Unraveling the efficacy of verbascoside in thwarting MRSA pathogenicity by targeting sortase A.

In the fight against hospital-acquired infections, the challenge posed by methicillin-resistant Staphylococcus aureus (MRSA) necessitates the development of novel treatment methods. This study focused on undermining the virulence of S. aureus, especially by targeting surface proteins crucial for bacterial adherence and evasion of the immune system. A primary aspect of our approach involves inhibiting sortase A (SrtA), a vital enzyme for attaching microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) to the bacterial cell wall, thereby reducing the pathogenicity of S. aureus. Verbascoside, a phenylethanoid glycoside, was found to be an effective SrtA inhibitor in our research. Advanced fluorescence quenching and molecular docking studies revealed a specific interaction between verbascoside and SrtA, pinpointing the critical active sites involved in this interaction. This molecular interaction significantly impedes the SrtA-mediated attachment of MSCRAMMs, resulting in a substantial reduction in bacterial adhesion, invasion, and biofilm formation. The effectiveness of verbascoside has also been demonstrated in vivo, as shown by its considerable protective effects on pneumonia and Galleria mellonella (wax moth) infection models. These findings underscore the potential of verbascoside as a promising component in new antivirulence therapies for S. aureus infections. By targeting crucial virulence factors such as SrtA, agents such as verbascoside constitute a strategic and potent approach for tackling antibiotic resistance worldwide. KEY POINTS: • Verbascoside inhibits SrtA, reducing S. aureus adhesion and biofilm formation. • In vivo studies demonstrated the efficacy of verbascoside against S. aureus infections. • Targeting virulence factors such as SrtA offers new avenues against antibiotic resistance.

Targeted delivery of CEBPA-saRNA for the treatment of pancreatic ductal adenocarcinoma by transferrin receptor aptamer decorated tetrahedral framework nucleic acid.

Pancreatic cancer, predominantly pancreatic ductal adenocarcinoma (PDAC), remains a highly lethal malignancy with limited therapeutic options and a dismal prognosis. By targeting the underlying molecular abnormalities responsible for PDAC development and progression, gene therapy offers a promising strategy to overcome the challenges posed by conventional radiotherapy and chemotherapy. This study sought to explore the therapeutic potential of small activating RNAs (saRNAs) specifically targeting the CCAAT/enhancer-binding protein alpha (CEBPA) gene in PDAC. To overcome the challenges associated with saRNA delivery, tetrahedral framework nucleic acids (tFNAs) were rationally engineered as nanocarriers. These tFNAs were further functionalized with a truncated transferrin receptor aptamer (tTR14) to enhance targeting specificity for PDAC cells. The constructed tFNA-based saRNA formulation demonstrated exceptional stability, efficient saRNA release ability, substantial cellular uptake, biocompatibility, and nontoxicity. In vitro experiments revealed successful intracellular delivery of CEBPA-saRNA utilizing tTR14-decorated tFNA nanocarriers, resulting in significant activation of tumor suppressor genes, namely, CEBPA and its downstream effector P21, leading to notable inhibition of PDAC cell proliferation. Moreover, in a mouse model of PDAC, the tTR14-decorated tFNA-mediated delivery of CEBPA-saRNA effectively upregulated the expression of the CEBPA and P21 genes, consequently suppressing tumor growth. These compelling findings highlight the potential utility of saRNA delivered via a designed tFNA nanocarrier to induce the activation of tumor suppressor genes as an innovative therapeutic approach for PDAC.

Physical symptoms and anxiety and depression in older patients with advanced cancer in China: a network analysis.

