The role of programmed cell death in osteosarcoma: From pathogenesis to therapy.

Osteosarcoma (OS) is a prevalent bone solid malignancy that primarily affects adolescents, particularly boys aged 14-19. This aggressive form of cancer often leads to deadly lung cancer due to its high migration ability. Experimental evidence suggests that programmed cell death (PCD) plays a crucial role in the development of osteosarcoma. Various forms of PCD, including apoptosis, ferroptosis, autophagy, necroptosis, and pyroptosis, contribute significantly to the progression of osteosarcoma. Additionally, different signaling pathways such as STAT3/c-Myc signal pathway, JNK signl pathway, PI3k/AKT/mTOR signal pathway, WNT/ß-catenin signal pathway, and RhoA signal pathway can influence the development of osteosarcoma by regulating PCD in osteosarcoma cell. Therefore, targeting PCD and the associated signaling pathways could offer a promising therapeutic approach for treating osteosarcoma.

Decadal analysis of efficacy and safety profiles of mesenchymal stem cells from varied sources in knee osteoarthritis patients: A systematic review and network meta-analysis.

OBJECTIVE: Knee Osteoarthritis (KOA) is a debilitating degenerative joint ailment afflicting millions of patients. Numerous studies have assessed the efficacy of mesenchymal stem cells (MSCs) derived from various sources for KOA treatment, yet direct comparisons are scarce and inconsistent. Furthermore, network meta-analysis (NMA) conclusions require updating, while the safety of MSCs therapy remains contentious. This study evaluates therapeutic approaches involving MSCs from different sources in patients with KOA through randomized controlled trials (RCTs) and cohort studies. The objective is to compare the effectiveness and safety of MSCs strategies from various sources for KOA treatment. METHODS: A systematic literature review was conducted to identify RCTs and cohort studies comparing different sources of MSCs in KOA patients. A randomized effects network meta-analysis was used to concurrently evaluate both direct and indirect comparisons across all protocols. RESULTS: The NMA included 16 RCTS and reported 1005 participants. Adipose-derived mesenchymal stem cells (AD-MSCs) were the most effective treatment, showing significant improvements in the Visual Analogue Scale (VAS), the Short Form 36 (SF-36 scale), the International Knee Literature Committee Knee Evaluation Scale (IKDC subjective scores), and the Knee Injury and OA Outcome Score (KOOS). The probabilities are P = 85.3, P = 70.5, P = 88 and P = 87, respectively. Compared with placebo, AD-MSCs resulted in a VAS Score (SMD 0.97; 95%CI 0.37, 1.57), IKDC subjective scores (SMD -0.71; 95%CI -1.20, -0.21) was significantly reduced. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) showed significant improvements in the University of Western Ontario and McMaster University OA (WOMAC) (P = 91.4). Compared with placebo, UC-MSCs had a higher WOMAC Score (SMD 1.65; 95%CI 0.27, 3.03) and ranked first. Compared with MSCs, placebo emerged as the safer option (P = 74.9), with a notable reduction in AEs associated with HA treatment (RR 0.77; 95%CI 0.61, 0.97). AD-MSCs were found to have the least favorable impact on AEs with a probability of P = 13.3. CONCLUSIONS: This network meta-analysis established that MSCs offer pain relief and enhance various knee scores in KOA patients compared to conventional treatment. It also identifies other therapeutic avenues warranting further exploration through high-quality studies. Nonetheless, it underscores the necessity to emphasize the potential complications and safety concerns associated with MSCs.

Improvement of Post-Surgery Constipation in Patients with Fractures by Lactobacillus rhamnosus JYLR-127: A Single-Blind Randomized Controlled Trial.

