Pseudorabies virus manipulates mitochondrial tryptophanyl-tRNA synthetase 2 for viral replication.

The pseudorabies virus (PRV) is identified as a double-helical DNA virus responsible for causing Aujeszky's disease, which results in considerable economic impacts globally. The enzyme tryptophanyl-tRNA synthetase 2 (WARS2), a mitochondrial protein involved in protein synthesis, is recognized for its broad expression and vital role in the translation process. The findings of our study showed an increase in both mRNA and protein levels of WARS2 following PRV infection in both cell cultures and animal models. Suppressing WARS2 expression via RNA interference in PK-15 â€‹cells led to a reduction in PRV infection rates, whereas enhancing WARS2 expression resulted in increased infection rates. Furthermore, the activation of WARS2 in response to PRV was found to be reliant on the cGAS/STING/TBK1/IRF3 signaling pathway and the interferon-alpha receptor-1, highlighting its regulation via the type I interferon signaling pathway. Further analysis revealed that reducing WARS2 levels hindered PRV's ability to promote protein and lipid synthesis. Our research provides novel evidence that WARS2 facilitates PRV infection through its management of protein and lipid levels, presenting new avenues for developing preventative and therapeutic measures against PRV infections.

THSG alleviates cerebral ischemia/reperfusion injury via the GluN2B-CaMKII-ERK1/2 pathway.

BACKGROUND: The potential therapeutic targeting of PINK1-PARK2-mediated mitophagy against cerebral ischemia/reperfusion (CI/R) injury involves the pathophysiological processes of neurovascular unit (NVU) and is closely associated with N-methyl-D-aspartate receptors (NMDARs) commonly expressed in NVU. 2,3,5,4'-Tetrahydroxy-stilbene-2-O-ß-D-glucoside (THSG), a compound derived from the traditional Chinese medicine Polygonum multiflorum Thunb., has demonstrated notable neuroprotective properties against CI/R injury. However, it remains unclear whether THSG exerts its protective effects through GluN2B related PINK1/ PARK2 pathway. PURPOSE: This study aims to explore the pharmacological effects of THSG on alleviating CI/R injury via the GluN2B-CaMKII-ERK1/2 pathway. METHODS: THSG neuroprotection against CI/R injury was studied in transient middle cerebral artery occlusion/reversion (tMCAO/R) model rats and in oxygen and glucose deprivation/ reoxygenation (OGD/R) induced neurons. PINK1-PARK2-mediated mitophagy involvement in the protective effect of THSG was investigated in tMCAO/R rats and OGD/R-induced neurons via THSG and 3-methyladenine (3-MA) treatment. Furthermore, the beneficial role of GluN2B in reperfusion and its contribution to the THSG effect via CaMKII-ERK1/2 and PINK1-PARK2-mediated mitophagy was explored using the GluN2B-selective antagonist Ro 25-6981 both in vivo and in vitro. Finally, the interaction between THSG and GluN2B was evaluated using molecular docking. RESULTS: THSG significantly reduced infarct volume, neurological deficits, penumbral neuron structure, and functional damage, upregulated the inhibitory apoptotic marker Bcl-2, and suppressed the increase of pro-apoptotic proteins including cleaved caspase-3 and Bax in tMCAO/R rats. THSG (1 µM) markedly improved the neuronal survival under OGD/R conditions. Furthermore, THSG promoted PINK1 and PARK2 expression and increased mitophagosome numbers and LC3-II-LC3-I ratio both in vivo and in vitro. The effects of THSG were considerably abrogated by the mitophagy inhibitor 3-MA in OGD/R-induced neurons. Inhibiting GluN2B profoundly decreased mitophagosome numbers and OGD/R-induced neuronal viability. Specifically, inhibiting GluN2B abolished the protection of THSG against CI/R injury and reversed the upregulation of PINK1-PARK2-mediated mitophagy by THSG. Inhibiting GluN2B eliminated THSG upregulation of ERK1/2 and CaMKII phosphorylation. The molecular docking analysis results demonstrated that THSG bound to GluN2B (binding energy: -5.2 ± 0.11 kcal/mol). CONCLUSIONS: This study validates the premise that THSG alleviates CI/R injury by promoting GluN2B expression, activating CaMKII and ERK1/2, and subsequently enhancing PINK1-PARK2-mediated mitophagy. This work enlightens the potential of THSG as a promising candidate for novel therapeutic strategies for treating ischemic stroke.

