ABSTRACT
Multi-resistant Staphylococcus aureus (S. aureus) infection is a significant global health concern owing to its high mortality and morbidity rates. Coagulase (Coa), a key enzyme that activates prothrombin to initiate host coagulation, has emerged as a promising target for anti-infective therapeutic approaches. This study identified sinigrin as a potent Coa inhibitor that significantly inhibited S. aureus-induced coagulation at concentration as low as 32 mg/L. Additionally, at a higher concentration of 128 mg/L, sinigrin disrupted the self-protection mechanism of S. aureus. Thermal shift and fluorescence-quenching assays confirmed the direct binding of sinigrin to the Coa protein. Molecular docking analysis predicted specific binding sites for sinigrin in the Coa molecule, and point mutation experiments highlighted the importance of Arg-187 and Asp-222 as critical binding sites for both Coa and sinigrin. In vivo studies demonstrated that the combination of sinigrin with oxacillin exhibited greater antibacterial efficacy than oxacillin alone in the treatment of S. aureus-induced pneumonia in mice. Furthermore, sinigrin was shown to reduce bacterial counts and inflammatory cytokine levels in the lung tissues of S. aureus-infected mice. In summary, sinigrin was shown to directly target Coa, resulting in the attenuation of S. aureus virulence, which suggests the potential of sinigrin as an adjuvant for future antimicrobial therapies.
ABSTRACT
The extracellular matrix (ECM) has been demonstrated to be dysregulated and crucial for malignant progression in gastric cancer (GC), but the mechanism is not well understood. Here, that discoidin domain receptor 1 (DDR1), a principal ECM receptor, is recognized as a key driver of GC progression is reported. Mechanistically, DDR1 directly interacts with the PAS domain of hypoxia-inducible factor-1α (HIF-1α), suppresses its ubiquitination and subsequently strengthens its transcriptional regulation of angiogenesis. Additionally, DDR1 upregulation in GC cells promotes actin cytoskeleton reorganization by activating HIF-1α/ Ras Homolog Family Member A (RhoA)/Rho-associated protein kinase 1 (ROCK1) signaling, which in turn enhances the metastatic capacity. Pharmacological inhibition of DDR1 suppresses GC progression and angiogenesis in patient-derived xenograft (PDX) and organoid models. Taken together, this work first indicates the effects of the DDR1-HIF-1α axis on GC progression and reveals the related mechanisms, providing experimental evidence for DDR1 as a therapeutic target for GC.
ABSTRACT
The increasing prevalence of infections related to methicillin-resistant Staphylococcus aureus (MRSA) necessitates the exploration of innovative therapeutic strategies that diverge from conventional antibiotic treatments. This is imperative to effectively combat resistance and manage these infections. The adoption of antivirulence strategies has emerged as a particularly promising avenue. This approach applies a heightened selective pressure on pathogens, thereby diminishing the likelihood of bacteria evolving resistance to antibiotics. In our pursuit of novel therapeutics for treating MRSA infections, we have focused on agents that inhibit the virulence of S. aureus without impeding its growth, aiming to minimize the development of drug resistance. α-Hemolysin, a critical virulence factor encoded by the hla gene, is a cytotoxin that forms pores in host cell membranes and plays a pivotal role in the progression of disease during bacterial infections. Herein, we identified that norwogonin could effectively inhibit Hla production via targeting agrAC, a crucial protein in quorum sensing, resulting in dose-dependent inhibition of hemolytic activity without suppressing S. aureus growth. In vitro assays illustrated that norwogonin decreased the thermal stability of agrAC, providing evidence of interaction between norwogonin and agrAC. Meanwhile, norwogonin alleviated Hla-mediated A549 cell damage and reduced lactate dehydrogenase release. In vivo studies suggested that norwogonin treatment blocked the establishment of a mouse model of pneumonia caused by S. aureus USA300. Notably, norwogonin enhanced the antibacterial potency of oxacillin. In conclusion, norwogonin is a promising candidate for treating S. aureus infections, offering a novel alternative to traditional antibiotics by targeting virulence factors and enhancing the efficacy of existing treatments.
