The emerging of emergent SARS-CoV-2 subvariants has reduced the protective efficacy of COVID-19 vaccines. Therefore, novel COVID-19 vaccines targeting these emergent variants are needed. We designed and prepared CoV072, an mRNA-based vaccine against SARS-CoV-2 Omicron (EG.5) and other emergent SARS-CoV-2 subvariants that encodes the EG.5 spike protein. Six-week-old female BALB/C mice were used to assess humoral and cellular immune responses and cross-reactive neutralizing activity against various SARS-CoV-2 subvariants. Meanwhile different immunization strategies and doses were performed to detect the immunogenicity of this mRNA vaccine. Our results show that two doses of 5 µg CoV072 or a single dose of 15 µg CoV072 both induced broad-spectrum cross-protection ability in mice. Compared with a single dose of 15 µg CoV072, two doses of 5 µg COV072 exhibited higher levels of pseudovirus neutralizing antibody (PNAb) and cross-reactive IgG responses to multiple variants. Moreover, higher levels of neutralizing antibody (NAb) against live XBB and EG.5 variants were also induced. Th1-biased cellular immune response was induced in all vaccination groups. The antigen design and immunization strategy of this study have reference significance for the research of the next generation of COVID-19 vaccine and other vaccines.

Agonists of the stimulator of interferon genes (STING) pathway are increasingly being recognized as a promising new approach in the treatment of cancer. Although progress in clinical trials for STING agonists in antitumor applications has been slow, there is still an urgent need for developing new potent STING agonists with versatile potential applications. Herein, we developed and identified a non-nucleotide STING agonist called DW18343. DW18343 showed robust activation across different STING isoforms. Crystallography analysis revealed that DW18343 binds more deeply into the ligand binding domain (LBD) pocket of STING-H232 compared to other agonists such as MSA-2, SR-717, or cGAMP, which likely contributes to its high potency. DW18343 triggered downstream p-TBK1/p-IRF3 signaling, leading to the production of multiple cytokines. Additionally, DW18343 displayed broad and long-lasting antitumor effects in various syngeneic mouse tumor models, whether administered locally or systemically. Moreover, DW18343 induced immune memory to combat the growth of rechallenged tumors. Finally, DW18343 was shown to be an activator of both the innate and adaptive antitumor immunity in tumor tissue, potentially explaining its strong antitumor effects in vivo. In conclusion, DW18343 serves as a novel non-nucleotide STING agonist with systemic antitumor effect through the activation of antitumor immunity.

Age-related hearing loss (ARHL) is considered one of the most common neurodegenerative disorders in the elderly; however, how it contributes to cognitive decline is poorly understood. With resting-state functional magnetic resonance imaging from 66 individuals with ARHL and 54 healthy controls, group spatial independent component analyses, sliding window analyses, graph-theory methods, multilayer networks, and correlation analyses were used to identify ARHL-induced disturbances in static and dynamic functional network connectivity (sFNC/dFNC), alterations in global network switching and their links to cognitive performances. ARHL was associated with decreased sFNC/dFNC within the default mode network (DMN) and increased sFNC/dFNC between the DMN and central executive, salience (SN), and visual networks. The variability in dFNC between the DMN and auditory network (AUN) and between the SN and AUN was decreased in ARHL. The individuals with ARHL had lower network switching rates than controls among global network nodes, especially in the DMN. Some disturbances within DMN were associated with disrupted executive and memory performance. The prolonged loss of sensory information associated with ARHL-induced compensatory within-network segregations and between-network integrations in the DMN might reduce network information processing and accelerate brain aging and cognitive decline.