Construction and validation of a machine learning model for the diagnosis of juvenile idiopathic arthritis based on fecal microbiota.

Purpose: Human gut microbiota has been shown to be significantly associated with various inflammatory diseases. Therefore, this study aimed to develop an excellent auxiliary tool for the diagnosis of juvenile idiopathic arthritis (JIA) based on fecal microbial biomarkers. Method: The fecal metagenomic sequencing data associated with JIA were extracted from NCBI, and the sequencing data were transformed into the relative abundance of microorganisms by professional data cleaning (KneadData, Trimmomatic and Bowtie2) and comparison software (Kraken2 and Bracken). After that, the fecal microbes with high abundance were extracted for subsequent analysis. The extracted fecal microbes were further screened by least absolute shrinkage and selection operator (LASSO) regression, and the selected fecal microbe biomarkers were used for model training. In this study, we constructed six different machine learning (ML) models, and then selected the best model for constructing a JIA diagnostic tool by comparing the performance of the models based on a combined consideration of area under receiver operating characteristic curve (AUC), accuracy, specificity, F1 score, calibration curves and clinical decision curves. In addition, to further explain the model, Permutation Importance analysis and Shapley Additive Explanations (SHAP) were performed to understand the contribution of each biomarker in the prediction process. Result: A total of 231 individuals were included in this study, including 203 JIA patients and Non-JIA individuals. In the analysis of diversity at the genus level, the alpha diversity represented by Shannon value was not significantly different between the two groups, while the belt diversity was slightly different. After selection by LASSO regression, 10 fecal microbe biomarkers were selected for model training. By comparing six different models, the XGB model showed the best performance, which average AUC, accuracy and F1 score were 0.976, 0.914 and 0.952, respectively, thus being used to construct the final JIA diagnosis model. Conclusion: A JIA diagnosis model based on XGB algorithm was constructed with excellent performance, which may assist physicians in early detection of JIA patients and improve the prognosis of JIA patients.

Saikosaponin F ameliorates depression-associated dry eye disease by inhibiting TRIM8-induced TAK1 ubiquitination.

AIMS: Saikosaponin F (SsF) is one of the major active ingredients of Radix Bupleuri, an herb widely used in the treatment of depression. Studies have shown that dry eye disease often occurs together with depression. The aim of this study is to investigate whether SsF can improve depression-associated dry eye disease and explore the underlying mechanism. METHODS: Behavioral test was used to verify the effect of SsF on CUMS-induced depression-like behaviors in mice. Corneal fluorescein staining, phenol red cotton thread test and periodic acid-Schiff (PAS) staining were used to observe the effect of SsF on depression-associated dry eye disease. Western blot (WB) was performed to observe the expression of TAK1 protein and key proteins of NF-κB and MAPK (P38) inflammatory pathways in the hippocampus and cornea. Immunohistochemical staining was used to observe the expression of microglia, and immunoprecipitation was used to observe K63-linked TAK1 ubiquitination. Subsequently, we constructed a viral vector sh-TAK1 to silence TAK1 protein to verify whether SsF exerted its therapeutic effect based on TAK1. The expression of inflammatory factors such as IL-1ß, TNF-α and IL-18 in hippocampus and cornea were detected by ELISA. Overexpression of TRIM8 (OE-TRIM8) by viral vector was used to verify whether SsF improved depression-associated dry eye disease based on TRIM8. RESULTS: SsF treatment significantly improved the depression-like behavior, increased tear production and restored corneal injury in depression-related dry eye model mice. SsF treatment downregulated TAK1 expression and TRIM8-induced K63-linked TAK1 polyubiquitination, while inhibiting the activation of NF-κB and MAPK (P38) inflammatory pathways and microglial expression. In addition, selective inhibition of TAK1 expression ameliorated depression-associated dry eye disease, while overexpression of TRIM8 attenuated the therapeutic effect of SsF on depression-associated dry eye disease. CONCLUSION: SsF inhibited the polyubiquitination of TAK1 by acting on TRIM8, resulting in the downregulation of TAK1 expression, inhibition of inflammatory response, and improvement of CUMS-induced depression-associated dry eye disease.