Subject(s)
Anti-Bacterial Agents , Bacterial Proteins , Hemolysin Proteins , Methicillin-Resistant Staphylococcus aureus , Virulence Factors , Animals , Female , Humans , Mice , A549 Cells , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Bacterial Toxins/metabolism , Disease Models, Animal , Hemolysin Proteins/metabolism , Hemolysis/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Mice, Inbred BALB C , Quorum Sensing/drug effects , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Virulence/drug effects , Virulence Factors/metabolismABSTRACT
TGFBR2, a key regulator of the TGFß signaling pathway, plays a crucial role in gastric cancer (GC) metastasis through its endosomal recycling process. Despite its importance, the mechanisms governing this process remain unclear. Here, we identify integrin ß5 (ITGB5) as a critical mediator that promotes TGFBR2 endosomal recycling. Our study reveals elevated expression of ITGB5 in GC, particularly in metastatic cases, correlating with poor patient outcomes. Knockdown of ITGB5 impairs GC cell metastasis both in vitro and in vivo. Mechanistically, ITGB5 facilitates epithelial-mesenchymal transition mediated by TGFß signaling, thereby enhancing GC metastasis. Acting as a scaffold, ITGB5 interacts with TGFBR2 and SNX17, facilitating SNX17-mediated endosomal recycling of TGFBR2 and preventing lysosomal degradation, thereby maintaining its surface distribution on tumor cells. Notably, TGFß signaling directly upregulates ITGB5 expression, establishing a positive feedback loop that exacerbates GC metastasis. Our findings shed light on the role of ITGB5 in promoting GC metastasis through SNX17-mediated endosomal recycling of TGFBR2, providing insights for the development of targeted cancer therapies.
Subject(s)
Endosomes , Epithelial-Mesenchymal Transition , Receptor, Transforming Growth Factor-beta Type II , Signal Transduction , Stomach Neoplasms , Animals , Humans , Mice , Cell Line, Tumor , Endosomes/metabolism , Gene Expression Regulation, Neoplastic , Integrin beta Chains/metabolism , Integrin beta Chains/genetics , Neoplasm Metastasis , Receptor, Transforming Growth Factor-beta Type II/genetics , Receptor, Transforming Growth Factor-beta Type II/metabolism , Sorting Nexins/genetics , Sorting Nexins/metabolism , Stomach Neoplasms/pathology , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Transforming Growth Factor beta/metabolismABSTRACT
The efficacy of neoadjuvant chemotherapy (NACT) in patients with advanced gastric cancer (GC) varies greatly. Thus, we aimed to verify the predictive value of tumor-infiltrating immune cells (TIICs) on the treatment response to NACT and the prognosis of patients with advanced GC, and to explore the impact of NACT on the tumor immune microenvironment (TIME). Paired tumor tissues (pre- and post-NACT) from patients with advanced GC were collected for this study. TIICs were assessed using immunohistochemistry staining and analyzed using logistic regression to establish an immune microenvironment score for GC (ISGC score) and predict NACT efficacy. Kaplan-Meier curves were used to evaluate the survival outcome of patients. The results showed that TIME was dramatically heterogeneous between NACT response and nonresponse patients. In the validation cohort, the ISGC score demonstrated good predictive performance for treatment response to NACT. Moreover, high ISGC indicated better long-term survival in patients with advanced GC. Furthermore, tumor-infiltrated T cells (CD3+ and CD8+) and CD11c+ macrophages were significantly increased in the response group, while CD163+ macrophages and FOXP3+ Treg cells were decreased after NACT. However, opposite results were exhibited in the nonresponse group. Finally, we found that the percentage of programmed cell death ligand 1 (PD-L1)-positive tumors was 31% (32/104) pre-NACT and 49% (51/104) post-NACT, and almost all patients with elevated PD-L1 were in the NACT response group. The ISGC model accurately predicted NACT efficacy and classified patients with GC into different survival groups. NACT regulates the TIME in GC, which may provide strategies for personalized immunotherapy.