BACKGROUND: Little is understood about the association between psychosomatic symptoms and advanced cancer among older Chinese patients. METHODS: This secondary analysis was part of a multicenter cross-sectional study based on an electronic patient-reported outcome platform. Patients with advanced cancer were included between August 2019 and December 2020 in China. Participants (over 60 years) completed the MD Anderson Symptom Inventory (MDASI) and Hospital Anxiety and Depression Scale (HADS) to measure symptom burden. Network analysis was also conducted to investigate the network structure, centrality indices (strength, closeness, and betweenness) and network stability. RESULTS: A total of 1022 patients with a mean age of 66 (60-88) years were included; 727 (71.1%) were males, and 295 (28.9%) were females. A total of 64.9% of older patients with advanced cancer had one or more symptoms, and up to 80% had anxiety and depression. The generated network indicated that the physical symptoms, anxiety and depression symptom communities were well connected with each other. Based on an evaluation of the centrality indices, 'distress/feeling upset' (MDASI 5) appears to be a structurally important node in all three networks, and 'I lost interest in my own appearance' (HADS-D4) had the lowest centrality indices. The network stability was relatively high (> 0.7). CONCLUSION: The symptom burden remains high in older patients with advanced cancer in China. Psychosomatic symptoms are highly interactive and often present as comorbidities. This network can be used to provide targeted interventions to optimize symptom management in older patients with advanced cancer in China. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR1900024957), registered on 06/12/2020.

Echinacoside, a promising sortase A inhibitor, combined with vancomycin against murine models of MRSA-induced pneumonia.

Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogenic bacterium responsible for a range of severe infections, such as skin infections, bacteremia, and pneumonia. Due to its antibiotic-resistant nature, current research focuses on targeting its virulence factors. Sortase A (SrtA) is a transpeptidase that anchors surface proteins to the bacterial cell wall and is involved in adhesion and invasion to host cells. Through fluorescence resonance energy transfer (FRET), we identified echinacoside (ECH), a natural polyphenol, as a potential SrtA inhibitor with an IC50 of 38.42 µM in vitro. It was demonstrated that ECH inhibited SrtA-mediated S. aureus fibrinogen binding, surface protein A anchoring, and biofilm formation. The fluorescence quenching assay determined the binding mode of ECH to SrtA and calculated the KA-binding constant of 3.09 × 105 L/mol, demonstrating the direct interaction between the two molecules. Molecular dynamics simulations revealed that ECH-SrtA interactions occurred primarily at the binding sites of A92G, A104G, V168A, G192A, and R197A. Importantly, the combination of ECH and vancomycin offered protection against murine models of MRSA-induced pneumonia. Therefore, ECH may serve as a potential antivirulence agent against S. aureus infections, either alone or in combination with vancomycin.

Inhibitory effect of bilobalide on Staphylococcus aureus von Willebrand factor-binding protein and its therapeutic effect in mice with pneumonia.

AIMS: Disabling bacterial virulence with small molecules has been proposed as a potential strategy to prevent bacterial pathogenicity. The von Willebrand factor-binding protein of Staphylococcus aureus was identified previously as a key virulence determinant. Our objective was to discover a von Willebrand-factor binding protein (vWbp) inhibitor distinct from the antibiotics used to prevent infections resulting from S. aureus. METHODS AND RESULTS: Using coagulation assays, we found that the sesquiterpene trilactone bilobalide blocks coagulation mediated by vWbp, but has no impact on the growth of S. aureus at a concentration of 128 µg ml-1. Moreover, a mouse model of pneumonia caused by S. aureus indicated that bilobalide could attenuate S. aureus virulence in vivo. This effect is achieved not by interfering with the expression of vWbp but by binding to vWbp, as demonstrated by western blotting, thermal shift assays, and fluorescence quenching assays. Using molecular dynamic simulations and point mutagenesis analysis, we identified that the Q17A and R453A residues are key residues for the binding of bilobalide to vWbp. CONCLUSIONS: Overall, we tested the ability of bilobalide to inhibit S. aureus infections by targeting vWbp and explored the potential mechanism of this activity.

Hinokiflavone Attenuates the Virulence of Methicillin-Resistant Staphylococcus aureus by Targeting Caseinolytic Protease P.