Role of mitophagy in the development and progression of liver-related diseases / 临床肝胆病杂志

Mitophagy is a type of selective autophagy during which cells specifically remove damaged mitochondria in response to nutrient deficiency or external stimulation and thus maintain the integrity of mitochondrial function and cellular homeostasis. In recent years， a large number of studies have shown that dysfunction of mitophagy is closely associated with the development and progression of various liver-related diseases such as nonalcoholic fatty liver disease， drug-related liver injury， viral hepatitis， and hepatocellular carcinoma. This article summarizes the specific mechanisms of mitophagy in regulating liver-related diseases and further elaborates on the potential therapeutic targets of mitophagy in liver-related diseases， in order to provide more effective therapeutic strategies for the clinical treatment of liver diseases.

Ablated Sonic Hedgehog Signaling in the Dentate Gyrus of the Dorsal and Ventral Hippocampus Impairs Hippocampal-Dependent Memory Tasks and Emotion in a Rat Model of Depression.

Specific memory processes and emotional aberrations in depression can be attributed to the different dorsal-ventral regions of the hippocampus. However, the molecular mechanisms underlying the differential functions of the dorsal hippocampus (dHip) and ventral hippocampus (vHip) remain unclear. As Sonic Hedgehog (Shh) is involved in the dorsal-ventral patterning of the neural tube and its signaling is dysregulated by chronic unpredictable mild stress (CUMS), we investigated its role in influencing the differential functions of the dHip and vHip. Here, CUMS downregulated the expression of Shh signaling markers, including Shh and its downstream effectors GLI family zinc finger 12 (Gli1/2), Patched (Ptch), and smoothened (Smo), in both the dHip and vHip of rats, though more so in the vHip. Additionally, Shh knockdown in the dorsal or ventral dentate gyrus (DG) resulted in restrained neurogenic activity in newborn neurons, especially in immature neurons through decreased expression of Shh signaling markers. Furthermore, Shh knockdown in the DG of the dHip led to memory impairment by inhibiting experience-dependent activation of immature neurons, whereas its knockdown in the DG of the vHip led to an emotional handicap by delaying the maturation of immature neurons. Finally, Shh knockdown in either the dDG or vDG of hippocampus abolished the corresponding cognitive enhancement and emotional recovery of fluoxetine. In conclusion, Shh is essential to maintain the functional heterogeneity of dHip and vHip in depressed rat, which was mainly mediating by local changes of dependent activation and maturity of immature neurons, respectively.

Integrating serum metabolomics and network analysis to explore the antidepressant activity of crocin in rats with chronic unexpected mild stress-induced depression.

CONTEXT: Crocin exhibits anti-depressant properties. However, its underlying mechanisms and its relationship with metabolomics remain unclear. OBJECTIVE: This study elucidates the mechanism of action and potential targets of crocin in treating chronic unexpected mild stress (CUMS)-induced depression in rats. MATERIALS AND METHODS: Male Sprague-Dawley (SD) rats underwent 4 weeks of CUMS to establish the depression model. The normal control (distilled water), crocin (25 mg/kg), and fluoxetine (5.4 mg/kg) groups were orally administered for 4-weeks. Behavioural tests evaluated the effects of crocin, while liquid chromatography-mass spectrometry metabolomics identified differential metabolites and their associated metabolic pathways. Subsequently, network pharmacology was utilized to predict the targets of crocin. RESULTS: Crocin significantly increased body weight (from 319.16 ± 4.84 g to 325.67 ± 2.84 g), sucrose preference (from 0.46 ± 0.09 to 0.70 ± 0.09), vertical activity (from 2.83 ± 1.94 to 8 ± 2.36), horizontal activity (from 1 ± 0.63 to 4.5 ± 3.08) and decreased immobilization time (from 13.16 ± 2.69 to 3.97 ± 3.00). Metabolomics analysis identified 7 metabolites and 5 associated metabolic pathways. From the combined analysis of network pharmacology and metabolomics, three targets (PRMT1, CYP3A4, and GLB1) are the overlapping targets and the two most important metabolic pathways are tryptophan metabolism and glycerolipid metabolism. DISCUSSION AND CONCLUSIONS: This study provides insights into the antidepressant therapeutic effect of crocin and its underlying mechanisms. The findings contribute to a better understanding of the metabolic mechanism involved in the anti-depressant effect of crocin, establishing a strong foundation for future research in this area.

Metabolism and senescence in the immune microenvironment of osteosarcoma: focus on new therapeutic strategies.