The high prevalence of constipation after fracture surgery brings intolerable discomfort to patients on the one hand, and affects post-surgery nutrient absorption on the other hand, resulting in poor prognosis. Given the acknowledged probiotic properties of Lactobacillus rhamnosus, 100 fracture patients with post-surgery constipation were centrally enrolled and administered orally with L. rhamnosus JYLR-127 to assess the efficacy of probiotic-adjuvant therapy in alleviating post-fracture constipation symptoms. The results showed that L. rhamnosus JYLR-127 improved fecal properties, promoted gastrointestinal recovery, and relieved constipation symptoms, which were mainly achieved by elevating Firmicutes (p < 0.01) and descending Bacteroidetes (p < 0.001), hence remodeling the disrupted intestinal microecology. In addition, blood routine presented a decrease in C-reactive protein levels (p < 0.05) and an increase in platelet counts (p < 0.05) after probiotic supplementation, prompting the feasibility of L. rhamnosus JYLR-127 in anti-inflammation, anti-infection and hemorrhagic tendency prevention after fracture surgery. Our study to apply probiotics in ameliorating constipation after fracture surgery is expected to bless the bothered patients, and provide broader application scenarios for L. rhamnosus preparations.

Esophageal cancer screening, early detection and treatment: Current insights and future directions.

Esophageal cancer ranks among the most prevalent malignant tumors globally, primarily due to its highly aggressive nature and poor survival rates. According to the 2020 global cancer statistics, there were approximately 604000 new cases of esophageal cancer, resulting in 544000 deaths. The 5-year survival rate hovers around a mere 15%-25%. Notably, distinct variations exist in the risk factors associated with the two primary histological types, influencing their worldwide incidence and distribution. Squamous cell carcinoma displays a high incidence in specific regions, such as certain areas in China, where it meets the cost-effectiveness criteria for widespread endoscopy-based early diagnosis within the local population. Conversely, adenocarcinoma (EAC) represents the most common histological subtype of esophageal cancer in Europe and the United States. The role of early diagnosis in cases of EAC originating from Barrett's esophagus (BE) remains a subject of controversy. The effectiveness of early detection for EAC, particularly those arising from BE, continues to be a debated topic. The variations in how early-stage esophageal carcinoma is treated in different regions are largely due to the differing rates of early-stage cancer diagnoses. In areas with higher incidences, such as China and Japan, early diagnosis is more common, which has led to the advancement of endoscopic methods as definitive treatments. These techniques have demonstrated remarkable efficacy with minimal complications while preserving esophageal functionality. Early screening, prompt diagnosis, and timely treatment are key strategies that can significantly lower both the occurrence and death rates associated with esophageal cancer.

[Circular RNA-Encoded Proteins in Gastrointestinal Cancer:A Review].

Circular RNAs(CircRNAs)are a class of non-coding RNAs with a covalently closed-loop structure,high stability,and tissue specificity,with the production mechanisms different from linear RNAs.Recent studies have discovered that some CircRNAs can encode proteins via cap-independent translation mechanisms such as internal ribosome entry site,N6-methyladenosine,and rolling loop translation.The encoded proteins regulate homologous linear proteins or downstream signaling pathways via protein bait or other mechanisms,thereby exerting biological functions.Studies have shown that CircRNAs play a role in various diseases,especially in tumor progression,proliferation,invasion,and metastasis and immune regulation.Therefore,by elucidating the expression and roles of proteins encoded by CircRNAs in tumorigenesis and development,this paper is expected to provide new tumor markers and potential targets for tumor diagnosis and treatment.

Upregulation of CYR61 by TGF-ß and YAP signaling exerts a counter-suppression of hepatocellular carcinoma.

