The U-Box E3 Ubiquitin Ligase PUB35 Negatively Regulates ABA Signaling through AFP1-mediated Degradation of ABI5.

Abscisic acid (ABA) signaling is crucial for plant responses to various abiotic stresses. The Arabidopsis (Arabidopsis thaliana) transcription factor ABA INSENSITIVE 5 (ABI5) is a central regulator of ABA signaling. ABI5 BINDING PROTEIN 1 (AFP1) interacts with ABI5 and facilitates its 26S-proteasome-mediated degradation, although the detailed mechanism has remained unclear. Here, we report that an ABA-responsive U-box E3 ubiquitin ligase, PLANT U-BOX 35 (PUB35), physically interacts with AFP1 and ABI5. PUB35 directly ubiquitinated ABI5 in a bacterially reconstituted ubiquitination system and promoted ABI5 protein degradation in vivo. ABI5 degradation was enhanced by AFP1 in response to ABA treatment. Phosphorylation of the T201 and T206 residues in ABI5 disrupted the ABI5-AFP1 interaction and affected the ABI5-PUB35 interaction and PUB35-mediated degradation of ABI5 in vivo. Genetic analysis of seed germination and seedling growth showed that pub35 mutants were hypersensitive to ABA as well as to salinity and osmotic stresses, whereas PUB35 overexpression lines were hyposensitive. Moreover, abi5 was epistatic to pub35, whereas the pub35-2 afp1-1 double mutant showed a similar ABA response to the two single mutants. Together, our results reveal a PUB35-AFP1 module involved in fine-tuning ABA signaling through ubiquitination and 26S-proteasome-mediated degradation of ABI5 during seed germination and seedling growth.

CCL2-CCR2 signaling axis in obesity and metabolic diseases.

Obesity and metabolic diseases, such as insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular ailments, represent formidable global health challenges, bearing considerable implications for both morbidity and mortality rates. It has become increasingly evident that chronic, low-grade inflammation plays a pivotal role in the genesis and advancement of these conditions. The involvement of C-C chemokine ligand 2 (CCL2) and its corresponding receptor, C-C chemokine receptor 2 (CCR2), has been extensively documented in numerous inflammatory maladies. Recent evidence indicates that the CCL2/CCR2 pathway extends beyond immune cell recruitment and inflammation, exerting a notable influence on the genesis and progression of metabolic syndrome. The present review seeks to furnish a comprehensive exposition of the CCL2-CCR2 signaling axis within the context of obesity and metabolic disorders, elucidating its molecular mechanisms, functional roles, and therapeutic implications.

Role of mitochondria in doxorubicin-mediated cardiotoxicity: from molecular mechanisms to therapeutic strategies.

This comprehensive review delves into the pivotal role of mitochondria in doxorubicin-induced cardiotoxicity, a significant complication limiting the clinical use of this potent anthracycline chemotherapeutic agent. Doxorubicin, while effective against various malignancies, is associated with dose-dependent cardiotoxicity, potentially leading to irreversible cardiac damage. The review meticulously dissects the molecular mechanisms underpinning this cardiotoxicity, particularly focusing on mitochondrial dysfunction, a central player in this adverse effect. Central to the discussion is the concept of mitochondrial quality control (MQC), including mitochondrial dynamics (fusion/fission balance) and mitophagy. The review presents evidence linking aberrations in these processes to cardiotoxicity in doxorubicin-treated patients. It elucidates how doxorubicin disrupts mitochondrial dynamics, leading to an imbalance between mitochondrial fission and fusion, and impairs mitophagy, culminating in the accumulation of dysfunctional mitochondria and subsequent cardiac cell damage. Furthermore, the review explores emerging therapeutic strategies targeting mitochondrial dysfunction. It highlights the potential of modulating mitochondrial dynamics and enhancing mitophagy to mitigate doxorubicin-induced cardiac damage. These strategies include pharmacological interventions with mitochondrial fission inhibitors, fusion promoters, and agents that modulate mitophagy. The review underscores the promising results from preclinical studies while advocating for more extensive clinical trials to validate these approaches in human patients. In conclusion, this review offers valuable insights into the intricate relationship between mitochondrial dysfunction and doxorubicin-mediated cardiotoxicity. It underscores the need for continued research into targeted mitochondrial therapies as a means to improve the cardiac safety profile of doxorubicin, thereby enhancing the overall treatment outcomes for cancer patients.