Osteosarcoma is a highly aggressive and metastatic malignant tumor. It has the highest incidence of all malignant bone tumors and is one of the most common solid tumors in children and adolescents. Osteosarcoma tissues are often richly infiltrated with inflammatory cells, including tumor-associated macrophages, lymphocytes, and dendritic cells, forming a complex immune microenvironment. The expression of immune checkpoint molecules is also high in osteosarcoma tissues, which may be involved in the mechanism of anti-tumor immune escape. Metabolism and senescence are closely related to the immune microenvironment, and disturbances in metabolism and senescence may have important effects on the immune microenvironment, thereby affecting immune cell function and immune responses. Metabolic modulation and anti-senescence therapy are gaining the attention of researchers as emerging immunotherapeutic strategies for tumors. Through an in-depth study of the interconnection of metabolism and anti- senescence in the tumor immune microenvironment and its regulatory mechanism on immune cell function and immune response, more precise therapeutic strategies can be developed. Combined with the screening and application of biomarkers, personalized treatment can be achieved to improve therapeutic efficacy and provide a scientific basis for clinical decision-making. Metabolic modulation and anti- senescence therapy can also be combined with other immunotherapy approaches, such as immune checkpoint inhibitors and tumor vaccines, to form a multi-level and multi-dimensional immunotherapy strategy, thus further enhancing the effect of immunotherapy. Multidisciplinary cooperation and integrated treatment can optimize the treatment plan and maximize the survival rate and quality of life of patients. Future research and clinical practice will further advance this field, promising more effective treatment options for patients with osteosarcoma. In this review, we reviewed metabolic and senescence characteristics in the immune microenvironment of osteosarcoma and related immunotherapies, and provide a reference for development of more personalized and effective therapeutic strategies.

A whole transcriptome profiling analysis for antidepressant mechanism of Xiaoyaosan mediated synapse loss via BDNF/trkB/PI3K signal axis in CUMS rats.

BACKGROUND: Depression is a neuropsychiatric disease resulting from deteriorations of molecular networks and synaptic injury induced by stress. Traditional Chinese formula Xiaoyaosan (XYS) exert antidepressant effect, which was demonstrated by a great many of clinical and basic investigation. However, the exact mechanism of XYS has not yet been fully elucidated. METHODS: In this study, chronic unpredictable mild stress (CUMS) rats were used as a model of depression. Behavioral test and HE staining were used to detect the anti-depressant effects of XYS. Furthermore, whole transcriptome sequencing was employed to establish the microRNA (miRNA), long non-coding RNA (lncRNA), circular RNA (circRNA), and mRNA profiles. The biological functions and potential mechanisms of XYS for depression were gathered from the GO and KEGG pathway. Then, constructed the competing endogenous RNA (ceRNA) networks to illustrate the regulatory relationship between non-coding RNA (ncRNA) and mRNA. Additionally, longest dendrite length, total length of dendrites, number of intersections, and density of dendritic spines were detected by Golgi staining. MAP2, PSD-95, SYN were detected by immunofluorescence respectively. BDNF, TrkB, p-TrkB, PI3K, Akt, p-Akt were measured by Western Blotting. RESULTS: The results showed that XYS could increase the locomotor activity and sugar preference, decreased swimming immobility time as well as attenuate hippocampal pathological damage. A total of 753 differentially expressed lncRNAs (DElncRNAs), 28 circRNAs (DEcircRNAs), 101 miRNAs (DEmiRNAs), and 477 mRNAs (DEmRNAs) were identified after the treatment of XYS in whole transcriptome sequencing analysis. Enrichment results revealed that XYS could regulate multiple aspects of depression through different synapse or synaptic associated signal, such as neurotrophin signaling and PI3K/Akt signaling pathways. Then, vivo experiments indicated that XYS could promote length, density, intersections of synapses and also increase the expression of MAP2 in hippocampal CA1, CA3 regions. Meanwhile, XYS could increase the expression of PSD-95, SYN in the CA1, CA3 regions of hippocampal by regulating the BDNF/trkB/PI3K signal axis. CONCLUSION: The possible mechanism on synapse of XYS in depression was successfully predicted. BDNF/trkB/PI3K signal axis were the potential mechanism of XYS on synapse loss for its antidepressant. Collectively, our results provided novel information about the molecular basis of XYS in treating depression.

Machine learning for the prediction of postoperative nosocomial pulmonary infection in patients with spinal cord injury.