Transforming growth factor-ß (TGF-ß) and Hippo signaling are two critical pathways engaged in cancer progression by regulating both oncogenes and tumor suppressors, yet how the two pathways coordinately exert their functions in the development of hepatocellular carcinoma (HCC) remains elusive. In this study, we firstly conducted an integrated analysis of public liver cancer databases and our experimental TGF-ß target genes, identifying CYR61 as a pivotal candidate gene relating to HCC development. The expression of CYR61 is downregulated in clinical HCC tissues and cell lines than that in the normal counterparts. Evidence revealed that CYR61 is a direct target gene of TGF-ß in liver cancer cells. In addition, TGF-ß-stimulated Smad2/3 and the Hippo pathway downstream effectors YAP and TEAD4 can form a protein complex on the promoter of CYR61, thereby activating the promoter activity and stimulating CYR61 gene transcription in a collaborative manner. Functionally, depletion of CYR61 enhanced TGF-ß- or YAP-mediated growth and migration of liver cancer cells. Consistently, ectopic expression of CYR61 was capable of impeding TGF-ß- or YAP-induced malignant transformation of HCC cells in vitro and attenuating HCC xenograft growth in nude mice. Finally, transcriptomic analysis indicates that CYR61 can elicit an antitumor program in liver cancer cells. Together, these results add new evidence for the crosstalk between TGF-ß and Hippo signaling and unveil an important tumor suppressor function of CYR61 in liver cancer.

Uncovering the flip side of immune checkpoint inhibitors: a comprehensive review of immune-related adverse events and predictive biomarkers.

Immune checkpoint inhibitors (ICIs) have generated considerable excitement as a novel class of immunotherapeutic agents due to their remarkable efficacy in treating various types of cancer. However, the widespread use of ICIs has brought about a number of safety concerns, especially the development of immune-related adverse events (irAEs). These serious complications could result in treatment discontinuation and even life-threatening consequences, making it critical to identify high-risk groups and predictive markers of irAEs before initiating therapy. To this end, the current article examines several potential predictive markers of irAEs in important organs affected by ICIs. While retrospective studies have yielded some promising results, limitations such as small sample sizes, variable patient populations, and specific cancer types and ICIs studied make it difficult to generalize the findings. Therefore, prospective cohort studies and real-world investigations are needed to validate the potential of different biomarkers in predicting irAEs risk. Overall, identifying predictive markers of irAEs is a crucial step towards improving patient safety and enhancing the management of irAEs. With ongoing research efforts, it is hoped that more accurate and reliable biomarkers will be identified and incorporated into clinical practice to guide treatment decisions and prevent the development of irAEs in susceptible patients.

Enhanced Antipediatric Sarcoma Effect of Everolimus with Secukinumab by Targeting IL17A.

In this study, we explored the therapeutic potential of everolimus, an mTOR inhibitor, in a patient-derived xenograft (PDX) of rhabdomyosarcoma, the most prevalent malignant pediatric sarcoma. In addition, rhabdoid tumor cell line A-204 and Ewings sarcoma cell line A-673 were cultured to assess the in vitro effect of everolimus. Furthermore, the cell-derived xenograft (CDX) of A-673 was established and treated with everolimus in vivo. IHC and Western blotting were performed to detect the expressions of pertinent proteins. Results showed that everolimus intervention had limited inhibitory effect on PDX tumor growth compared with cyclophosphamide. Nevertheless, everolimus treatment significantly influenced the phosphorylation levels of S6 kinase beta 1 (S6K1) and eIF4E-binding protein 1 (p-4E-BP1), resulting in the inhibition of angiogenesis in vitro and in vivo. Interestingly, everolimus led to an upregulation in the level of IL17A in sarcoma cells. Notably, when secukinumab, a mAb of IL17A, was combined with everolimus, it synergistically enhanced the inhibitory effect of everolimus on sarcoma cell proliferation in vitro and on the growth of PDX or CDX xenograft tumors in vivo. Importantly, this combination therapy did not affect the mTOR signaling. These results indicate that everolimus exerts an antipediatric sarcoma effect by inhibiting mTOR signal. However, everolimus induces sarcoma cells to produce IL17A, which promotes tumor cell survival and counteracts its antipediatric sarcoma effect. The combination of secukinumab effectively eliminates the effects of IL17A, thereby improving the therapeutic efficacy of everolimus in the context of pediatric sarcomas.