The left ventricular trabecular fractal dimension (LVTFD) derived from cardiac magnetic resonance reflects myocardial trabecular complexity, which is associated with cardiovascular disease risk. Baseline risk stratification of cancer therapy–related cardiac dysfunction (CTRCD) in patients with breast cancer who received anthracycline is a very important clinical issue. In this study, we used the Cox model to derive and validate a new score system based on LVTFD for baseline risk stratification of CTRCD in breast cancer patients receiving anthracycline. We also compare the performance of LVTFD-based score with the Heart Failure Association-International Cardio-Oncology Society (HFA-ICOS) score using C-index. This study enrolled 370 participants, of whom 73 participants developed CTRCD. The C-indices of LVTFD-based score integrating age, hypertension, previous cardiovascular disease, and maximal apical fractal dimension were higher than those of HFA-ICOS score for stratifying CTRCD (0.834 vs. 0.642 and 0.834 vs. 0.633, respectively, in derivation and validation cohort). LVTFD-based score can stratify the CTRCD risk, but HFA-ICOS score cannot. The above results reveal that the LVTFD-based score is an alternative method for baseline risk stratification of CTRCD in breast cancer who received anthracycline.

Metastasis continues to pose a significant challenge in tumor treatment. Evidence indicates that choline dehydrogenase (CHDH) is crucial in tumorigenesis. However, the functional role of CHDH in colorectal cancer (CRC) metastasis remains unreported. The study explored the functional role and mechanism of CHDH in CRC metastasis using human CRC tissues and a xenograft mouse model. CHDH expression was significantly higher in CRC compared to normal tissues and showed a positively correlation with CRC tumor-nodes-metastasis stage. CRC cell lines showed increased CHDH expression compared to normal controls. CHDH knockdown suppressed cell migration in vitro and tumor metastasis in vivo. Similarly, ectopic CHDH expression enhanced cell migration in vitro and tumor metastasis in vivo. Results suggested that CHDH affected the histone H3 trimethylation levels, which upregulated prolyl 4-hydroxylase α-subunit (P4HA) family gene (P4HA1/2/3) expression, further stabilizing collagen I expression and increasing IL17RB expression, which promoted downstream c-Jun activation. Together, P4HA and IL17RB promote CRC cell metastasis. P4HA and c-Jun inhibitors abolished CHDH-mediated CRC cell metastasis in vitro and in vivo. Collectively, the above findings provide novel evidence that that CHDH mediates CRC cell metastasis and may be a promising target for metastatic CRC therapy.

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that is primarily known for causing severe joint and muscle symptoms, but its pathological effects have extended beyond these tissues. In this study, we conducted a comprehensive proteomic analysis across various organs in rodent and nonhuman primate models to investigate CHIKV’s impact on organs beyond joints and muscles and to identify key host factors involved in its pathogenesis. Our findings reveal significant species-specific similarities and differences in immune responses and metabolic regulation, with proteins like Interferon-Stimulated Gene 15 (ISG15) and Retinoic Acid-Inducible Gene I (RIG-I) playing crucial roles in the anti-CHIKV defense. We observed upregulated and downregulated metabolic status in CHIKV-infected rhesus monkeys and mice, respectively. Additionally, we identified host factors such as S100 Calcium-Binding Protein A8/A9 (S100A8/A9), Voltage-Dependent Anion Channel 1/2 (VDAC1/2), Complement Component 3 (C3), Apoptosis-Inducing Factor Mitochondria-Associated 1 (AIFM1), Endothelial Cell-Specific Chemotaxis Regulator (ECSCR), and Kininogen 1 (KNG1) that may contribute to CHIKV-induced inflammation and hemorrhage. These insights put emphases on the importance of understanding CHIKV’s impact on organs beyond joints and muscles, providing potential therapeutic targets and enhancing our understanding of CHIKV pathogenesis. This research underscores the need for appropriate animal models in CHIKV studies and informs the development of targeted therapies to address its systemic effects.