PURPOSE: The purpose of this study was to establish the best prediction model for postoperative nosocomial pulmonary infection through machine learning (ML) and assist physicians to make accurate diagnosis and treatment decisions. METHODS: Patients with spinal cord injury (SCI) who admitted to a general hospital between July 2014 and April 2022 were included in this study. The data were segmented according to the ratio of seven to three, 70% were randomly selected to train the model, and the other 30% were used for testing. We used LASSO regression to screen the variables, and the selected variables were used in the construction of six different ML models. Shapley additive explanations and permutation importance were used to explain the output of the ML models. Finally, sensitivity, specificity, accuracy and area under receiver operating characteristic curve (AUC) were used as the evaluation index of the model. RESULTS: A total of 870 patients were enrolled in this study, of whom 98 (11.26%) developed pulmonary infection. Seven variables were used for ML model construction and multivariate logistic regression analysis. Among these variables, age, ASIA scale and tracheotomy were found to be the independent risk factors for postoperative nosocomial pulmonary infection in SCI patients. Meanwhile, the prediction model based on RF algorithm performed best in the training and test sets. (AUC = 0.721, accuracy = 0.664, sensitivity = 0.694, specificity = 0.656). CONCLUSION: Age, ASIA scale and tracheotomy were the independent risk factors of postoperative nosocomial pulmonary infection in SCI. The prediction model based on RF algorithm had the best performance.

A practical dynamic nomogram model for predicting bone metastasis in patients with thyroid cancer.

Purpose: The aim of this study was to established a dynamic nomogram for assessing the risk of bone metastasis in patients with thyroid cancer (TC) and assist physicians to make accurate clinical decisions. Methods: The clinical data of patients with TC admitted to the First Affiliated hospital of Nanchang University from January 2006 to November 2016 were included in this study. Demographic and clinicopathological parameters of all patients at primary diagnosis were analyzed. Univariate and multivariate logistic regression analysis was applied to build a predictive model incorporating parameters. The discrimination, calibration, and clinical usefulness of the nomogram were evaluated using the C-index, ROC curve, calibration plot, and decision curve analysis. Internal validation was evaluated using the bootstrapping method. Results: A total of 565 patients were enrolled in this study, of whom 25 (4.21%) developed bone metastases. Based on logistic regression analysis, age (OR=1.040, P=0.019), hemoglobin (HB) (OR=0.947, P<0.001) and alkaline phosphatase (ALP) (OR=1.006, P=0.002) levels were used to construct the nomogram. The model exhibited good discrimination, with a C-index of 0.825 and good calibration. A C-index value of 0.815 was achieved on interval validation analysis. Decision curve analysis showed that the nomogram was clinically useful when intervention was decided at a bone metastases possibility threshold of 1%. Conclusions: This dynamic nomogram, with relatively good accuracy, incorporating age, HB, and ALP, could be conveniently used to facilitate the prediction of bone metastasis risk in patients with TC.

Leonurine Regulates Hippocampal Nerve Regeneration in Rats with Chronic and Unpredictable Mild Stress by Activating SHH/GLI Signaling Pathway and Restoring Gut Microbiota and Microbial Metabolic Homeostasis.

Depression is a highly prevalent and heterogeneous disorder that requires new strategies to overcome depression. In this study, we aimed to investigate whether leonurine modulated hippocampal nerve regeneration in chronic and unpredictable mild stress (CUMS) rats through the SHH/GLI signaling pathway and restoring gut microbiota and microbial metabolic homeostasis. The CUMS rat model was constructed and treated with leonurine. The body weight of rats was recorded, and a series of tests were performed. Western blot was utilized to measure the expression of BDNF and 5-HT in the hippocampus. Then the expression of SHH, GLI, PTCH, and SMO were measured by qRT-PCR and western blot. The colocalization of BrdU+DCX and BrdU+NeuN was evaluated by IF. 16S rDNA high-throughput sequencing was applied to detect the composition and distribution of gut microbiota. The differential metabolites were analyzed by untargeted metabolomics. The correlation between gut microbiota and microbial metabolites was analyzed by Pearson correlation coefficient. After CUMS modeling, the body weight of rats was decreased, and the expression of BDNF and 5-HT were decreased, while the body weight was recovered, and the expression of BDNF and 5-HT were increased after leonurine treatment. Leonurine reversed the reduction in the colocalization of BrdU+DCX and BrdU+NeuN and the reduction in the levels of SHH, GLI, PTCH, and SMO induced by CUMS modeling. Leonurine also restored gut microbiota and microbial metabolites homeostasis in CUMS rats. Furthermore, Prevotellaceae_Ga6A1_group was negatively correlated with 3-Oxocholic acid, nutriacholic acid, and cholic acid. Collectively, leonurine regulated hippocampal nerve regeneration in CUMS rats by activating the SHH/GLI signaling pathway and restoring gut microbiota and microbial metabolic homeostasis.