Correlation Between Risk Factors, Degree of Vascular Restenosis, and Inflammatory Factors After Interventional Treatment for Stroke: A Two-center Retrospective Study.

OBJECTIVE: To study the correlation between risk factors, degree of vascular restenosis, and inflammatory factors after interventional treatment for stroke. METHODS: The clinical data of 96 stroke patients who received interventional therapy in our hospital from April 2020 to June 2021 were selected for retrospective study, and the postoperative follow-up was 1 year. Univariate and multivariate regression were used to analyze identified factors associated with interventional stroke efficacy. At the same time, the value of inflammatory factor levels in predicting vascular restenosis after interventional stroke was analyzed. RESULTS: According to our findings, several risk factors, including body mass index ≥ 25.51 kg/m2, smoking, drinking, hypertension, and diabetes, were identified as contributors to poor postoperative efficacy following stroke intervention (P<0.05). Furthermore, a notable association was observed between the severity of vascular stenosis (P<0.001) and the levels of interleukin 6, interleukin 2, TNF-α, and C-reactive protein. The combined assessment of these serum inflammatory factors exhibited excellent predictive capability for postoperative vascular restenosis and stenosis severity, yielding a sensitivity of 84.30%, a specificity of 81.20%, and an area under the curve of 0.882. CONCLUSIONS: Obesity, smoking, alcohol consumption, hypertension, and diabetes have been found to be associated with suboptimal outcomes following interventional treatment for stroke. The assessment of preoperative levels of inflammatory factors holds promise in predicting the likelihood of postoperative restenosis to a certain degree.

Knee arthroscopy has limited effects on relieving local symptoms of knee osteoarthritis: an analysis of data from the Osteoarthritis Initiative.

BACKGROUND: Knee arthroscopy's efficacy in symptom improvement for knee osteoarthritis remains debated. In this study, we analyzed a multicenter database to investigate local symptom improvement. METHODS: We extracted and analyzed the data of 163 patients from the Osteoarthritis Initiative cohort who underwent unilateral knee arthroscopy (UKA) and were followed up for at least 24 months. UKA patients were matched to non-UKA patients (n = 163) according to sex, age, abdominal circumference, and Kellgren-Lawrence grade. The verified KOOS questionnaires (knee catching, locking, grinding, or clicking) and common local symptoms (frequent knee pain, aching, or stiffness) were set as outcomes. Furthermore, we built a binary logistic regression model to examine the relationship between UKA and local symptom improvement and new-onset symptoms, adjusting for conservative therapeutic covariables (injection of steroids or transparent acid into the knee joint, oral chondroitin sulfate, amino glucose, or analgesics). RESULT: Analysis showed that the UKA and non-UKA groups showed no obvious difference in the three knee symptoms, but the probability of new-onset grinding or clicking, and frequent knee pain, aching, or stiffness symptoms in the UKA group were respectively 5.82 and 5.65-fold higher than that in the non-UKA group. After analyzing conservative treatment data using a multiple imputation method, the results were consistent with previous regression analyses. CONCLUSION: Compared to the non-UKA group, the UKA group showed no noticeable differences in the improvement of the three knee symptoms and showed an increased the probability of new-onset grinding or clicking and frequent knee pain, aching, or stiffness symptoms. Key Points • Knee arthroscopy may increase the probability of new-onset grinding or clicking and frequent knee pain, aching, or stiffness symptoms. • We found no difference in the improvement of local knee symptoms (knee catching, locking, grinding, clicking or frequent pain, aching, or stiffness) improvement between the two groups with or without knee arthroscopy.

Advances in NIR-Responsive Natural Macromolecular Hydrogel Assembly Drugs for Cancer Treatment.

