between NfL levels and multiple non-motor symptoms linked to early PD in the general population. Therefore, this study aims to determine the association of NfL with early symptoms of PD, and effectively respond to the development of early symptoms of PD. We examined the relationship between serum NfL and early non-motor symptoms of PD (smell dysfunction, sleep problems, cognitive function) and serum Klotho levels in the general population using data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES). The relationship between serum NfL and early symptoms of PD in 1125 participants was analyzed by multiple linear regression and logistic regression models. The results showed a significant association between serum NfL and early symptoms of PD. There was a significant positive correlation between NfL and smell dysfunction, short sleep and long sleep. There was a significant negative correlation between NfL and Klotho levels and cognitive function test results. Further, we observed gender and age differences in the association of NfL with early symptoms of PD. Our study demonstrate that elevated serum NfL levels are positively associated with an increased risk of early PD-related symptoms, suggesting that serum NfL can be a promising biomarker for early PD.

Exploring Shared Biomarkers of Myocardial Infarction and Alzheimer's Disease via Single-Cell/Nucleus Sequencing and Bioinformatics Analysis.

BACKGROUND: Patients are at increased risk of dementia, including Alzheimer's disease (AD), after myocardial infarction (MI), but the biological link between MI and AD is unclear. OBJECTIVE: To understand the association between the pathogenesis of MI and AD and identify common biomarkers of both diseases. METHODS: Using public databases, we identified common biomarkers of MI and AD. Least absolute shrinkage and selection operator (LASSO) regression and protein-protein interaction (PPI) network were performed to further screen hub biomarkers. Functional enrichment analyses were performed on the hub biomarkers. Single-cell/nucleus analysis was utilized to further analyze the hub biomarkers at the cellular level in carotid atherosclerosis and AD datasets. Motif enrichment analysis was used to screen key transcription factors. RESULTS: 26 common differentially expressed genes were screened between MI and AD. Function enrichment analyses showed that these differentially expressed genes were mainly associated with inflammatory pathways. A key gene, Regulator of G-protein Signaling 1 (RGS1), was obtained by LASSO regression and PPI network. RGS1 was confirmed to mainly express in macrophages and microglia according to single-cell/nucleus analysis. The difference in expression of RGS1 in macrophages and microglia between disease groups and controls was statistically significant (p < 0.0001). The expression of RGS1 in the disease groups was upregulated with the differentiation of macrophages and microglia. RelA was a key transcription factor regulating RGS1. CONCLUSION: Macrophages and microglia are involved in the inflammatory response of MI and AD. RGS1 may be a key biomarker in this process.

Tunable Sulfated Alginate-based Hydrogel Platform with enhanced anti-inflammatory and antioxidant capacity for promoting burn wound repair.

Amidst progressive advancements in tissue engineering, there has been a significant enhancement in the efficacy of anti-inflammatory hydrogel dressings, addressing a myriad of clinical challenges on wound healing. A frequent complication during the initial stages of deep second-degree burn wound healing is the onset of an inflammatory storm, typically occurring without effective intervention. This event disrupts normal biological healing sequences, leading to undesirable regression. In response, we have customized a tunable, multidimensional anti-inflammatory hydrogel platform based on sulfated alginates (Algs), loaded with Prussian blue (PB) nanozymes. This platform competently eliminates surplus reactive oxygen species (ROS) present in the wound bed. Algs, functioning as a mimic of sulfated glycosaminoglycans (including heparin, heparan sulfate, and chondroitin sulfate) in the extracellular matrices (ECM), demonstrate a high affinity towards inflammatory chemokines such as interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1). This affinity effectively impedes the infiltration of inflammatory cells into the wound. Concurrently, Algs markedly modulate the macrophage phenotype transition from M1 to M2. Ultimately, our potent anti-inflammatory hydrogels, which strategically target inflammatory chemokines, M1 macrophages, and ROS, successfully attenuate dysregulated hyperinflammation in wound sites. Precise immunomodulation administered to deep second-degree burn wounds in mice has demonstrated promotion of neovascular maturation, granulation tissue formation, collagen deposition, and wound closure. Our biomimetic hydrogels, therefore, represent a significant expansion in the repertoire of anti-inflammatory strategies available for clinical practice.