Pyruvate kinase M2 sustains cardiac mitochondrial integrity in septic cardiomyopathy by regulating PHB2-dependent mitochondrial biogenesis.

Previous studies have highlighted the protective effects of pyruvate kinase M2 (PKM2) overexpression in septic cardiomyopathy. In our study, we utilized cardiomyocyte-specific PKM2 knockout mice to further investigate the role of PKM2 in attenuating LPS-induced myocardial dysfunction, focusing on mitochondrial biogenesis and prohibitin 2 (PHB2). Our findings confirmed that the deletion of PKM2 in cardiomyocytes significantly exacerbated LPS-induced myocardial dysfunction, as evidenced by impaired contractile function and relaxation. Additionally, the deletion of PKM2 intensified LPS-induced myocardial inflammation. At the molecular level, LPS triggered mitochondrial dysfunction, characterized by reduced ATP production, compromised mitochondrial respiratory complex I/III activities, and increased ROS production. Intriguingly, the absence of PKM2 further worsened LPS-induced mitochondrial damage. Our molecular investigations revealed that LPS disrupted mitochondrial biogenesis in cardiomyocytes, a disruption that was exacerbated by the absence of PKM2. Given that PHB2 is known as a downstream effector of PKM2, we employed PHB2 adenovirus to restore PHB2 levels. The overexpression of PHB2 normalized mitochondrial biogenesis, restored mitochondrial integrity, and promoted mitochondrial function. Overall, our results underscore the critical role of PKM2 in regulating the progression of septic cardiomyopathy. PKM2 deficiency impeded mitochondrial biogenesis, leading to compromised mitochondrial integrity, increased myocardial inflammation, and impaired cardiac function. The overexpression of PHB2 mitigated the deleterious effects of PKM2 deletion. This discovery offers a novel insight into the molecular mechanisms underlying septic cardiomyopathy and suggests potential therapeutic targets for intervention.

Dual H2 O2 -Amplified Nanofactory for Simultaneous Self-Enhanced NIR-II Fluorescence Activation Imaging and Synergistic Tumor Therapy.

Activatable fluorescence imaging in the second near-infrared window (NIR-II FL, 1000-1700 nm) is of great significance for accurate tumor diagnosis and targeting therapy. However, the clinical translation of most stimulus-activated nanoprobes is severely restricted by insufficient tumor response and out-of-synchronization theranostic process. Herein, an intelligent nanofactory AUC-GOx/Cel that possesses the "external supply, internal promotion" dual H2 O2 -amplification strategy for homologous activated tumor theranostic is designed. This nanofactory is constructed via a two-step biomineralization method using Au-doped Ag2 S as a carrier for glucose oxidase (GOx) and celastrol, followed by the growing of CuS to "turn off" the NIR-II FL signal. In the overexpressed H2 O2 tumor-microenvironment, the CuS featuring a responsive-degradability behavior can effectively release Cu ions, resulting in the "ON" state of NIR-II FL and Fenton-like activity. The exposed GOx can realize the intratumoral H2 O2 supply (external supply) via the effective conversion of glucose, and mediating tumor-starvation therapy; the interaction of celastrol and mitochondria can offer a substantial increase in the endogenous H2 O2 level (internal promotion), thereby significantly promoting the chemodynamic therapy (CDT) efficacy. Meanwhile, the dual H2 O2 -enhancement performance will in turn accelerate the degradation of AUC-GOx/Cel, and achieve a positive feedback mechanism for self-reinforcing CDT.