Drug-resistant bacteria was the third leading cause of death worldwide in 2019, which sounds like a cautionary note for global public health. Therefore, developing novel strategies to combat Methicillin-resistant Staphylococcus aureus (MRSA) infections is the need of the hour. Caseinolytic protease P (ClpP) represents pivotal microbial degradation machinery in MRSA involved in bacterial homeostasis and pathogenicity, considered an ideal target for combating S. aureus infections. Herein, we identified a natural compound, hinokiflavone, that inhibited the activity of ClpP of MRSA strain USA300 with an IC50 of 34.36 µg/mL. Further assays showed that hinokiflavone reduced the virulence of S. aureus by inhibiting multiple virulence factors expression. Results obtained from cellular thermal transfer assay (CETSA), thermal shift assay (TSA), local surface plasmon resonance (LSPR) and molecular docking (MD) assay enunciated that hinokiflavone directly bonded to ClpP with confirmed docking sites, including SER-22, LYS-26 and ARG-28. In vivo, the evaluation of anti-infective activity showed that hinokiflavone in combination with vancomycin effectively protected mice from MRSA-induced fatal pneumonia, which was more potent than vancomycin alone. As mentioned above, hinokiflavone, as an inhibitor of ClpP, could be further developed into a promising adjuvant against S. aureus infections.

Kaempferol inhibits the expression of α-hemolysin and protects mice from methicillin-resistant Staphylococcus aureus-induced lethal pneumonia.

Staphylococcus aureus (S. aureus) is a common pathogenic bacterium that induces a variety of diseases in humans and animals. The significant pathogenicity of S. aureus is due to its expression of several virulence factors. Alpha-hemolysin (Hla) has attracted attention as a virulence factor in staphylococcal pathogenesis and has been the predominant focus of intense research. In this study, we found that kaempferol, a flavonoid compound, inhibited hemolysis at a low concentration (32 µg/mL) and exerted no effect on bacterial growth. Western blot and RT-qPCR assays further demonstrated that kaempferol downregulated the expression of Hla in S. aureus. We observed that kaempferol alleviated the damage from S. aureus Hla in A549 cells. More importantly, kaempferol showed a potent protective effect on mice pneumonia induced by MRSA, as evidenced by a significant improvement in the survival of mice, a reduction in the number of colonized colonies in lung tissue and a decrease in the pathological damage to lung tissues. In summary, the results demonstrate the protective effect of kaempferol on MRSA-induced lethal pneumonia in mice and indicate that kaempferol could be developed as a potential anti-MRSA drug.

Suicidal ideation in advanced cancer patients without major depressive disorder.

INTRODUCTION: Major depressive disorder (MDD) is associated with an increased risk of suicide and suicide attempt among cancer patients. However, we do not know how many cancer patients without MDD have suicidal ideation (SI). OBJECTIVES: This study aimed to investigate the prevalence, characteristics and correlated factors of SI among advanced cancer patients without MDD. METHODS: This is a multi-center, cross-sectional study based on an electronic patient-reported outcome systems in patients who were diagnosed with advanced lung, liver, gastric, esophageal, colorectal or breast cancer, the top six prevalent cancers in China. A total of 2930 advanced cancer patients were recruited from 10 regional representative cancer centers across China from August 2019 to December 2020. Patients completed the Patient Health Questionnaire-9 regarding if they had thoughts of being better off dead or of hurting themselves in some way in the previous 2 weeks. Patients also completed the symptom inventory and quality of life assessment. Generalized estimating equation model was performed to explore the correlated factors associated with SI among the patients without MDD. RESULTS: The overall prevalence of SI among advanced cancer patients without MDD was 13.1%. The prevalence was higher in older patients. After adjusted for existing conditions, patients with vomiting symptom (p < 0.001), poorer life quality (p < 0.001), and middle education level (p = 0.031) were correlated factors of SI. CONCLUSIONS: The suicidal ideation is common in advanced cancer patients without MDD. Patients with vomiting, poor quality of life, and middle education level should be screened and monitored for suicidal ideation even without MDD. CLINICAL TRIAL INFORMATION: ChiCTR1900024957.

Functions of lncRNA DUXAP8 in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) poses a serious threat to public health due to its significant morbidity and mortality rates. The processes of NSCLC formation and development are quite complex and involve numerous regulatory biomolecules. Long non-coding RNAs (lncRNAs) have attracted attention since they have been found to play critical roles in the tumorigenesis of various human malignancies. Recently, double homeobox A pseudogene 8 (DUXAP8) was identified as an oncogenic lncRNA that is overexpressed in different tumor types. In NSCLC, high expression of DUXAP8 is associated with poor prognosis in patients. The regulatory mechanism underlying the oncogenic effects of DUXAP8 can be divided into transcriptional level and post-transcriptional level. DUXAP8 promotes proliferation, epithelial-mesenchymal transition, and aerobic glycolysis in NSCLC cells. Moreover, DUXAP8 shows potential for the diagnosis and treatment of NSCLC. Herein, we review the molecular mechanisms underlying the DUXAP8-mediated phenotypes of NSCLC as well as its potential clinical applications.