Subject(s)
Lymphocytes, Tumor-Infiltrating , Neoadjuvant Therapy , Stomach Neoplasms , Tumor Microenvironment , Humans , Stomach Neoplasms/pathology , Stomach Neoplasms/immunology , Stomach Neoplasms/drug therapy , Stomach Neoplasms/mortality , Female , Male , Middle Aged , Lymphocytes, Tumor-Infiltrating/immunology , Aged , Prognosis , Chemotherapy, Adjuvant , Treatment Outcome , Biomarkers, Tumor/analysis , Adult , Predictive Value of TestsABSTRACT
Postharvest rot, caused by Penicillium expansum, in tomatoes poses significant economic and health risks. Traditional control methods, such as the use of fungicides, raise concerns about pathogen resistance, food safety, and environmental impact. In search of sustainable alternatives, plant secondary metabolites, particularly phenolic compounds and their derivatives, have emerged as promising natural antimicrobials. Among these, feruloyl glyceride (FG), a water-soluble derivative of ferulic acid, stands out due to its antioxidant properties, antibacterial properties, and improved solubility. In this study, we provide evidence demonstrating FG is capable of inhibiting the spore germination of P. expansum and effectively reducing the incidence rate of Penicillium rot of tomatoes, without compromising quality. Electron microscopy observations combined with metabolite and transcriptomic analyses revealed that FG treatments resulted in enhanced suberin accumulation through promoting the expression of suberin synthesis related genes and, consequently, inhibited the growth and expansion of P. expansum on the fruits. This work sheds light on the mechanisms underlying FG's inhibitory effects, allowing its potential application as a natural and safe alternative to replace chemical fungicides for postharvest preservation.
ABSTRACT
BACKGROUND: Circular RNAs (circRNAs) have been proved to play crucial roles in the development of various cancers. However, the molecular mechanism of circGLIS3 involved in gastric cancer (GC) tumorigenesis has not been elucidated. METHODS: The higher expression level of circGLIS3 was identified in GC through RNA sequencing and subsequent tissue verification using Quantitative real-time PCR (qRT-PCR). A series of functional experiments in vitro and in vivo were performed to evaluated the effects of circGLIS3 on tumor growth and metastasis in GC. The interaction and regulation of circGLIS3/miR-1343-3p/PGK1 axis was confirmed by RNA pulldown, western blot, and rescue experiments. RIP and western blot were performed to demonstrate the role of circGLIS3 in regulating phosphorylation of VIMENTIN. We then used qRT-PCR and co culture system to trace circGLIS3 transmission via exosomal communication and identify the effect of exosomal circGLIS3 on gastric cancer and macrophages. Finally, RIP experiments were used to determine that EIF4A3 regulates circGLIS3 expression. RESULTS: CircGLIS3(hsa_circ_0002874) was significantly upregulated in GC tissues and high circGLIS3 expression was associated with advanced TNM stage and lymph node metastasis in GC patients. We discovered that overexpression of circGLIS3 promoted GC cell proliferation, migration, invasion in vitro and in vivo, while suppression of circGLIS3 exhibited the opposite effect. Mechanistically, circGLIS3 could sponge miR-1343-3p and up-regulate the expression of PGK1 to promote GC tumorigenesis. We also found that circGLIS3 reduced the phosphorylation of VIMENTIN at ser 83 site by binding with VIMENTIN. Moreover, it was proven that exosomal circGLIS3 could promote gastric cancer metastasis and the M2 type polarization of macrophages. In the final step, the mechanism of EIF4A3 regulating the generation of circGLIS3 was determined. CONCLUSION: Our findings demonstrate that circGLIS3 promotes GC progression through sponging miR-1343-3p and regulating VIMENTIN phosphorylation. CircGLIS3 is a potential therapeutic target for GC patients.