An N-glycoproteomic site-mapping analysis reveals glycoprotein alterations in esophageal squamous cell carcinoma.

BACKGROUND: Aberrant glycosylation has been recognized as a hallmark of cancer and N-glycosylation is one of the main types of glycosylation in eukaryotes. Although N-glycoproteomics has made contributions to the discovery of biomarkers in a variety of cancers, less is known about the abnormal glycosylation signatures in esophageal squamous cell carcinoma (ESCC). METHODS: In this study, we reported the proteomics and N-glycoproteomic site-mapping analysis of eight pairs of ESCC tissues and adjacent normal tissues. With zic-HILIC enrichment, TMT-based isobaric labeling, LC-MS/MS analysis, differentially expressed N-glycosylation was quantitatively characterized. Lectin affinity enrichment combined with western blot was used to validate the potential biomarkers in ESCC. RESULTS: A series of differentially expressed glycoproteins (e.g., LAMP2, PLOD2) and enriched signaling pathways (e.g., metabolism-related pathway, ECM-receptor interaction, focal adhesion) were identified. Besides that, seven significantly enriched motifs were found from the identified N-glycosylation sites. Three clusters were identified after conducting the dynamic profiling analysis of glycoprotein change during lymph node metastasis progression. Further validation found that the elevated fucosylation level of ITGB1, CD276 contributed to the occurrence and development of ESCC, which might be the potential biomarkers in ESCC. CONCLUSION: In summary, we characterized the N-glycosylation and N-glycoprotein alterations associated with ESCC. The typical changes in glycoprotein expression and glycosylation occupancy identified in our study will not only be used as ESCC biomarkers but also improve the understanding of ESCC biology.

Logistic regression models of cytokines in differentiating vitreoretinal lymphoma from uveitis.

BACKGROUND: Vitreoretinal lymphoma (VRL) can commonly masquerade as chronic idiopathic uveitis due to its nonspecific clinical presentation. Thus, its early diagnosis is difficult. In this study, new logistic regression models were used to classify VRL and uveitis. Additionally, the diagnostic performance of interleukin (IL)-10, the IL-10/IL-6, and the Interleukin Score for IntraOcular Lymphoma Diagnosis (ISOLD) are evaluated. METHODS: Sixty-nine aqueous humors (AH) (46 VRL, 23 uveitis) and 65 vitreous humors (VH) (49 VRL, 16 uveitis) were collected from a single-center retrospective cohort. Logistic regression models were conducted based on IL-6 and IL-10. The cut-off values, area under the receiver operating characteristic curve (ROC) curve (AUC), sensitivity and specificity of IL-10, the IL-10/IL-6, the ISOLD, and the models were calculated from the ROC. Furthermore, Spearman's rank correlation analysis was performed to determine cytokine levels in VH and AH. RESULTS: We redefined the cut-off values of IL-10, the IL-10/IL-6, the ISOLD, and the logistic regression models. In AH, the AUC values of IL-10, ISOLD, IL10/IL6, and the model were 0.91, 0.953, 0.952, and 0.967. In VH, they were 0.93, 0.95, 0.954, and 0.954, respectively. IL-6 (r = 0.7844) and IL-10 (r = 0.8506) in AH and VH showed a strong correlation. CONCLUSIONS: IL-6 and IL-10 levels were introduced into new logistic regression models. The diagnostic efficacy of the models improved compared to the indicators mentioned above among Chinese patients. Additionally, the models could predict the probability of VRL more accurately. A strong correlation of cytokine levels showed the great potential of AH as prioritized auxiliary diagnostic for VRL.

All-in-One Zeolite-Carbon-Based Nanotheranostics with Adjustable NIR-II Window Photoacoustic/Fluorescence Imaging Performance for Precise NIR-II Photothermal-Synergized Catalytic Antitumor Therapy.