Tamarixetin Attenuated the Virulence of Staphylococcus aureus by Directly Targeting Caseinolytic Protease P.

Staphylococcus aureus, especially drug-resistant S. aureus infections, is a worldwide healthcare challenge. There is a growing focus on antivirulence therapy against S. aureus. Caseinolytic protease p (ClpP) is a protein hydrolase essential for pathogenicity in S. aureus. A flavonoid compound, tamarixetin, which was screened in this work, was specifically able to inhibit the hydrolytic activity of ClpP on the fluorescent substrate Suc-LY-AMC with an IC50 of 49.73 µM, without affecting the growth of methicillin-resistant S. aureus strain USA300 and was without obvious cytotoxicity. Further assays found that tamarixetin inhibited the transcription of hla, agr, RNAIII, pvl, PSM-α, and spa genes as well as suppressed the protein expression levels of Hla and PVL. Moreover, tamarixetin was observed to dramatically inhibit the hemolytic activity of hla in S. aureus. Consistent with that of S. aureus USA300-ΔclpP, tamarixetin was shown to increase urease expression. The thermal shift and cellular thermal shift assays showed that tamarixetin markedly changed the thermal stability of ClpP. The dissociation constant (KD) value of tamarixetin with ClpP was 2.52 × 10-6 M measured by surface plasmon resonance. The molecular docking and ClpP point mutation results also demonstrated that tamarixetin had a strong interaction with ClpP. In vivo study showed that tamarixetin was effective in protecting mice from S. aureus pneumonia by increasing survival, reducing lung tissue load, and slowing down the infiltration of inflammatory factors. In addition, tamarixetin was able to enhance the antibacterial activity of cefotaxime in combination. In conclusion, tamarixetin was promising as a ClpP inhibitor for S. aureus infections.

The protection effect of rhodionin against methicillin-resistant Staphylococcus aureus-induced pneumonia through sortase A inhibition.

Methicillin-resistant Staphylococcus aureus (MRSA) is a zoonotic antibiotic-resistant pathogen that negatively impacts society from medical, veterinary, and societal standpoints. The search for alternative therapeutic strategies and innovative anti-infective agents is urgently needed. Among the pathogenic mechanisms of Staphylococcus aureus (S. aureus), sortase A is a virulence factor of great concern because it is highly linked with the ability of MRSA to invade the host. In this study, we identified that rhodionin, a natural compound of flavonoid glucosides, effectively inhibited the activity of SrtA without affecting the survival and growth of bacteria, and its half maximal inhibitory concentration (IC50) value was 22.85 µg/mL. In vitro, rhodionin prominently attenuated the virulence-related phenotype of SrtA by reducing the adhesion of S. aureus to fibrinogen, reducing the capacity of protein A (SpA) on the bacterial surface and biofilm formation. Subsequently, fluorescence quenching and molecular docking were performed to verify that rhodionin directly bonded to SrtA molecule with KA value of 6.22 × 105 L/mol. More importantly, rhodionin showed a significant protective effect on mice pneumonia model and improved the survival rate of mice. According to the above findings, rhodionin achieved efficacy in the treatment of MRSA-induced infections, which holds promising potential to be developed into a candidate used for MRSA-related infections.

7,8-Dihydroxyflavone attenuates the virulence of Staphylococcus aureus by inhibiting alpha-hemolysin.