Subject(s)
MicroRNAs , Stomach Neoplasms , Humans , Carcinogenesis , Cell Line, Tumor , Cell Proliferation/genetics , Cell Transformation, Neoplastic , DEAD-box RNA Helicases , Eukaryotic Initiation Factor-4A , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Phosphoglycerate Kinase , Phosphorylation , Stomach Neoplasms/genetics , Vimentin/geneticsABSTRACT
Liver metastasis is the leading cause of mortality in patients with colorectal cancer. Given the significance of both epithelial-mesenchymal transition (EMT) of tumor cells and the immune microenvironment in colorectal cancer liver metastasis (CRLM), the interplay between them could hold the key for developing improved treatment options. We employed multiomics analysis of 130 samples from 18 patients with synchronous CRLM integrated with external datasets to comprehensively evaluate the interaction between immune cells and EMT of tumor cells in liver metastasis. Single-cell RNA sequencing analysis revealed distinct distributions of nonmalignant cells between primary tumors from patients with metastatic colorectal cancer (mCRC) and non-metastatic colorectal cancer, showing that Th17 cells were predominantly enriched in the primary lesion of mCRC. TWEAK, a cytokine secreted by Th17 cells, promoted EMT by binding to receptor Fn14 on tumor cells, and the TWEAK-Fn14 interaction enhanced tumor migration and invasion. In mouse models, targeting Fn14 using CRISPR-induced knockout or lipid nanoparticle-encapsulated siRNA alleviated metastasis and prolonged survival. Mice lacking Il17a or Tnfsf12 (encoding TWEAK) exhibited fewer metastases compared with wild-type mice, while cotransfer of Th17 with tumor cells promoted liver metastasis. Higher TWEAK expression was associated with a worse prognosis in patients with colorectal cancer. In addition, CD163L1+ macrophages interacted with Th17 cells, recruiting Th17 via the CCL4-CCR5 axis. Collectively, this study unveils the role of immune cells in the EMT process and identifies TWEAK secreted by Th17 as a driver of CRLM. SIGNIFICANCE: TWEAK secreted by Th17 cells promotes EMT by binding to Fn14 on colorectal cancer cells, suggesting that blocking the TWEAK-Fn14 interaction may be a promising therapeutic approach to inhibit liver metastasis.
Subject(s)
Colorectal Neoplasms , Liver Neoplasms , Humans , Animals , Mice , Th17 Cells , Cytokine TWEAK , Epithelial-Mesenchymal Transition/genetics , Prognosis , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Liver Neoplasms/genetics , Liver Neoplasms/secondary , TWEAK Receptor/genetics , Cell Line, Tumor , Cell Movement/genetics , Tumor MicroenvironmentABSTRACT
Purpose: To evaluate the course of the cutaneous nerve regarding the first extensor compartment to determine whether the dorsal or volar approach is safer for local injection into the first extensor compartment guided by ultrasound. Methods: We dissected the radial side of the wrists from 28 cadavers (52 wrists). Four-points along the imaginary line were set: the styloid process and 1 cm, 2 cm, and 3 cm proximal to the styloid process. The numbers of superficial radial nerve (SRN) and lateral antebrachial cutaneous nerve (LACN) branches were counted, and distances from the imaginary line at these points and nerve diameters were recorded. Digital images were superimposed to observe overall distribution of cutaneous nerve. Results: There were means of 3.3 SRN and 0.9 LACN branches observed in each wrist. The mean number of both SRN and LACN branches was 2.3 on the dorsal side and 1.9 on the volar side. The superimposed images indicated that both the dorsal and volar sides comprised abundant cutaneous nerves and that their paths varied markedly between patients. However, we observed that larger nerves with meaningful diameters were more abundant on the dorsal than the volar side. Conclusion: There were similar numbers of cutaneous nerves on both the dorsal and volar sides; however, we observed greater abundance of thicker cutaneous nerves on the dorsal side, and these were closer to the reference line than on the volar side. This anatomical study suggests that the risk imposed to cutaneous nerves would therefore be reduced when injection on the volar side.