N4-acetylcytidine (ac4C) modification is a crucial RNA modification widely present in eukaryotic RNA. Previous studies have demonstrated that ac4C plays a pivotal role in viral infections. Despite numerous studies highlighting the strong correlation between ac4C modification and cancer progression, its detailed roles and molecular mechanisms in normal physiological processes and cancer progression remain incompletely understood. This review first outlines the key regulatory enzyme mediating ac4C modification, N-acetyltransferase 10 (NAT10), including its critical roles in regulating RNA stability, transcriptional efficiency, and translational fidelity. Additionally, it systematically summarizes the essential functions and mechanisms of ac4C modification in normal biological processes, including stem cell fate determination, spermatogenesis and oogenesis, embryonic development, cellular senescence, and bone remodeling. Furthermore, this review delves into the central roles and molecular mechanisms of ac4C modification in regulating malignant proliferation, cell cycle arrest, EMT, drug resistance, cell death, cancer metabolism, and tumor immunotherapy. It also emphasizes the potential of NAT10 as a prognostic biomarker and its therapeutic potential as a target for disease treatment. In summary, this review clarifies the multifaceted roles of ac4C modification in both health and disease and explores NAT10-targeted therapies with the aim of advancing cancer research and improving patient outcomes.

Metastatic brain tumors, also called brain metastasis (BM), represent a challenging complication of advanced tumors. Tumors that commonly metastasize to the brain include lung cancer and breast cancer. In recent years, the prognosis for BM patients has improved, and significant advancements have been made in both clinical and preclinical research. This review focuses on BM originating from lung cancer and breast cancer. We briefly overview the history and epidemiology of BM, as well as the current diagnostic and treatment paradigms. Additionally, we summarize multiomics evidence on the mechanisms of tumor occurrence and development in the era of artificial intelligence and discuss the role of the tumor microenvironment. Preclinically, we introduce the establishment of BM models, detailed molecular mechanisms, and cutting-edge treatment methods. BM is primarily treated with a comprehensive approach, including local treatments such as surgery and radiotherapy. For lung cancer, targeted therapy and immunotherapy have shown efficacy, while in breast cancer, monoclonal antibodies, tyrosine kinase inhibitors, and antibody–drug conjugates are effective in BM. Multiomics approaches assist in clinical diagnosis and treatment, revealing the complex mechanisms of BM. Moreover, preclinical agents often need to cross the blood–brain barrier to achieve high intracranial concentrations, including small-molecule inhibitors, nanoparticles, and peptide drugs. Addressing BM is imperative.

Sarcopenia is defined as a muscle-wasting syndrome that occurs with accelerated aging, while cachexia is a severe wasting syndrome associated with conditions such as cancer and immunodeficiency disorders, which cannot be fully addressed through conventional nutritional supplementation. Sarcopenia can be considered a component of cachexia, with the bidirectional interplay between adipose tissue and skeletal muscle potentially serving as a molecular mechanism for both conditions. However, the underlying mechanisms differ. Recognizing the interplay and distinctions between these disorders is essential for advancing both basic and translational research in this area, enhancing diagnostic accuracy and ultimately achieving effective therapeutic solutions for affected patients. This review discusses the muscle microenvironment’s changes contributing to these conditions, recent therapeutic approaches like lifestyle modifications, small molecules, and nutritional interventions, and emerging strategies such as gene editing, stem cell therapy, and gut microbiome modulation. We also address the challenges and opportunities of multimodal interventions, aiming to provide insights into the pathogenesis and molecular mechanisms of sarcopenia and cachexia, ultimately aiding in innovative strategy development and improved treatments.

This multicenter, single-arm, phase II clinical trial (NCT04034589) evaluated the efficacy and safety of pyrotinib combined with fulvestrant in patients with HR-positive/HER2-positive metastatic breast cancer who had experienced trastuzumab treatment failure. A total of 46 patients were enrolled, receiving pyrotinib orally once daily and fulvestrant intramuscularly on days 1 and 15 of cycle 1, followed by monthly doses on day 1. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. The median PFS was 18.2 months (95% CI, 11.9–31.1) overall, 19.5 months (95% CI, 10.6–NA) for those receiving the combination as first-line therapy, and 18.4 months (95% CI, 16.7–NA) for patients with brain metastases. Median OS was not reached, with a 3-year OS rate of 75.2% (95% CI, 62.8–90.2%). The ORR was 32.5%, and the DCR was 97.5%. Responses were observed in patients with low tumor mutation burden and ZNF217 mutation. Importantly, no grade 4 or higher treatment-related adverse events or deaths were reported, indicating a favorable safety profile. In conclusion, the combination of pyrotinib and fulvestrant demonstrated promising antitumor activity and acceptable safety in HR-positive/HER2-positive metastatic breast cancer patients.