In the second near-infrared (NIR-II) biowindow, multimodal optical imaging-guided precise antitumor therapy is a novel strategy for high-efficiency tumor theranostics, however, the all-in-one dual NIR-II photoacoustic (NIR-II PA) and NIR-II fluorescence (NIR-II FL) nanoprobes have been rarely reported mainly due to the short of a simple and universal design approach. Herein, a NIR-II PA/NIR-II FL imaging-adjustable nanozyme (HSC-2) is designed and developed to guide precise photothermal-catalytic synergistic therapy. Based on the ionic liquids adsorption capacity, the electronic structure of zeolite nano-Beta (three dimensional 12-ring pore system and large surface area) can be turned from the indirect band gap to direct band gap via doping carbon in the framework, resulting in outstanding NIR-II FL emission characteristics. As the silicon etching reaction proceeds, HSC-2 shows superior dual-modal NIR-II PA/NIR-II FL imaging performance facilitated by the optimal silicon-to-carbon ratio, simultaneously ensuring efficient tumor photothermal therapy (PTT) in the NIR-II window. Impressively, the peroxidase-mimic activity of HSC-2 in the tumor microenvironment could be further remarkably enhanced by its photothermal effect, leading to excellent synergistic PTT/catalytic therapy. Moreover, the HSC-2 exhibits dual-enzyme activity, and its catalase-like property could effectively eliminate excessive ROS for protection of the normal cells.

[Role of NLRP1 and NLRP3 inflammasome signaling pathways in the immune mechanism of inflammatory bowel disease in children].

OBJECTIVE: To study the role of nucleotide-binding oligomerization domain-like receptor proteins 1 and 3 (NLRP1 and NLRP3) inflammasome signaling pathways in the immune mechanism of inflammatory bowel disease (IBD) in children. METHODS: A total of 126 children with IBD were enrolled as the study group, including 32 children with Crohn's disease (CD) and 94 children with ulcerative colitis (UC). A total of 120 children who underwent colectomy were enrolled as the control group. The mRNA expression of NLRP1, NLRP3, Caspase-1, and interleukin-1ß (IL-1ß) was compared between groups. RESULTS: The study group had significantly higher mRNA expression of NLRP1, NLRP3, Caspase-1, and IL-1ß than the control group, and their mRNA expression levels tended to increase with the severity of CD or UC (P<0.05). In the children with UC or CD, the mRNA expression levels of NLRP1, NLRP3, Caspase-1, and IL-1ß were positively correlated with serum IgM and IgG levels (P<0.05), and the mRNA expression levels of NLRP1 and NLRP3 were positively correlated with those of Caspase-1 and IL-1ß (P<0.05). CONCLUSIONS: The NLRP1 and NLRP3 inflammasome signaling pathways may regulate the immune mechanism of IBD in children by upregulating the expression of Caspase-1 and IL-1ß.

Comprehensive analysis of aberrantly expressed profiles of messenger RNA in alcoholic liver disease.

BACKGROUND: Alcoholic liver disease (ALD) is one of the major cause of morbidity and mortality of clinical liver disease worldwide. Until today, although many general therapies are carried out and several molecular targets have been proposed to act as the potential therapeutic targets, more accurate molecular targets and more effective therapeutic methods remain needed. MATERIAL AND METHODS: In the study, we analyze the differential expression genes (DEGs) between the patients with ALD and healthy controls. Gene Ontology enrichment and KEGG signaling pathway analysis are performed to identify the function of DEGs. Some significant molecules are proposed to act as the potential therapeutic targets for ALD. RNA data of 15 ALD tissues and 7 normal tissues for RNA expression analysis were obtained. DEGs in ALD samples compared with normal tissues identified through the limma R package and subjected to network analysis. RESULTS: As a result, we obtained a total of 274 DEGs that mainly involved in biological processes related to the angiogenesis, stress reaction, synthesis, and metabolism of organic acids. Network analysis obtained several genes with high network degree and fold change. Some significant molecules are proposed to act as the potential therapeutic targets for ALD. CONCLUSIONS: Our research identified some new progression-related genes of alcohol liver diseases, which could be regarded as the new targets for the early diagnosis and therapeutic management in ALD.