ABSTRACT
BACKGROUND: Right hemicolectomy is the standard treatment for right-sided colon cancer. There is variation in the technical aspects of performing right hemicolectomy as well as in short-term outcomes. It is therefore necessary to explore best clinical practice following right hemicolectomy in expert centres. METHODS: This snapshot study of right hemicolectomy for colon cancer in China was a prospective, multicentre cohort study in which 52 tertiary hospitals participated. Eligible patients with stage I-III right-sided colon cancer who underwent elective right hemicolectomy were consecutively enrolled in all centres over 10 months. The primary endpoint was the incidence of postoperative 30-day anastomotic leak. RESULTS: Of the 1854 patients, 89.9 per cent underwent laparoscopic surgery and 52.3 per cent underwent D3 lymph node dissection. The overall 30-day morbidity and mortality were 11.7 and 0.2 per cent, respectively. The 30-day anastomotic leak rate was 1.4 per cent. In multivariate analysis, ASA grade > II (P < 0.001), intraoperative blood loss > 50â ml (P = 0.044) and D3 lymph node dissection (P = 0.008) were identified as independent risk factors for postoperative morbidity. Extracorporeal side-to-side anastomosis (P = 0.031), intraoperative blood loss > 50â ml (P = 0.004) and neoadjuvant chemotherapy (P = 0.004) were identified as independent risk factors for anastomotic leak. CONCLUSION: In high-volume expert centres in China, laparoscopic resection with D3 lymph node dissection was performed in most patients with right-sided colon cancer, and overall postoperative morbidity and mortality was low. Further studies are needed to explore the optimal technique for right hemicolectomy in order to improve outcomes further.
Subject(s)
Colonic Neoplasms , Laparoscopy , Humans , Anastomotic Leak/epidemiology , Anastomotic Leak/etiology , Anastomotic Leak/surgery , Cohort Studies , Prospective Studies , Blood Loss, Surgical , Colonic Neoplasms/pathology , Colectomy/adverse effects , Colectomy/methods , Morbidity , Risk Factors , Laparoscopy/adverse effects , Laparoscopy/methods , Retrospective StudiesABSTRACT
Hydrogen sulfide (H2S) is a gasotransmitter with significant physiological effects, including anti-inflammatory properties, regulation of oxidative stress, and vasodilation, thus regulating body functions. Functional therapy involves using treatments that target the underlying cause of a disease, rather than simply treating symptoms. Epigenetics refers to changes in gene expression that occur through modifications to DNA, to the proteins that package DNA, or to noncoding RNA mechanisms. Recent research advances suggest that H2S may play a role in epigenetic regulation by altering DNA methylation patterns and regulating histone deacetylases, enzymes that modify histone proteins, or modulating microRNA mechanisms. These critical findings suggest that H2S may be a promising molecule for functional therapy in various diseases where epigenetic modifications are dysregulated. We reviewed the relevant research progress in this area, hoping to provide new insights into the epigenetic mechanisms of H2S. Despite the challenges of clinical use of H2S, future research may lead to the progress of new therapeutic approaches. Antioxid. Redox Signal. 40, 110-121.