Staphylococcus aureus (S. aureus), a Gram-positive bacteria, is an incurable cause of hospital and community-acquired infections. Inhibition bacterial virulence is a viable strategy against S. aureus infections based on the multiple virulence factors secreted by S. aureus. Alpha-hemolysin (Hla) plays a crucial role in bacteria virulence without affecting bacterial viability. Here, we identified that 7,8-Dihydroxyflavone (7,8-DHF), a natural compound, was able to decrease the expression of and did not affect the in vitro growth of S. aureus USA300 at a concentration of 32 µg/mL. It was verified by western blot and RT-qPCR that the natural compound could inhibit the transcription and translation of Hla. Further mechanism studies revealed that 7,8-DHF has a negative effect on transcriptional regulator agrA and RNAIII, preventing the upregulation of virulence gene. Cytotoxicity assays showed that 7,8-DHF did not produce significant cytotoxicity to A549 cells. Animal experiments showed that the combination of 7,8-DHF and vancomycin had a more significant therapeutic effect on S. aureus infection, reflecting the synergistic effect of 7,8-DHF with antibiotics. In conclusion, 7,8-DHF was able to target Hla to protect host cells from hemolysis while limiting the development of bacterial resistance.

Biochanin A as an α-hemolysin inhibitor for combating methicillin-resistant Staphylococcus aureus infection.

Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant pathogen that poses a significant risk to global health today. In S. aureus, α-hemolysin is an important virulence factor as it contributes to the capacity of the bacteria to infect the host. Here, we showed that biochanin A (bioA), an isoflavone present in red clover, cabbage and alfalfa, effectively inhibited hemolytic activity at a dose as low as 32 µg/mL. Further, western blot and RT-qPCR data showed that bioA reduced the production and expression of MRSA hemolysin in a dose-dependent manner. In addition, when different concentrations of bioA were added to a coculture system of A549 cells and S. aureus, it could significantly decrease cell injury. Importantly, the in vivo study showed that bioA could protect mice from pneumonia caused by a lethal dose of MRSA, as evidenced by improving their survival and reducing the number of bacterial colonies in lung tissues, the secretion of hemolysin into alveolar lavage fluid and the degree of pulmonary edema. In conclusion, biochanin A protected the host from MRSA infection by inhibiting the expression of the hemolysin of MRSA, which may provide experimental evidence for its development to a potential anti-MRSA drug.

The Small Glutathione Peroxidase Mimic 5P May Represent a New Strategy for the Treatment of Liver Cancer.

Glutathione peroxidase (GPx) is an antioxidant protein containing selenium. Owing to the limitations of native GPx, considerable efforts have been made to develop GPx mimics. Here, a short 5-mer peptides (5P) was synthesized and characterized using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Enzyme coupled assays were used to evaluate GPx activity. The cell viability and apoptosis of H22 cells were tested, and mice bearing H22 cell-derived tumors were used to determine the effects of 5P on tumor inhibition. In comparison with other enzyme models, 5P provided a suitable substrate with proper catalytic site positions, resulting in enhanced catalytic activity. In our mouse model, 5P showed excellent inhibition of tumor growth and improved immunity. In summary, our findings demonstrated the design and synthesis of the small 5P molecule, which inhibited tumor growth and improved immunity. Notably, 5P could inhibit tumor growth without affecting normal growth. Based on these advantages, the novel mimic may have several clinical applications.

Thwarting resistance: MgrA inhibition with methylophiopogonanone a unveils a new battlefront against S. aureus.

Limitations in the clinical treatment of Staphylococcus aureus (S. aureus) infections have arisen due to the advent of antibiotic-resistant strains. Given the immense potential of therapeutic strategies targeting bacterial virulence, the role of MgrA as a pivotal virulence determinant in S. aureus-orchestrating resistance, adherence, and hundreds of virulence targets-becomes indispensable. In this investigation, leveraging advanced virtual screening and fluorescence anisotropy assays, we discerned methylophiopogonanone A (Mo-A), a flavonoid derivative, as a potent disruptor of the MgrA-DNA interaction nexus. Subsequent analysis revealed that Mo-A effectively inhibits the expression of virulence factors such as Hla and Pvl in S. aureus and markedly reduces its adhesion capability to fibrinogen. On a cellular landscape, Mo-A exerts a mitigating influence on the deleterious effects inflicted by S. aureus USA300 on A549 cells. Furthermore, our data indicate that Mo-A downregulates the transcription of genes associated with immune evasion, such as nucleases (nuc), Staphylococcal Chemotaxis Inhibitory Protein (chips), and Staphylococcal Complement Inhibitor (scin), thereby undermining immune escape and amplifying neutrophil chemotaxis. Upon application in an in vivo setting, Mo-A assumes a protective persona in a murine model of S. aureus USA300-induced pneumonia and demonstrates efficacy in the Galleria mellonella infection model. Of note, S. aureus displayed no swift acquisition of resistance to Mo-A, and the effect was synergistically enhanced when used in combination with vancomycin. Our findings add substantive weight to the expanding field of virulence-targeted therapeutic strategies and set the stage for more comprehensive exploration of Mo-A potential in combating antibiotic-resistant S. aureus.