Digital droplet polymerase chain reaction analysis of common viruses in the aqueous humour of patients with Posner-Schlossman syndrome in Chinese population.

BACKGROUND: To compare the detection results consistency of quantitative polymerase chain reaction (qPCR) and digital droplet polymerase chain reaction (ddPCR), and determine the value of ddPCR for viral detection in the aqueous humour. METHODS: A total of 130 aqueous humour samples were collected, including 60 patients with Posner-Schlossman syndrome (PSS) in case group and 70 elderly patients with senile cataract in control group. The target nucleic acid fragments of human cytomegalovirus (HCMV), herpes simplex virus, Epstein-Barr virus and varicella zoster virus in aqueous humour were analysed by qPCR and ddPCR, respectively, for the diagnosis and curative effect monitoring of pathogen-induced PSS. Samples with inconsistent results were verified by next-generation sequencing. RESULTS: There were 27 and 20 HCMV-positive cases detected in the case group by ddPCR and qPCR, respectively. ddPCR increased the sensitivity for the HCMV virus detection from 400 to 100 copies/mL. No other pathogens were found in this study. The results of ddPCR were consistent with that of next generation sequencing. The mean (SD) of Lg (HCMV copies/mL) detected by ddPCR and qPCR were 1.66 (1.92) and 1.10 (1.61), respectively (P < 0.001). Compared with qPCR, results of ddPCR showed better consistency with validity of clinical treatment. All patients with ddPCR-positive results had good validity on antiviral therapy, exhibiting anterior chamber inflammation remission, resolution of corneal oedema and good IOP control within 1 month. CONCLUSIONS: HCMV was the leading cause of pathogen-induced PSS in the Chinese population. ddPCR was a promising tool for early detection, accurate diagnosis and therapeutic validity monitoring of pathogen-induced PSS. The high sensitivity of ddPCR could avoid repeated anterior chamber tap.

Quantitative proteomic analysis of exosome protein content changes induced by hepatitis B virus in Huh-7 cells using SILAC labeling and LC-MS/MS.

Hepatitis B virus (HBV) infection could cause hepatitis, liver cirrhosis, and hepatocellular carcinoma. HBV-mediated pathogenesis is only partially understood, but X protein (HBx) reportedly possesses oncogenic potential. Exosomes are small membrane vesicles with diverse functions released by various cells including hepatocytes, and HBV harnesses cellular exosome biogenesis and export machineries for virion morphogenesis and secretion. Therefore, HBV infection might cause changes in exosome contents with functional implications for both virus and host. In this work, exosome protein content changes induced by HBV and HBx were quantitatively analyzed by SILAC/LC-MS/MS. Exosomes prepared from SILAC-labeled hepatoma cell line Huh-7 transfected with HBx, wildtype, or HBx-null HBV replicon plasmids were analyzed by LC-MS/MS. Systematic analyses of MS data and confirmatory immunoblotting showed that HBx overexpression and HBV, with or without HBx, replication in Huh-7 cells indeed caused marked and specific changes in exosome protein contents. Furthermore, specific changes in protein contents were also detected in exosomes purified from HBV-infected patients' sera compared with control sera negative for HBV markers. These results illustrate a new aspect of interactions between HBV and the host and provide the foundation for future research into roles played by exosomes in HBV infection and pathogenesis.

[Chemical constituents from Callicarpa nudiflora and their cytotoxic activities].