Cancer is a serious disease with an abnormal proliferation of organ tissues; it is characterized by malignant infiltration and growth that affects human life. Traditional cancer therapies such as resection, radiotherapy and chemotherapy have a low cure rate and often cause irreversible damage to the body. In recent years, since the traditional treatment of cancer is still very far from perfect, researchers have begun to focus on non-invasive near-infrared (NIR)-responsive natural macromolecular hydrogel assembly drugs (NIR-NMHADs). Due to their unique biocompatibility and extremely high drug encapsulation, coupling with the spatiotemporal controllability of NIR, synergistic photothermal therapy (PTT), photothermal therapy (PDT), chemotherapy (CT) and immunotherapy (IT) has created excellent effects and good prospects for cancer treatment. In addition, some emerging bioengineering technologies can also improve the effectiveness of drug delivery systems. This review will discuss the properties of NIR light, the NIR-functional hydrogels commonly used in current research, the cancer therapy corresponding to the materials encapsulated in them and the bioengineering technology that can assist drug delivery systems. The review provides a constructive reference for the optimization of NIR-NMHAD experimental ideas and its application to human body.

Effect of laparoscopic sleeve gastrectomy on related variables of obesity complicated with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is closely related to obesity, and weight loss can significantly improve the metabolic, endocrine and reproductive functions of obese individuals with PCOS. However, the efficacy of laparoscopic sleeve gastrectomy (LSG) for obesity with PCOS are unclear. AIM: The purpose of the study was to investigate the effect of LSG on related variables in obese patients with PCOS. METHODS: A retrospective analysis was performed on 32 obese patients with PCOS who received LSG treatment at the Third Hospital of Shanxi Medical University from 2013 to 2020. The changes in anthropometric indices, insulin, testosterone, estradiol, follicle stimulating hormone (FSH), luteinizing hormone (LH), menstrual cycle and LH/FSH ratio before and 1 mo, 3 mo, 6 mo and 12 mo after the operation were statistically analyzed. RESULTS: At 1 mo, 3 mo, 6 mo and 12 mo after surgery, the anthropometric indices, such as body weight and body mass index, of all patients were lower than those before the operation. The percentage excess weight loss (EWL%) at 1 mo, 3 mo, 6 mo and 1 year of follow-up were 25, 40, 46 and 65, respectively. The PCOS-related indices, such as insulin, testosterone, estradiol, follicle stimulating hormone (FSH), luteinizing hormone (LH) and menstrual cycle, were improved to varying degrees. During the 1-year follow-up, the average serum testosterone decreased from preoperative 0.72 ng/mL to 0.43 ng/mL (P < 0.05), average fasting insulin level (9.0 mIU/mL, preoperative 34.2 mil, LH level, 4.4 mIU/mL, preoperative 6.1 mIU/mL). The level of FSH (3.8 U/L, 4.8 U/p0.05) and the ratio of LH/FSH (0.7, 1.3/p0.05) were more relieved than those before surgery. During the postoperative follow-up, it was found that the menstrual cycle of 27 patients (nasty 27) returned to normal, and 6 patients (18%) who intended to become pregnant became pregnant within 1 year after surgery. CONCLUSION: The weight loss effect of LSG is obvious and affirmative, and the endocrine index of obese patients with PCOS is also improved to some extent, although the mechanism is not clear. Laparoscopic sleeve gastrectomy is expected to become a backup choice for patients with polycystic ovaries in the future.

Inducing and monitoring mitochondrial pH changes with an iridium(III) complex via two-photon lifetime imaging.

Real-time monitoring of mitochondrial dynamic changes plays a key role in the development of mitochondria-targeted anticancer theranostic agents. In this work, a pH-responsive and mitochondria-targeted cyclometalated iridium(III) complex MitoIr-NH has been explored as a novel anticancer agent. MitoIr-NH displayed pH-responsive phosphorescence intensity and lifetime, accumulated in mitochondria, showed higher antiproliferative activity and induced a series of mitochondria-related events. Moreover, MitoIr-NH could simultaneously induce mitophagy and quantitatively monitor mitochondrial pH changes through two-photon phosphorescence lifetime imaging microscopy (TPPLIM) in a real-time manner.