The mutual regulation between γδ T cells and macrophages during wound healing.

Macrophages are the main cells shaping the local microenvironment during wound healing. As the prime T cells in the skin, γδ T cells participate in regulating microenvironment construction, determining their mutual regulation helps to understand the mechanisms of wound healing, and explore innovative therapeutic options for wound repair. This review introduced their respective role in wound healing firstly, and then summarized the regulatory effect of γδ T cells on macrophages, including chemotaxis, polarization, apoptosis and pyroptosis. Lastly, the retrograde regulation on γδ T cells by macrophages was also discussed. The main purpose is to excavate novel interventions for treating wound, and provide new thought for further research.

Drug Repurposing-Based Brain-Targeting Self-Assembly Nanoplatform Using Enhanced Ferroptosis against Glioblastoma.

Glioblastoma (GBM), the most aggressive and lethal form of malignant brain tumor, is a therapeutic challenge due to the drug filtration capabilities of the blood-brain barrier (BBB). Interestingly, glioblastoma tends to resist apoptosis during chemotherapy, but is susceptible to ferroptosis. Developing therapies that can effectively target glioblastoma by crossing the BBB and evoke ferroptosis are, therefore, crucial for improving treatment outcomes. Herein, a versatile biomimetic nanoplatform, L-D-I/NPs, is designed that self-assembled by loading the antimalarial drug dihydroartemisinin (DHA) and the photosensitizer indocyanine green (ICG) onto lactoferrin (LF). This nanoplatform can selectively target glioblastoma by binding to low-density lipoprotein receptor-related protein-1 (LRP1) and crossing the BBB, thus inducing glioblastoma cell ferroptosis by boosting intracellular reactive oxygen species (ROS) accumulation and iron overload. In addition, L-D-I/NPs have demonstrated the ability to effectively suppress the progression of orthotopic glioblastoma and significantly prolong survival in a mouse glioblastoma model. This nanoplatform has facilitated the application of non-chemotherapeutic drugs in tumor treatment with minimal adverse effects, paving the way for highly efficient ferroptosis-based therapies for glioblastoma.

Mitochondrial dysfunction and mitophagy: crucial players in burn trauma and wound healing.

Burn injuries are a significant cause of death worldwide, leading to systemic inflammation, multiple organ failure and sepsis. The progression of burn injury is explicitly correlated with mitochondrial homeostasis, which is disrupted by the hyperinflammation induced by burn injury, leading to mitochondrial dysfunction and cell death. Mitophagy plays a crucial role in maintaining cellular homeostasis by selectively removing damaged mitochondria. A growing body of evidence from various disease models suggest that pharmacological interventions targeting mitophagy could be a promising therapeutic strategy. Recent studies have shown that mitophagy plays a crucial role in wound healing and burn injury. Furthermore, chemicals targeting mitophagy have also been shown to improve wound recovery, highlighting the potential for novel therapeutic strategies based on an in-depth exploration of the molecular mechanisms regulating mitophagy and its association with skin wound healing.

Exposure to volatile organic compounds is a risk factor for diabetes: A cross-sectional study.

Currently, more studies showed that environmental chemicals were associated with the development of diabetes. However, the effect of volatile organic compounds (VOCs) on diabetes remained uncertain and needed to be studied. This cross-sectional study examined whether exposure to low levels of VOCs was associated with diabetes, insulin resistance (TyG index) and glucose-related indicators (FPG,HbA1c, insulin) in the general population by using the NHANES dataset (2013-2014 and 2015-2016). We analyzed the association between urinary VOC metabolism (mVOCs) and these indicators in 1409 adults by multiple linear regression models or logistic regression models, further Bayesian kernel machine regression (BKMR) models were performed for mixture exposure analysis. The results showed positive associations between multiple mVOCs and diabetes, TyG index, FPG, HbA1c and insulin, respectively. Among them, HPMMA concentration in urine was significantly positively correlated with diabetes and related indicators (TyG index, FPG and HbA1c), and the concentration of CEMA was significantly positively correlated with insulin. The positive association of mVOCs with diabetes and its related indicators was more significant in the female group and in the 40-59 years group. Thus, our study suggested that exposure to VOCs affected insulin resistance and glucose homeostasis, further affecting diabetes levels, which had important public health implications.