Subject(s)
Hydrogen Sulfide , MicroRNAs , Epigenesis, Genetic , Hydrogen Sulfide/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , DNA Methylation , DNA/metabolismABSTRACT
BACKGROUND: The purpose of this study was to determine the distribution of the angular artery (AA) in the medial canthal area with the aim of defining an arterial course to prevent AA injury during facial surgery in this region. METHODS: The authors dissected 36 hemifaces of 18 cadavers. The horizontal distance from the vertical level through the medial canthus to the AAs was measured. The AA course of each specimen was then recorded, and all of them were then superimposed to determine the AA course. The diameter and depth of the AA around the medial canthal area were also investigated using ultrasonography on living subjects. RESULTS: The horizontal distances from the medial canthus level and 2 cm below the medial canthus were 9.0 ± 2.0 mm (mean ± SD) and 1.9 ± 2.4 mm, respectively. The superimposed image demonstrated that most of the AAs were present inside the vertical line through the medial canthus. Ultrasonography indicated that the AA was 2.3 ± 0.9 mm below the skin and 1.7 ± 0.3 mm in diameter. CONCLUSIONS: The AA course was relatively constant along the nasojugal fold. The AAs were most often present between the middle of the medial canthus and the facial midline, but were very scarce in both the medial and lateral thirds. Knowledge of the detailed course of the AA may help surgeons to avoid arterial injury and decrease the risk of surgical morbidities around the nasal root and medial canthal area.
Subject(s)
Lacrimal Apparatus , Vascular System Injuries , Humans , Face/diagnostic imaging , Face/surgery , Nose/blood supply , Ultrasonography , Arteries/diagnostic imagingABSTRACT
Objective To investigate the relationship between serum stem cell factor receptor(c-kit)and myocardial fibrosis,cardiac function and prognosis in patients with dilated cardiomyopathy(DCM)complicat-ed with heart failure.Methods A total of 77 patients with DCM complicated with heart failure who were trea-ted in 3201 Hospital from May 2020 to June 2022 were enrolled in the study as study group,and 70 DCM pa-tients without heart failure were enrolled as the control group.The levels of serum c-kit mRNA and three my-ocardial fibrosis markers[α-smooth muscle actin(α-SMA),collagen type Ⅰ and collagen type Ⅲ]were detec-ted in the two groups.Cardiac function parameters were obtained by echocardiography.The relationship be-tween serum c-kit mRNA level and myocardial fibrosis and cardiac function was analyzed.According to the oc-currence of major adverse cardiovascular events(MACE),the patients were divided into poor prognosis group and good prognosis group.Multivariate Logistic regression analysis was used to analyze the factors affecting the prognosis of DCM patients complicated with heart failure.Receiver operating characteristic(ROC)curve was used to analyze the efficacy of serum c-kit mRNA level in predicting the prognosis of DCM patients.Results The serum c-kit mRNA level in the study group was lower than that in the control group(P<0.05).The levels of three myocardial fibrosis indicators in the study group were higher than those in the con-trol group(P<0.05).The left ventricular ejection fraction(LVEF)in the study group was lower than that in the control group(P<0.05),and the left ventricular end-diastolic volume(LVEDV)and left ventricular end-systolic volume(LVESV)in the study group were higher than those in the control group(P<0.05).Pearson correlation analysis showed that serum c-kit mRNA level was positively correlated with LVEF(r=0.677,P<0.05),while negatively correlated with α-SMA,collagen type Ⅰ,collagen type Ⅲ,LVEDV and LVESV(r=-0.725,-0.748,-0.744,-0.745,-0.662,P<0.05).Multivariate Logistic regression analysis showed that serum c-kit mRNA level is an independent factor for the prognosis of DCM patients with heart failure.ROC curve analysis showed that serum c-kit mRNA level had a sensitivity of 82.80%,a specificity of 81.80%,and an area under the curve of 0.829(95%CI:0.745-0.912,P<0.001)for evaluating the progno-sis of DCM patients complicated with heart failure.Conclusion The serum c-kit mRNA level is significantly decreased in patients with DCM complicated with heart failure,and the serum c-kit mRNA level is correlated with myocardial fibrosis and cardiac function.The detection of serum c-kit mRNA level has a high efficacy in evaluating the prognosis of patients with DCM complicated with heart failure.