The protective effect of luteolin on the depression-related dry eye disorder through Sirt1/NF-κB/NLRP3 pathway.

Luteolin has been reported to exhibit therapeutic effect on depressive-like behaviors in mice. Nevertheless, the therapeutic effect of luteolin on the depression-related dry eye disorder remains inconclusive. In this study, C57 mice were subjected to chronic unpredictable mild stress in a dry environment (relative humidity in the cage <40%). The behavioral test and phenol red cotton thread test were employed to select the mice with both dry eye and depression-like behavior. The mechanism of luteolin on depression-related dry eye disorder was assessed by the Sirt1 selective inhibitor EX-527. Luteolin alleviated depressive-like behaviors induced by CUMS, increased tear secretion and restored corneal defects in mice. The secretions of pro-inflammatory factors IL-1ß, IL-6, IL-18 and TNF-α were decreased in hippocampi and corneal tissues by Luteolin treatment. Luteolin treatment up-regulated Sirt1 expression and down-regulated Ac-NF-κB, NLRP3, Ac-Caspase-1, GSDMD-N, Cleaved IL-1ß, and Cleaved IL-18 expressions. In addition, the selective inhibition of Sirt1 could weaken the therapeutic effect of luteolin on depression-related dry eye disorder. The beneficial effect of luteolin through Sirt1/NF-κB/NLRP3 signaling pathway might be a therapeutic strategy for the depression-related dry eye disorder.

Effects of extramedullary disease on patients with newly diagnosed multiple myeloma / 中华血液学杂志

Objective: To summarize the characteristics of patients with newly diagnosed multiple myeloma (NDMM) admitted at Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine. We compared the clinical characteristics and prognoses among patients with non-extramedullary disease (EMD), bone-related extramedullary (EM-B) disease, and extraosseous extramedullary (EM-E) disease and further explored the effects of autologous hematopoietic stem cell transplantation (ASCT) for EMD. Methods: From January 2015 to January 2022, data of 114 patients (22%) with EMD out of 515 patients with NDMM were retrospectively analyzed; 91 (18%) and 23 (4%) patients comprised the EM-B and EM-E groups, respectively. The clinical characteristics of patients in all groups were compared with the Chi-square test. Progression-free survival (PFS) and overall survival (OS) of patients were analyzed by the Kaplan-Meier method. Independent prognostic factors were determined using multivariate Cox proportional hazard model. Results: There were no significant differences in age, gender, ISS stage, light chain, creatinine clearance, cytogenetic risk, 17p deletion, ASCT, and induction regimens among the three groups. Overall, 13% of EM-E patients had IgD-type M protein, which was significantly higher than that in EM-B patients (P=0.021). The median PFS of patients in the non-EMD, EM-B, and EM-E groups was 27.4, 23.1, and 14.0 months; the median OS was not reached, 76.8 months, and 25.6 months, respectively. The PFS (vs non-EMD, P=0.004; vs EM-B, P=0.036) and OS (vs non-EMD, P<0.001; vs EM-B, P=0.002) were significantly worse in patients with EM-E, while those were not significantly different between patients with EM-B and those with non-EMD. In the multivariate analysis, EM-E was an independent prognostic factor for OS in patients with NDMM (HR=8.779, P<0.001) and negatively impacted PFS (HR=1.874, P=0.050). In those who did not undergo ASCT, patients with EM-B had significantly worse OS than those with non-EMD (median 76.8 months vs. not reached, P=0.029). However, no significant difference was observed in the PFS and OS of patients with EM-B and those with non-EMD who underwent ASCT. Conclusions: Compared to patients with either non-EMD or EM-B, those with EM-E had the worst prognosis. EM-E was an independent risk factor for OS in patients with NDMM. ASCT can overcome the poor prognosis of EM-B.