Development and external validation of a novel nomogram to predict intravesical recurrence after radical nephroureterectomy: a multicenter study.

OBJECTIVE: This study aimed to establish and validate nomograms to predict the probability of intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for upper urinary tract epithelial carcinoma (UTUC). METHODS: Clinical data of 528 patients with UTUC after RNU were collected from two medical centers between 2009 and 2020. We used the least absolute shrinkage and selection operator (LASSO) regression to select variables for multivariable Cox regression analysis in the training cohort and included independent risk factors into nomogram models predicting IVR-free survival (IVRFS). Another center was applied as the external cohort to validate the predictive accuracy and discriminative ability of the nomogram by performing area under the receiver operating curve (AUC), consistency index (C-index), and calibration curve. RESULTS: History of bladder cancer, tumor size, preoperative urine cytology, postoperative instillation, Ki-67, and platelet-to-lymphocyte ratio (PLR) were identified as independent risk factors for IVR. The prognosis model including these predictors demonstrated excellent discriminatory performance in both the training cohort (C-index, 0.814) and external validation cohort (C-index, 0.748). The calibration plots of the nomogram revealed good consistency in both cohorts. Finally, patients could be classified into two risk groups based on scores obtained from the nomogram, with significant differences in IVRFS. CONCLUSION: Our study provided a reliable nomogram for predicting the probability of IVR in patients with UTUC after RNU. Risk stratification based on this model may assist urologists make optimal clinical decisions on the management of UTUC.

Do patients with metastatic renal cell carcinoma obtain survival benefits from cytoreductive nephrectomy? A population-based study.

PURPOSE: This study aimed to explore the value of cytoreductive nephrectomy (CN) and develop nomograms to predict the prognosis of metastatic renal cell carcinoma (mRCC) patients with receiving radiology therapy or/and chemotherapy (RT/&CT). METHODS: Clinical data of patients with mRCC between 2010 and 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Prognostic nomograms were constructed to predict the overall survival (OS) and cancer-specific survival (CSS) probability for 1-, 3-, and 5- years in patients with mRCC. A series of validation methods were used to validate the accuracy and reliability of the model, including area under the receiver operating curve (AUC), consistency index (C-index), calibration curve, and decision curve analysis (DCA). RESULTS: 1394 patients were enrolled in this study. All patients were randomly divided into the training cohort (n = 976) and the validation cohort (n = 418). In the training cohort, multivariate Cox regression analysis suggested that pathology grade, histology type, T stage, N stage, surgery, and distant metastasis were independent risk factors for OS and CSS. The AUC and C-index were both over 0.65 in both cohorts, indicating that the nomograms for OS and CSS had satisfactory discriminative power. The calibration curves revealed that the predictive nomograms had a good consistency between the observed and the predicted survival. CONCLUSION: This study provided evidence that mRCC patients underwent RT/&CT could gain survival benefits from CN. The prognostic nomogram constructed in our study is reliable and practical, may help guide clinical strategies in the treatment of mRCC.

Protein persulfidation: Rewiring the hydrogen sulfide signaling in cell stress response.