Periodontitis is a chronic periodontal inflammatory disease caused by periodontal pathogens commonly seen in adults. Eupalinolide B (EB) is a sesquiterpenoid natural product extracted from Eupatorium lindleyanum and has been reported as a potential drug for cancers and immune disorders. Here, we explored the ameliorative effects and underlying molecular mechanism of EB on periodontitis for the first time. We demonstrated that EB ameliorates periodontal inflammation and alveolar bone resorption with a ligated periodontitis mouse model. In addition, the impact of EB on macrophages inflammation was examined in the Raw264.7 cell line. We identified ubiquitin-conjugating enzyme, UBE2D3, as the direct covalent binding protein targets of EB by using a chemoproteomic method based on activity-based protein profiling, biolayer interferometry method, and cellular thermal shift assay. Furthermore, the direct binding site of EB to UBE2D3 was identified using high-resolution mass spectrometry and confirmed by experiments. Taken together, EB ameliorates periodontitis by targeting UBE2D3 to suppress the ubiquitination degradation of IκBα, leading to inactivation of nuclear transcription factor-κB signaling pathway. And this was confirmed by siRNA-mediated gene knockdown in inflammatory macrophages. Our results suggested that EB may be a new kind of UBE2D3 inhibitor and may become a promising therapeutic agent for anti-periodontitis.

Messenger RNA (mRNA) therapeutics have garnered considerable attention due to their remarkable efficacy in the treatment of various diseases. The COVID-19 mRNA vaccine and RSV mRNA vaccine have been approved on the market. Due to the inherent nuclease-instability and negative charge of mRNA, delivery systems are developed to protect the mRNA from degradation and facilitate its crossing cell membrane to express functional proteins or peptides in the cytoplasm. However, the deficiency in transfection efficiency and targeted biological distribution are still the major challenges for the mRNA delivery systems. In this review, we first described the physiological barriers in the process of mRNA delivery and then discussed the design approach and recent advances in mRNA delivery systems with an emphasis on their tissue/cell-targeted abilities. Finally, we pointed out the existing challenges and future directions with deep insights into the design of efficient mRNA delivery systems. We believe that a high-precision targeted delivery system can greatly improve the therapeutic effects and bio-safety of mRNA therapeutics and accelerate their clinical transformations. This review may provide a new direction for the design of mRNA delivery systems and serve as a useful guide for researchers who are looking for a suitable mRNA delivery system.

Cancer-associated fibroblasts (CAFs) are intrinsic components of the tumor microenvironment that promote cancer progression and metastasis. Through an unbiased integrated analysis of gastric tumor grade and stage, we identified a subset of proangiogenic CAFs characterized by high podoplanin (PDPN) expression, which are significantly enriched in metastatic lesions and secrete chemokine (CC-motif) ligand 2 (CCL2). Mechanistically, PDPN(+) CAFs enhance angiogenesis by activating the AKT/NF-κB signaling pathway. The canonical NF-κB signaling protein P65 binds to the promoter region of CCL2, inducing its expression. Additionally, we found that CCL2 interacts with its nonclassical receptor ACKR1 (expressed on endothelial cells) to exert its proangiogenic effects. Furthermore, the disruption of CCL2-ACKR1 communication via a CCL2 neutralizing antibody or the inhibition of AKT signaling transduction using AKT inhibitors effectively suppressed tumor growth. Together, this study elucidates the mechanism by which PDPN(+) CAFs promote angiogenesis, providing a deeper understanding of the molecular processes underlying CAF-mediated angiogenesis and suggesting potential therapeutic targets for gastric cancer treatment.