ABSTRACT
Objective:Anterior cruciate ligament injury is the most common type of knee joint ligament injury.Anterior cruciate ligament reconstruction has a high failure rate,with bone tunnel abnormalities as the most significant factor in these failures.Digital orthopedic technology can effectively develop implementation plans for the revision,thus increasing the success rate.This study aims to develop a surgical plan for anterior cruciate ligament revision by employing multiplanar reconstruction(MPR)for measuring bone tunnel position and diameter,and simulating bone tunnel creation via 3D printing preoperatively. Methods:A total of 12 patients who underwent anterior cruciate ligament revision at the Third Xiangya Hospital of Central South University between 2014 and 2021 were retrospectively studied.The data included patient demographics,preoperative formulated knee joint 3D printing models,and preoperative knee CT scans.The study measured the bone tunnel's diameter and position to guide the establishment of revision bone tunnels during surgery,reassessed the postoperative bone tunnels,and evaluated knee joint functional scores[including International Knee Documentation Committee Knee Evaluation Form(IKDC)score,Lysholm score,and Tegner exercise level score]. Results:Preoperative measurements revealed suboptimal femoral tunnels positions in 4 patients and tibial tunnels positions in 2 patients.MPR and 3D printing technology were used to guide the establishment of a new bone canal during surgery,and postoperative measurements were satisfactory for all patients.Preoperative measurements demonstrated the interclass correlation coefficient for femoral tunnels and tibial tunnels diameters were 0.843(P<0.05)and 0.889(P<0.001),respectively.Meanwhile,the intraclass correlation coefficient were 0.811(P<0.05)and 0.784(P<0.05),respectively.The intraoperative diameter of femoral and tibial tunnels showed excellent correlation with postoperative CT measurements,with intraclass correlation coefficient values of 0.995(P<0.001)and 0.987(P<0.001),respectively.All bone tunnel positions were within the normal range.At the final follow-up,knee joint function scores in all 12 patients improved significantly compared to pre-surgery(P<0.001),and the reoperation rate was zero. Conclusion:MPR and 3D printing technology can accurately measure the parameters of reconstructed anterior cruciate ligament bone tunnels.Personalized revision plans for patients with reconstruction failure enhances the success rate of revision surgery and improves patient prognosis.
ABSTRACT
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.
Subject(s)
Methicillin-Resistant Staphylococcus aureus , Pneumonia , Animals , Mice , Humans , Methicillin-Resistant Staphylococcus aureus/metabolism , Vancomycin/pharmacology , Vancomycin/therapeutic use , Staphylococcus aureus/metabolism , Disease Models, Animal , Bacterial Proteins/metabolismABSTRACT
With the global epidemic and prevention of the COVID-19, long COVID-19 sequelae and its comprehensive prevention have attracted widespread attention. Long COVID-19 sequelae refer to that three months after acute COVID-19, the test of SARS-CoV-2 is negative, but some symptoms still exist, such as cough, prolonged dyspnea and fatigue, shortness of breath, palpitations and insomnia. Its pathological mechanism is related to direct viral damage, immunopathological response, endocrine and metabolism disorders. Although there are more effective methods for treating COVID-19, the treatment options available for patients with long COVID-19 remain quite limited. Psychophysical therapies, such as exercise, oxygen therapy, photobiomodulation, and meditation, have been attempted as treatment modalities for long COVID-19, which have the potential to promote recovery through immune regulation, antioxidant effects, and neuroendocrine regulation. Neuroendocrine regulation plays a significant role in repairing damage after viral infection, regulating immune homeostasis, and improving metabolic activity in patients with long COVID-19. This review uses oxytocin as an example to examine the neuroendocrine mechanisms involved in the psychophysical therapies of long COVID-19 syndrome and proposes a psychophysical strategy for the treatment of long COVID-19.