Effect of noise on hearing loss among workers in a fastener manufacturing enterprise / 预防医学

Objective @#To investigate the current status of hearing loss in a fastener manufacturing enterprise, and to analyze its influencing factors, so as to provide insights into occupational disease prevention and control. @*Methods@#The occupational health examination data of noise exposed workers and the workplace occupational disease hazard factors detection data in a fastener manufacturing enterprise in Jiaxing City in 2022 were collected through the Occupational Disease and Occupational Health Hazard Factors Detection System of China Disease Prevention and Control Information System, and factors affecting the development of high-frequency noise-induced hearing loss (HFNIHL) and speech-frequency noise-induced hearing loss (SFNIHL) were analyzed. @*Results@#Totally 625 workers were investigated, with a median age of 44.00 (interquartile range, 13.00) years and a median length of service of 8.00 (interquartile range, 9.00) years, and including 519 men (83.04%) and 106 women (16.96%). There were 309 workers with single noise exposure (49.44%) and 316 workers with joint noise exposure (50.56%), and 518 workers exposed to noise with the normalized continuous A-weighted sound pressure level equivalent to a 40 h working week (LEX,40 h) that exceeded the national standard (82.88%). The detection rates of HFNIHL and SFNIHL were 49.12% and 35.04%, respectively. Multivariable logistic regression analysis indicated that males (OR=10.528, 95%CI: 5.271-21.025), length of service of 10 years and longer (OR=2.451, 95%CI: 1.599-3.759), LEX,40 h of >85 dB (A) (OR=2.227, 95%CI: 1.318-3.764) and joint noise exposure (OR=3.002, 95%CI: 2.080-4.334) were associated with an increased risk of HFNIHL, and male (OR=9.400, 95%CI: 4.211-20.985), LEX,40 h of >85 dB (A) (OR=2.305, 95%CI: 1.345-3.951), and joint noise exposure (OR=3.880, 95%CI: 2.677-5.623) were associated with an increased risk of SFNIHL.@*Conclusion@#Gender, length of service, noise intensity and exposure mode are factors affecting the risk of HFNIHL, while gender, noise intensity and exposure mode are factors affecting the risk of SFNIHL.

Newly developed gas-assisted sonodynamic therapy in cancer treatment

Sonodynamic therapy (SDT) is an emerging noninvasive treatment modality that utilizes low-frequency and low-intensity ultrasound (US) to trigger sensitizers to kill tumor cells with reactive oxygen species (ROS). Although SDT has attracted much attention for its properties including high tumor specificity and deep tissue penetration, its anticancer efficacy is still far from satisfactory. As a result, new strategies such as gas-assisted therapy have been proposed to further promote the effectiveness of SDT. In this review, the mechanisms of SDT and gas-assisted SDT are first summarized. Then, the applications of gas-assisted SDT for cancer therapy are introduced and categorized by gas types. Next, therapeutic systems for SDT that can realize real-time imaging are further presented. Finally, the challenges and perspectives of gas-assisted SDT for future clinical applications are discussed.

Insm1 promotes differentiation of retinal progenitor cells toward photoreceptor cells in the developing retina through up-regulation of SHH.

This article investigated the effect of Insm1 on RPC differentiation in mice and the underlying mechanism. The retinal tissues of mouse embryo at 12.5 days (E12.5) and postnatal 14 days (P14) were collected, following by the detection of Insm1 and corresponding markers by immunofluorescent staining. RPCs isolated from retinal tissues at P1 were cultured in culture medium for 7 days. The differentiation of photoreceptor and glial cells was assessed after RPCs transferred to the differentiation medium for 20 days. Next, the effect of Insm1 overexpression on the differentiation of RPCs toward rod photoreceptor and glial cells were assessed. Insm1 was highly expressed in RPCs of retinal tissues and decline in photoreceptor cells, while hardly expressed in glial cells. Based on the results of Pax-6 positive immunofluorescent staining and flow cytometry detection, RPCs were successfully isolated from retinal tissues. After the culture in differentiation medium, RPCs showed positive staining of Rhodopsin and glial fibrillary acidic protein (GFAP). Further results showed that overexpression of Insm1 significantly increased the percentage of Rhodopsin positive cells, and up-regulated Sonic Hedgehog (SHH), hairy and enhancer of split homolog-1(Hes1), S-opsin and Rhodopsin levels, while decreased the percentage of Glutamine synthetase positive cells, and reduced Glutamine synthetase and GFAP levels. Whereas, the effect of Insm1 overexpression on these protein levels were partly abolished by the knockdown of SHH or Hes1. We conclude that Insm1 promotes the differentiation of RPCs into photoreceptor cells in the developing retina through up-regulation of SHH.

Acacetin protects against depression-associated dry eye disease by regulating ubiquitination of NLRP3 through gp78 signal.