The chemical consitituents from cytotoxic fraction of the Callicarpa nudiflora extract were isolated and purified by a combination of HP-20 macroporous resin, silica gel and Sephadex LH-20 column chromatographies. The structures were elucidated on the basis of the spectroscopic data and comparison of their spectroscopic data with reported data. The cytotoxicity was evaluated by the MTT assay. The 50% and 70% EtOH elutions of EtOH-extract showed significant cytotoxic activities, leading to the isolation of twelve compounds, which were identified as luteoloside(1), lutedin-4'-O-ß-D-glucoside(2), 6-hydroxyluteolin-7-O-ß-glucoside(3), lutedin-7-O-neohesperidoside(4), rhoifolin (5), luteolin-7, 4'-di-O-glucoside (6), forsythoside B (7), acteoside (8), alyssonoside (9), catalpol(10), nudifloside(11), and leonuride(12). Compounds 3-6, 10 and 12 were isolated from this genus for the first time, and compound 9 was isolated from this plant for the first time. The cytotoxicity assay demonstrated that flavonoids 1-6, in various concentrations, showed monolithic proliferation inhibitory activities against Hela, A549 and MCF-7 cell lines. Compounds 3, 5 and iridoid glycoside 11 possessed higher cytotoxicacivities. In short, flavonoids are the main components of cytotoxic extract from C. nudiflora, while phenylethanoid glycosides are the predominant ingredient but inactive to cancer cell lines. In addition, the minor iridoid glycoside expressed weak cytotoxic activity.

Role of mitochondria in doxorubicin-mediated cardiotoxicity: From molecular mechanisms to therapeutic strategies.

This comprehensive review delves into the pivotal role of mitochondria in doxorubicin-induced cardiotoxicity, a significant complication limiting the clinical use of this potent anthracycline chemotherapeutic agent. Doxorubicin, while effective against various malignancies, is associated with dose-dependent cardiotoxicity, potentially leading to irreversible cardiac damage. The review meticulously dissects the molecular mechanisms underpinning this cardiotoxicity, particularly focusing on mitochondrial dysfunction, a central player in this adverse effect. Central to the discussion is the concept of mitochondrial quality control, including mitochondrial dynamics (fusion/fission balance) and mitophagy. The review presents evidence linking aberrations in these processes to cardiotoxicity in doxorubicin-treated patients. It elucidates how doxorubicin disrupts mitochondrial dynamics, leading to an imbalance between mitochondrial fission and fusion, and impairs mitophagy, culminating in the accumulation of dysfunctional mitochondria and subsequent cardiac cell damage. Furthermore, the review explores emerging therapeutic strategies targeting mitochondrial dysfunction. It highlights the potential of modulating mitochondrial dynamics and enhancing mitophagy to mitigate doxorubicin-induced cardiac damage. These strategies include pharmacological interventions with mitochondrial fission inhibitors, fusion promoters, and agents that modulate mitophagy. The review underscores the promising results from preclinical studies while advocating for more extensive clinical trials to validate these approaches in human patients. In conclusion, this review offers valuable insights into the intricate relationship between mitochondrial dysfunction and doxorubicin-mediated cardiotoxicity. It underscores the need for continued research into targeted mitochondrial therapies as a means to improve the cardiac safety profile of doxorubicin, thereby enhancing the overall treatment outcomes for cancer patients.

MBIP promotes ESCC metastasis by activating MAPK pathway.

MBIP is a component of the Ada2A containing complex (ATAC) and has been identified as a susceptibility gene in several cancers. However, the role and molecular mechanism of MBIP in esophageal squamous cell carcinoma (ESCC) remain unclear. Our finding indicated that the expression level of MBIP in ESCC was higher than that in normal tissue (P < 0.05) based on the data from the Cancer Gene Atlas (TCGA) and Gene Expression Omnibus (GEO). Kaplan-Meier analysis showed that high MBIP expression was closely associated with deeper invasion and worse prognosis. Transwell assay and mouse xenograft assay demonstrated that MBIP overexpression promoted migration and invasion in vitro and in vivo, while MBIP knockdown played the opposite role. Furthermore, the results of RNA-seq, qRT-PCR, western blotting and rescue experiments revealed that MBIP promoted epithelial-mesenchymal transition (EMT) via the phosphorylation JNK/p38 in ESCC. Our study indicates that MBIP plays a significant role in the prognosis and metastasis of ESCC, suggesting that MBIP might serve as an ESCC prognostic biomarker.