Subject(s)
COVID-19 , Post-Acute COVID-19 Syndrome , Humans , COVID-19/therapy , SARS-CoV-2 , Neurosecretory Systems , Disease ProgressionABSTRACT
BACKGROUND: Long non-coding RNAs (lncRNAs) plays an important role in the progression of gastric cancer (GC). Their involvement ranges from genetic regulation to cancer progression. However, the mechanistic roles of RP11-789C1.1 in GC are not fully understood. METHODS: We identified the expression of lncRNA RP11-789C1.1 in GC tissues and cell lines by real-time fluorescent quantitative polymerase chain reaction. A series of functional experiments revealed the effect of RP11-789C1.1 on the proliferation of GC cells. In vivo experiments verified the effect of RP11-789C1.1 on the biological behavior of a GC cell line. RNA pull-down unveiled RP11-789C1.1 interacting proteins. Western blot analysis indicated the downstream pathway changes of RP11-789C1.1, and an oxaliplatin dosing experiment disclosed the influence of RP11-789C1.1 on the drug sensitivity of oxaliplatin. RESULTS: Our results demonstrated that RP11-789C1.1 inhibited the proliferation of GC cells and promoted the apoptosis of GC cells. Mechanistically, RP11-789C1.1 inhibited checkpoint kinase 1 (CHK1) phosphorylation by binding ataxia-telangiectasia mutated and Rad3 related (ATR), a serine/threonine-specific protein kinase, promoted GC apoptosis, and mediated oxaliplatin sensitivity. CONCLUSION: In general, we discovered a tumor suppressor molecule RP11-789C1.1 and confirmed its mechanism of action, providing a theoretical basis for targeted GC therapy.
ABSTRACT
Staphylococcus aureus (S. aureus) induces a variety of infectious diseases in humans and animals and is responsible for hospital- and community-acquired infections. The aim of this study was to investigate how bilobetin, a natural compound, attenuates S. aureus virulence by inhibiting two key virulence factors, von Willebrand factor-binding protein (vWbp) and staphylocoagulase (Coa). The results showed that bilobetin inhibited Coa- or vWbp-induced coagulation without affecting S. aureus proliferation. The Western blotting and fluorescence quenching assays indicated that bilobetin did not affect the expression of vWbp and Coa but directly bound to the proteins with KA values of 1.66 × 104 L/mol and 1.04 × 104 L/mol, respectively. To gain further insight into the mechanism of interaction of bilobetin with these virulence factors, we performed molecular docking and point mutation assays, which indicated that the TYR-6 and TYR-18 residues on vWbp and the ALA-190 and ASP-189 residues on Coa were essential for the binding of bilobetin. In addition, the in vivo studies showed that bilobetin ameliorated lung tissue damage and inflammation caused by S. aureus, thereby improving the survival of mice. Furthermore, the use of bilobetin as an adjuvant in combination with vancomycin was more effective in the treatment of a mouse model of pneumonia. Taken together, bilobetin had a dual inhibitory effect on vWbp and Coa by reducing the virulence of S. aureus, suggesting that it is a viable lead compound against S. aureus infections.
Subject(s)
Coagulase , Staphylococcal Infections , Humans , Mice , Animals , Coagulase/genetics , Coagulase/metabolism , Coagulase/pharmacology , Carrier Proteins/metabolism , Staphylococcus aureus , Virulence , von Willebrand Factor/metabolism , von Willebrand Factor/pharmacology , Molecular Docking Simulation , Staphylococcal Infections/drug therapy , Virulence Factors/genetics , Virulence Factors/metabolismABSTRACT
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.
Subject(s)
Bilobalides , Pneumonia , Staphylococcal Infections , Mice , Animals , Carrier Proteins/metabolism , von Willebrand Factor/genetics , von Willebrand Factor/metabolism , Staphylococcus aureus/metabolism , Staphylococcal Infections/drug therapyABSTRACT
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 inâ 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 inâ 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.