The past few decades have witnessed significant progress in the discovery of hydrogen sulfide (H2S) as a ubiquitous gaseous signaling molecule in mammalian physiology, akin to nitric oxide and carbon monoxide. As the third gasotransmitter, H2S is now known to exert a wide range of physiological and cytoprotective functions in the biological systems. However, endogenous H2S concentrations are usually low, and its potential biologic mechanisms responsible have not yet been fully clarified. Recently, a growing body of evidence has demonstrated that protein persulfidation, a posttranslational modification of cysteine residues (RSH) to persulfides (RSSH) elicited by H2S, is a fundamental mechanism of H2S-mediated signaling pathways. Persulfidation, as a biological switch for protein function, plays an important role in the maintenance of cell homeostasis in response to various internal and external stress stimuli and is also implicated in numerous diseases, such as cardiovascular and neurodegenerative diseases and cancer. In this review, the biological significance of protein persulfidation by H2S in cell stress response is reviewed providing a framework for understanding the multifaceted roles of H2S. A mechanism-guided perspective can help open novel avenues for the exploitation of therapeutics based on H2S-induced persulfidation in the context of diseases.

Epigenetic regulation of macrophage polarization in wound healing.

The immune microenvironment plays a critical role in regulating skin wound healing. Macrophages, the main component of infiltrating inflammatory cells, play a pivotal role in shaping the immune microenvironment in the process of skin wound healing. Macrophages comprise the classic proinflammatory M1 subtype and anti-inflammatory M2 population. In the early inflammatory phase of skin wound closure, M1-like macrophages initiate and amplify the local inflammatory response to disinfect the injured tissue. In the late tissue-repairing phase, M2 macrophages are predominant in wound tissue and limit local inflammation to promote tissue repair. The biological function of macrophages is tightly linked with epigenomic organization. Transcription factors are essential for macrophage polarization. Epigenetic modification of transcription factors determines the heterogeneity of macrophages. In contrast, transcription factors also regulate the expression of epigenetic enzymes. Both transcription factors and epigenetic enzymes form a complex network that regulates the plasticity of macrophages. Here, we describe the latest knowledge concerning the potential epigenetic mechanisms that precisely regulate the biological function of macrophages and their effects on skin wound healing.

EVA1A regulates hematopoietic stem cell regeneration via ER-mitochondria mediated apoptosis.

Excessive protein synthesis upon enhanced cell proliferation frequently results in an increase of unfolded or misfolded proteins. During hematopoietic regeneration, to replenish the hematopoietic system, hematopoietic stem cells (HSCs) are activated and undergo a rapid proliferation. But how the activated HSCs respond to the proliferation pressure is still ambiguous; The proper control of the functional reservoir in the activated HSCs remains poorly understood. Here, we show a significant upregulation of EVA1A protein associated with the increase of ER stress during hematopoietic regeneration. Deletion of Eva1a significantly enhances the regeneration capacity of HSCs by inhibiting the ER stress-induced apoptosis. Mechanistically, the expression of EVA1A protein was upregulated by CHOP, and thereby promoted the ER-mitochondria interlinking via MCL1, which resulted in mitochondria-mediated apoptosis. These findings reveal a pathway for ER stress responses of HSCs by the EVA1A mediated apoptosis, which play an important role in HSCs regeneration.

Protein degradation: expanding the toolbox to restrain cancer drug resistance.

Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain drug resistance has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib and proteolysis-targeting chimeric have been developed. Compared with intervention at the transcriptional level, targeting the degradation process seems to be a more rapid and direct strategy. Proteasomal proteolysis and lysosomal proteolysis are the most critical quality control systems responsible for the degradation of proteins or organelles. Although proteasomal and lysosomal inhibitors (e.g., bortezomib and chloroquine) have achieved certain improvements in some clinical application scenarios, their routine application in practice is still a long way off, which is due to the lack of precise targeting capabilities and inevitable side effects. In-depth studies on the regulatory mechanism of critical protein degradation regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), and chaperones, are expected to provide precise clues for developing targeting strategies and reducing side effects. Here, we discuss the underlying mechanisms of protein degradation in regulating drug efflux, drug metabolism, DNA repair, drug target alteration, downstream bypass signaling, sustaining of stemness, and tumor microenvironment remodeling to delineate the functional roles of protein degradation in drug resistance. We also highlight specific E3 ligases, DUBs, and chaperones, discussing possible strategies modulating protein degradation to target cancer drug resistance. A systematic summary of the molecular basis by which protein degradation regulates tumor drug resistance will help facilitate the development of appropriate clinical strategies.