Targeted genome engineering based on CRISPR/Cas9 system to enhance FVIII expression in vitro.

BACKGROUND: Hemophilia A is caused by a deficiency of coagulation factor VIII in the body due to a defect in the F8 gene. The emergence of CRISPR/Cas9 gene editing technology will make it possible to alter the expression of the F8 gene in hemophiliacs, while achieving a potential cure for the disease. METHODS: Initially, we identified high-activity variants of FVIII and constructed donor plasmids using enzymatic digestion and ligation techniques. Subsequently, the donor plasmids were co-transfected with sgRNA-Cas9 protein into mouse Neuro-2a cells, followed by flow cytometry-based cell sorting and puromycin selection. Finally, BDD-hF8 targeted to knock-in the mROSA26 genomic locus was identified and validated for FVIII expression. RESULTS: We identified the p18T-BDD-F8-V3 variant with high FVIII activity and detected the strongest pX458-mROSA26-int1-sgRNA1 targeted cleavage ability and no cleavage events were found at potential off-target sites. Targeted knock-in of BDD-hF8 cDNA at the mROSA26 locus was achieved based on both HDR/NHEJ gene repair approaches, and high level and stable FVIII expression was obtained, successfully realizing gene editing in vitro. CONCLUSIONS: Knock-in of exogenous genes based on the CRISPR/Cas9 system targeting genomic loci is promising for the research and treatment of a variety of single-gene diseases.

Mitophagy as a mitochondrial quality control mechanism in myocardial ischemic stress: from bench to bedside.

Myocardial ischemia reduces the supply of oxygen and nutrients to cardiomyocytes, leading to an energetic crisis or cell death. Mitochondrial dysfunction is a decisive contributor to the reception, transmission, and modification of cardiac ischemic signals. Cells with damaged mitochondria exhibit impaired mitochondrial metabolism and increased vulnerability to death stimuli due to disrupted mitochondrial respiration, reactive oxygen species overproduction, mitochondrial calcium overload, and mitochondrial genomic damage. Various intracellular and extracellular stress signaling pathways converge on mitochondria, so dysfunctional mitochondria tend to convert from energetic hubs to apoptotic centers. To interrupt the stress signal transduction resulting from lethal mitochondrial damage, cells can activate mitophagy (mitochondria-specific autophagy), which selectively eliminates dysfunctional mitochondria to preserve mitochondrial quality control. Different pharmacological and non-pharmacological strategies have been designed to augment the protective properties of mitophagy and have been validated in basic animal experiments and pre-clinical human trials. In this review, we describe the process of mitophagy in cardiomyocytes under ischemic stress, along with its regulatory mechanisms and downstream effects. Then, we discuss promising therapeutic approaches to preserve mitochondrial homeostasis and protect the myocardium against ischemic damage by inducing mitophagy.

Possible correlated signaling pathways with chronic urate nephropathy: A review.

Hyperuricemia nephropathy, also known as gouty nephropathy, refers to renal damage induced by hyperuricemia caused by excessive production of serum uric acid or low excretion of uric acid. the persistence of symptoms will lead to changes in renal tubular phenotype and accelerate the progress of renal fibrosis. The existence and progressive aggravation of symptoms will bring a heavy burden to patients, their families and society, affect their quality of life and reduce their well-being. With the increase of reports on hyperuricemia nephropathy, the importance of related signal pathways in the pathogenesis of hyperuricemia nephropathy is becoming more and more obvious, but most studies are limited to the upper and lower mediating relationship between 1 or 2 signal pathways. The research on the comprehensiveness of signal pathways and the breadth of crosstalk between signal pathways is limited. By synthesizing the research results of signal pathways related to hyperuricemia nephropathy in recent years, this paper will explore the specific mechanism of hyperuricemia nephropathy, and provide new ideas and methods for the treatment of hyperuricemia nephropathy based on a variety of signal pathway crosstalk and personal prospects.