Dry eye disease (DED) is a multifactorial syndrome that commonly occurs with depression. However, therapies targeting depression-related dry eye disease are rare. In the current study, we studied the beneficial effect of a natural flavone, acacetin, in depression-associated dry eye disease by utilizing the chronic unpredictable mild stress (CUMS) depression model. Our data showed that acacetin improved the depressive behaviors in sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST); relieved the dry eye symptoms including corneal epithelial impairments, tear production decrease and goblet cell loss in CUMS mice. Acacetin also inhibited NOD-like receptor protein 3 (NLRP3) inflammasome expression levels and suppressed inflammatory responses via enhancing glycoprotein 78 (gp78)/Insulin induced gene-1 (Insig-1)-controlled NLRP3 ubiquitination in CUMS mice. Furthermore, knockdown of gp78 compromised acacetin-conferred protective efficacy in depression-related dry eye disease. In summary, our findings indicated that acacetin exerts beneficial effect in depression-associated dry eye disease, which is tightly related to gp78-mediated NLRP3 ubiquitination.

Breast Cancer Prognosis Prediction and Immune Pathway Molecular Analysis Based on Mitochondria-Related Genes.

Background: Mitochondria play an important role in breast cancer (BRCA). We aimed to build a prognostic model based on mitochondria-related genes. Method: Univariate Cox regression analysis, random forest, and the LASSO method were performed in sequence on pretreated TCGA BRCA datasets to screen out genes from a Gene Set Enrichment Analysis, Gene Ontology: biological process gene set to build a prognosis risk score model. Survival analyses and ROC curves were performed to verify the model by using the GSE103091 dataset. The BRCA datasets were equally divided into high- and low-risk score groups. Comparisons between clinical features and immune infiltration related to different risk scores and gene mutation analysis and drug sensitivity prediction were performed for different groups. Result: Four genes, MRPL36, FEZ1, BMF, and AFG1L, were screened to construct our risk score model in which the higher the risk score, the poorer the prognosis. Univariate and multivariate analyses showed that the risk score was significantly associated with age, M stage, and N stage. The gene mutation probability in the high-risk score group was significantly higher than that in the low-risk score group. Patients with higher risk scores were more likely to die. Drug sensitivity prediction in different groups indicated that PF-562271 and AS601245 might be new inhibitors of BRCA. Conclusion: We developed a new workable risk score model based on mitochondria-related genes for BRCA prognosis and identified new targets and drugs for BRCA research.

Luteolin Induced Hippocampal Neuronal Pyroptosis Inhibition by Regulation of miR-124-3p/TNF-α/TRAF6 Axis in Mice Affected by Breast-Cancer-Related Depression.

Background: Breast-cancer-related depression (BCRD) is associated with an increased mortality rate among breast cancer (BC) survivors. Luteolin has many pharmacological effects, particularly in the treatment of BC. In this study, we aimed to explore the anti-BCRD activity of luteolin and its underlying functional mechanism. Methods: A BCRD mouse model was induced by injecting 4T1 cells and corticosterone (COR). Behavioral test, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, Nissl staining, immunofluorescence, reverse-transcription quantitative PCR (RT-qPCR), and western blotting were used to study the effect of luteolin in mice with BCRD in vivo. A COR-induced neuron injury model was established in HT-22 cells in vitro. The role of miR-124-3p in the anti-BCRD effects of luteolin was studied using a miR-124-3p inhibitor. Results: Luteolin significantly reduced the size and weight of the tumor, increased the mice entry frequency in the symmetrical sector, and reduced the duration of immobility in the tail suspension and forced swimming tests of mice affected by BCRD. Simultaneously, apoptosis of hippocampal neurons was inhibited, and the number of Nissl bodies increased with luteolin treatment. In addition, luteolin resulted in the upregulation of miR-124-3p expression in the hippocampus and downregulated the expression of tumor necrosis factor-α (TNF-α) and TNF receptor-associated factor 6 (TRAF6), as well as lowered the phosphorylation levels of nuclear factor-kappa B (NF-κB) and IkappaB (IκB). Luteolin also inhibited pyroptosis of hippocampal neurons in mice affected by BCRD, as revealed by the low protein levels of NOD-like receptor protein 3 (NLRP3), caspase-1, gasdermin D-N (GSDMD-N), interleukin (IL)-1ß, and IL-18. However, the miR-124-3p inhibitor significantly reversed the therapeutic effect of luteolin on COR-induced HT-22 cells. Conclusion: Our study demonstrated that the anti-BCRD function of luteolin was mediated by regulating the miR-124-3p/TNF-α/TRAF6-related pathway and inhibiting neuronal cell pyroptosis and subsequent inflammation. Therefore, luteolin may be a potential drug candidate in the treatments of BCRD.