Suicidal ideation in Chinese patients with advanced breast cancer: a multi-center mediation model study.

PURPOSE: The pathways underpinning suicide ideation (SI) and certain physical and psychological factors in patients with advanced breast cancer remain unclear. This study develops and validates a mediation model that delineates the associations between several multidimensional variables and SI in Chinese patients with advanced breast cancer. METHODS: Patients with advanced breast cancer (n = 509) were recruited as study participants from 10 regional cancer centers across China from August 2019 to December 2020. Participants were required to complete five questionnaires using an electronic patient-reported outcomes (ePRO) system: 9 item- Patient Health Questionnaire (PHQ-9), Hospital Anxiety and Depression Scale (HADS), Insomnia Severity Index (ISI), 5-level EQ-5D (EQ-5D-5L), and MD Anderson Symptom Inventory (MDASI). Risk factors for SI were identified using multivariable logistic regression, and inputted into serial multiple mediation models to elucidate the pathways linking the risk factors to SI. RESULTS: SI prevalence was 22.8% (116/509). After adjusting for covariates, depression (odds ratio [OR] = 1.384), emotional distress (OR = 1.107), upset (OR = 0.842), and forgetfulness (OR = 1.236) were identified as significant independent risk factors (all p < 0.05). The ORs indicate that depression and distress have the strongest associations with SI. Health status has a significant indirect effect (OR=-0.044, p = 0.005) and a strong total effect (OR=-0.485, p < 0.001) on SI, mediated by insomnia severity and emotional distress. CONCLUSIONS: There is a high SI prevalence among Chinese patients with advanced breast cancer. Our analysis revealed predictive pathways from poor health to heightened SI, mediated by emotional distress and insomnia. Regular management of distress and insomnia can decrease suicide risk in this vulnerable population.

Development of a prediction model for suicidal ideation in patients with advanced cancer: A multicenter, real-world, pan-cancer study in China.

BACKGROUND: Patients diagnosed with advanced stage cancer face an elevated risk of suicide. We aimed to develop a suicidal ideation (SI) risk prediction model in patients with advanced cancer for early warning of their SI and facilitate suicide prevention in this population. PATIENTS AND METHODS: We consecutively enrolled patients with multiple types of advanced cancers from 10 cancer institutes in China from August 2019 to December 2020. Demographic characteristics, clinicopathological data, and clinical treatment history were extracted from medical records. Symptom burden, psychological status, and SI were assessed using the MD Anderson Symptom Inventory (MDASI), Hospital Anxiety and Depression Scale (HADS), and Patient Health Questionnaire-9 (PHQ-9), respectively. A multivariable logistic regression model was employed to establish the model structure. RESULTS: In total, 2814 participants were included in the final analysis. Nine predictors including age, sex, number of household members, history of previous chemotherapy, history of previous surgery, MDASI score, HADS-A score, HADS-D score, and life satisfaction were retained in the final SI prediction model. The model achieved an area under the curve (AUC) of 0.85 (95% confidential interval: 0.82-0.87), with AUCs ranging from 0.75 to 0.95 across 10 hospitals and higher than 0.83 for all cancer types. CONCLUSION: This study built an easy-to-use, good-performance predictive model for SI. Implementation of this model could facilitate the incorporation of psychosocial support for suicide prevention into the standard care of patients with advanced cancer.

Association between anxiety, depression, and symptom burden in patients with advanced colorectal cancer: A multicenter cross-sectional study.