Roles of mitochondrial dynamics and mitophagy in diabetic myocardial microvascular injury.

Myocardial microvessels are composed of a monolayer of endothelial cells, which play a crucial role in maintaining vascular barrier function, luminal latency, vascular tone, and myocardial perfusion. Endothelial dysfunction is a key factor in the development of cardiac microvascular injury and diabetic cardiomyopathy. In addition to their role in glucose oxidation and energy metabolism, mitochondria also participate in non-metabolic processes such as apoptosis, intracellular ion handling, and redox balancing. Mitochondrial dynamics and mitophagy are responsible for regulating the quality and quantity of mitochondria in response to hyperglycemia. However, these endogenous homeostatic mechanisms can both preserve and/or disrupt non-metabolic mitochondrial functions during diabetic endothelial damage and cardiac microvascular injury. This review provides an overview of the molecular features and regulatory mechanisms of mitochondrial dynamics and mitophagy. Furthermore, we summarize findings from various investigations that suggest abnormal mitochondrial dynamics and defective mitophagy contribute to the development of diabetic endothelial dysfunction and myocardial microvascular injury. Finally, we discuss different therapeutic strategies aimed at improving endothelial homeostasis and cardiac microvascular function through the enhancement of mitochondrial dynamics and mitophagy.

Time series analysis revealed prognostic value of continuous nasopharyngeal SARS-CoV-2 nucleic acid quantification for COVID-19: A retrospective study of >3000 COVID-19 patients from 2 centers.

BACKGROUND: Early stratification of disease progression remains one of the major challenges towards the post-coronavirus disease 2019 (COVID-19) era. The clinical relevance of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid load is debated due to the heterogeneity in patients' underlying health conditions. We determined the prognostic value of nasopharyngeal viral load dynamic conversion for COVID-19. METHODS: The cycling threshold (Ct) values of 28,937 nasopharyngeal SARS-CoV-2 RT-PCRs were retrospectively collected from 3,364 COVID-19 patients during hospitalization and coordinated to the onset of disease progression. The ROC curve was utilized to determine the predictive performance of the rate of Ct value alteration between two consecutive RT-PCR runs within 48 h (ΔCt%) for disease transformation across patients with different COVID-19 severity and immune backgrounds, and further validated with 1,860 SARS-CoV-2 RT-PCR results from an independent validation cohort of 262 patients. For the 67 patients with severe COVID-19, Kaplan-Meier analysis was performed to evaluate the difference in survival between patients stratified by the magnitude of Ct value alteration between the late and early stages of hospitalization. RESULTS: The kinetics of viral nucleic acid conversion diversified across COVID-19 patients with different clinical characteristics and disease severities. The ΔCt% is a clinical characteristic- and host immune status-independent indicator for COVID-19 progression prediction (AUC = 0.79, 95 % CI = 0.76 to 0.81), which outperformed the canonical blood test markers, including c-reactive protein (AUC = 0.57, 95 % CI = 0.53 to 0.61), serum amyloid A (AUC = 0.61, 95 % CI = 0.54 to 0.68), lactate dehydrogenase (AUC = 0.61, 95 % CI = 0.56 to 0.67), d-dimer (AUC = 0.56, 95 % CI = 0.46 to 0.66), and lymphocyte count (AUC = 0.62, 95 % CI = 0.58 to 0.66). Patients with persistent high SARS-CoV-2 viral load (an increase of mean Ct value < 50 %) during the first 3 days of hospitalization demonstrated a significantly unfavorable survival (HR = 0.16, 95 % CI = 0.04 to 0.65, P = 2.41 × 10-3). CONCLUSIONS: Viral nucleic acid dynamics of SARS-CoV-2 eliminates the inter-patient variance of basic health conditions and therefore, can serve as a prognostic marker for COVID-19.