Multiple sclerosis is associated with adverse outcomes following hip and knee arthroplasty: A systematic review and meta-analysis of observational studies.

BACKGROUND: The association of multiple sclerosis (MS) with joint diseases has been established. However, the impact of MS on postoperative outcomes following total joint arthroplasty (TJA) remains controversial. Therefore, a systematic review of the literature is warranted to ascertain the relationship between MS and adverse outcomes post-TJA. METHODS: A systematic literature search of PubMed, Embase, Scopus, and the Cochrane Library from inception to 1 March 2023 was conducted to identify observational studies comparing post-TJA outcomes in MS and non-MS patients. Two investigators independently screened titles, abstracts, and full-text articles for eligibility. A random-effects model was used to calculate odds ratios (OR), mean differences (MD), and corresponding 95% confidence intervals (CI). RESULTS: Seven retrospective cohort studies published between 2018 and 2022 met the inclusion criteria. Patients with MS had a higher risk of medical, surgical, and overall complications than patients without MS. Similarly, the MS group was more likely to experience an extended hospital stay, non-home discharge, and revision surgery compared to the control group. Joint infection and implant instability were also more common in patients with MS. CONCLUSION: Although TJA may benefit MS patients, current evidence suggests that their postoperative outcomes may be inferior to those of non-MS patients. Thus, orthopaedic surgeons should inform MS patients of potential risks and perform preoperative optimization individually when considering elective arthroplasty.

SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53.

Pancreatic cancer cells undergo intricate metabolic reprogramming to sustain their survival and proliferation. p53 exhibits a dual role in tumor cell ferroptosis. However, the precise role and mechanisms underlying wild-type p53 activation in promoting ferroptosis in pancreatic cancer cells remain obscure. In this study, we applied bioinformatics tools and performed an analysis of clinical tissue sample databases and observed a significantly upregulated expression of solute carrier family 35 member F2 (SLC35F2) in pancreatic cancer tissues. Our clinical investigations indicated that elevated SLC35F expression was related to adverse survival outcomes. Through multi-omics analyses, we discerned that SLC35F2 influences the transcriptome and inhibits ferroptosis in pancreatic cancer cells. Moreover, our findings reveal the pivotal involvement of p53 in mediating SLC35F2-mediated ferroptosis, both in vitro and in vivo. SLC35F2 inhibits ferroptosis by facilitating TRIM59-mediated p53 degradation. Further mechanistic investigations demonstrated that SLC35F2 competitively interacts with the E3 ubiquitin ligase SYVN1 of TRIM59, thereby stabilizing TRIM59 expression and consequentially promoting p53 degradation. Utilizing protein 3D structure analysis and drug screening, we identified irinotecan hydrochloride and lapatinib ditosylate as compounds targeting SLC35F2, augmenting the antitumor effect of imidazole ketone erastin (IKE) in a wild-type p53 patient-derived xenograft (PDX) model. However, in the p53 mutant PDX model, irinotecan hydrochloride and lapatinib ditosylate did not alter the sensitivity of the tumor xenograft model to IKE-triggered ferroptosis. In summary, our work establishes a novel mechanism wherein the SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Thus, SLC35F2 emerges as a promising therapeutic target for treating pancreatic cancer.

Whole-transcriptome sequencing with ceRNA regulation network construction and verification in glioblastoma.