OBJECTIVES: Patients with advanced colorectal cancer (CRC) have multiple concurrent physical and psychological symptoms. This study aimed to explore the relationship between anxiety, depression, and symptom burden in advanced CRC. METHODS: A multicenter cross-sectional study was conducted in 10 cancer centers from geographically and economically diverse sites in China. A total of 454 patients with advanced CRC completed the Hospital Anxiety and Depression Scale and the MD Anderson Symptom Inventory. Multiple regression analysis was applied to explore the relationship between anxiety, depression and symptom burden. RESULTS: About one-third of the patients showed symptoms of anxiety or depression. Patients with anxiety or depression reported significantly higher symptom burden than those without (p < 0.001). Patients with anxiety or depression reported a higher proportion of moderate-to-severe (MS) symptom number than those without (p < 0.001). About 52% of the patients with anxiety or depression reported at least three MS symptoms. The prevalence of MS symptoms was ranging from 7.3% (shortness of breath) to 22% (disturbed sleep), and in patients with anxiety or depression was 2-10 times higher than in those without (p < 0.001). Disease stage (ß = -2.55, p = 0.003), anxiety (ß = 15.33, p < 0.001), and depression (ß = 13.63, p < 0.001) were associated with higher symptom burden. CONCLUSIONS: Anxiety and depression in patients with advanced cancer correlated with higher symptom burden. Findings may lead oncology professionals to pay more attention to unrecognized and untreated psychological symptoms in symptom management for advanced cancer patients.

Inhibitory Effect of Salicin on Staphylococcus aureus Coagulase.

The massive use of antibiotics has resulted in an alarming increase in antibiotic resistance in Staphylococcus aureus (S. aureus). This study aimed to identify the inhibitory effect of salicin on S. aureus. Coagulase (Coa) activity was assessed using in vitro Coa assays and Western blot, thermal shift assay (TSA), fluorescence quenching and molecular docking experiments were conducted to verify the interaction between salicin and Coa. An in vivo mouse pneumonia model demonstrated that salicin can reduce the virulence of S. aureus. In vitro Coa assays elucidated that salicin directly inhibited Coa activity. The Western blot and TSA results suggested that salicin did not block the expression of Coa but affected the thermal stability of the protein by binding to Coa. The fluorescence quenching, molecular docking and molecular dynamics assays have found that the most promising binding site between salicin and Coa was GLN-97. The pneumonia model of mice infected with S. aureus revealed that salicin could not only reduce the content of lung bacteria in mice but also prolong their survival. Salicin was identified as a novel anti-infective candidate compound with the potential to target Coa and inhibit its activity by binding to it, which would facilitate the development of roadmaps for future research.

Loganin reduces diabetic kidney injury by inhibiting the activation of NLRP3 inflammasome-mediated pyroptosis.

Diabetic kidney disease (DKD) is an essential cause of end-stage renal disease. The ongoing inflammatory response in the proximal tubule promotes the progression of DKD. Timely and effective blockade of the inflammatory process to protect the kidney during DKD progression is a proven strategy. The purpose of this study was to investigate the protective effect of loganin on diabetic nephropathy in vivo and in vitro and whether this effect was related to the inhibition of pyroptosis. The results indicated that loganin reduced fasting blood glucose, blood urea nitrogen and serum creatinine concentrations, and alleviated renal pathological changes in DKD mice. In parallel, loganin downregulated the expression of pyroptosis related proteins in the renal tubules of DKD mice and decreased serum levels of interleukin-1beta (IL-1ß) and interleukin-18 (IL-18). Furthermore, in vitro experiments showed that loganin attenuated high glucose-induced HK-2 cell injury by reducing the expression of pyroptosis-related proteins, and cytokine levels were also decreased. These fundings were also confirmed in the polyphyllin VI (PPVI) -induced HK-2 cell pyroptosis model. Loganin reduces high glucose induced HK-2 cells pyroptosis by inhibiting reactive oxygen species (ROS) production and NOD-like receptor protein 3 (NLRP3) inflammasome activation. In conclusion, the inhibition of pyroptosis via inhibition of the NLRP3/Caspase-1/Gasdermin D (GSDMD) pathway might be an essential mechanism for loganin treatment of DKD.