OBJECTIVES: To explore the key genes involved in the occurrence and development of glioblastoma (GBM) by analyzing whole-transcriptome sequencing and biologic data from GBM and normal cerebral cortex tissues and to search for important noncoding RNA (ncRNA) molecular markers based on the competitive endogenous RNA (ceRNA) network. METHODS: Ten GBM and normal cerebral cortex tissues were collected for full transcriptome sequencing, screened for differentially expressed (DE) mRNAs, miRNAs, lncRNAs, and circRNAs, and subjected to bioinformatic analysis. We constructed a Protein-Protein Interaction (PPI) network and a circRNA/lncRNA-miRNA-mRNA regulatory network and identified them using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Finally, The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases were used to validate and conduct a survival analysis of the target genes. RESULTS: A total of 5341 DEmRNAs, 259 DEmiRNAs, 3122 DElncRNAs, and 2135 DEcircRNAs were identified. Enrichment analysis showed that target genes regulated by DEmiRNA, DElncRNA, and DEcircRNA were closely related to chemical synaptic transmission and ion transmembrane transport. A PPI network analysis screened 10 hub genes that directly participate in tumor cell mitosis regulation. In addition, the ceRNA composite network showed that hsa-miR-296-5p and hsa-miR-874-5p were the central nodes of the network, and the reliability of relevant key molecules was successfully verified through RT-qPCR identification and the TCGA database. The CGGA database survival analysis produced 8 DEmRNAs closely related to GBM patient survival prognosis. CONCLUSIONS: This study revealed the important regulatory functions and molecular mechanisms of ncRNA molecules and identified hsa-miR-296-5p and hsa-miR-874-5p as key molecules in the ceRNA network. They may play an important role in GBM pathogenesis, treatment, and prognosis.

Activation of receptor-interacting protein 3-mediated necroptosis accelerates periodontitis in mice.

OBJECTIVE: To investigate the involvement and role of receptor-interacting protein 3 (RIP3)-mediated necroptosis in periodontitis. METHODS: A periodontitis murine model was established by oral infection with Porphyromonas gingivalis, and activation of necroptosis pathway was identified by immunohistochemistry. Adeno-associated virus was used to knock down Rip3 and the effect of Rip3 knockdown on periodontal inflammation was examined by Micro-CT, qRT-PCR and histological staining. In vitro, P. gingivalis-LPS was used to infect fibroblast cell line L929 and siRNA was used to knock down Rip3. Necroptosis pathway signalling and inflammation in cells were detected by cell viability and death assay, Western Blot, qRT-PCR and immunofluorescence analysis. RESULTS: Phosphorylation of RIP3 and mixed lineage kinase domain-like protein (MLKL) was increased in the periodontal ligament of mice infected with P. gingivalis. RIP3 knockdown reduced osteoclastogenesis and inflammatory cytokines in the periodontal area, and alleviated alveolar bone loss in vivo. In vitro, P. gingivalis-LPS-induced RIP3-mediated necroptosis in L929 cells, and knockdown of RIP3 by siRNA decreased the expression of inflammatory cytokines. CONCLUSION: RIP3-mediated necroptosis is activated in periodontitis and blocking necroptosis alleviates disease progression, indicating that RIP3 may be a potential target for periodontitis treatment.

CD168+ macrophages promote hepatocellular carcinoma tumor stemness and progression through TOP2A/ß-catenin/YAP1 axis.

Liver cancer stem-like cells (LCSCs) are the main cause of heterogeneity and poor prognosis in hepatocellular carcinoma (HCC). In this study, we aimed to explore the origin of LCSCs and the role of the TOP2A/ß-catenin/YAP1 axis in tumor stemness and progression. Using single-cell RNA-seq analysis, we identified TOP2A+CENPF+ LCSCs, which were mainly regulated by CD168+ M2-like macrophages. Furthermore, spatial location analysis and fluorescent staining confirmed that LCSCs were enriched at tumor margins, constituting the spatial heterogeneity of HCC. Mechanistically, TOP2A competitively binds to ß-catenin, leading to disassociation of ß-catenin from YAP1, promoting HCC stemness and overgrowth. Our study provides valuable insights into the spatial transcriptome heterogeneity of the HCC microenvironment and the critical role of TOP2A/ß-catenin/YAP1 axis in HCC stemness and progression.