The precise mechanisms behind early embryonic arrest due to sperm-related factors and the most effective strategies are not yet fully understood. Here, we present two cases of male infertility linked to novel TDRD6 variants, associated with oligoasthenoteratozoospermia (OAT) and early embryonic arrest. To investigate the underlying mechanisms and promising therapeutic approaches, Tdrd6 knock-in and knock-out mice were generated. The Tdrd6 variant male mice demonstrated OAT and embryonic arrest, mirroring the clinical observations of our patients. Sperm from both affected individuals and mice exhibited aberrant localization of phospholipase C zeta and oocyte activation deficiency (OAD). The application of artificial oocyte activation (AOA) effectively overcame the infertility caused by the variants, facilitating successful pregnancies and live births in both human and mice. Additionally, our research revealed that OAD influences the expression of multitude of genes at the 2-pronuclear (2PN) stage, with the Mos gene playing a pivotal role in early embryonic arrest. The injection of Mos mRNA can mitigate this arrest. To our knowledge, this is the first study to show that sperm-related OAD affects gene expression at the 2PN stage and elucidate how AOA overcomes male factor-derived embryonic arrest, enabling successful pregnancies and live births.

Therapies against hematological malignancies using chimeric antigen receptors (CAR)-T cells have shown great potential; however, therapeutic success in solid tumors has been constrained due to limited tumor trafficking and infiltration, as well as the scarcity of cancer-specific solid tumor antigens. Therefore, the enrichment of tumor-antigen specific CAR-T cells in the desired region is critical for improving therapy efficacy and reducing systemic on-target/off-tumor side effects. Here, we functionalized human CAR-T cells with superparamagnetic iron oxide nanoparticles (SPIONs), making them magnetically controllable for site-directed targeting. SPION-loaded CAR-T cells maintained their specific cytolytic capacity against melanoma cells expressing the CAR-specific antigen chondroitin sulfate proteoglycan (CSPG4). Importantly, SPIONs suppressed cytokine release in the loaded CAR-T cells, shifting the cell death phenotype in the tumor cells from pyroptosis to apoptosis. Furthermore, SPION-loaded CAR-T cells could be enriched in a dynamic flow model through an external magnetic field and be detected in MRI. These results demonstrate that lytic cytotoxicity is retained after SPION-functionalization and provides a basis for future site-specific immunotherapies against solid tumors with reduced systemic adverse side effects.

Gout, a common chronic disease, is characterized by the formation and deposition of monosodium urate (MSU) crystal deposition in articular and nonarticular structures. Osteoarthritis (OA), the most prevalent type of arthritis, is a progressive degenerative joint disease. Previous clinical studies have reported that gout frequently affects OA joints; however, the underlying mechanism remains unidentified. Recently, OA synovium has been proposed as a favorable vehicle for MSU crystal deposition. Therefore, this study aimed to investigate whether OA synovium acts as a nidus for MSU crystal deposition inducing severe gout flares, using label-free, highly-specific stimulated Raman scattering (SRS) microscopy combined with innovative preclinical models—synovial organoids. Crystal deposition, cellular phagocytosis, and subsequent inflammation intensity was imaged in ex vivo synovial organoids using SRS microscopy and other biochemical techniques. Results revealed that MSU crystals were more likely to deposit in OA synovium than in normal synovium. Furthermore, OA synoviocytes were more capable of phagocytosing crystals, leading to severe inflammation, and thus, expediting gout. These findings offer a potential explanation for why gout is preferred in OA joints and offer significant insights into the pathophysiology of gout, thereby informing prevention and management strategies for OA to prevent or alleviate the subsequent progression of gout.

An imbalance in the serum sodium to chloride ratio (Na/Cl) was linked to higher mortality among heart failure patients. Nonetheless, the prognostic significance of Na/Cl in individuals undergoing peritoneal dialysis (PD) remains unexplored. This study seeks to explore the association between initial Na/Cl levels and mortality in PD patients. The study, conducted across multiple centers, included 3341 patients undergoing PD from January 1, 2005, to December 31, 2021. Patients were stratified into quartiles according to baseline Na/Cl and followed up for a median of 5.77 years. To explore the association between Na/Cl levels and mortality, we employed Cox proportional hazards models, competing risks models, and restricted cubic spline analysis. Of 3341 patients, 722 patients died, including 259 cardiovascular deaths. Following adjustments for comorbidities and multiple covariates, individuals in the highest Na/Cl quartile (>1.42) exhibited lower all-cause mortality (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.47–0.86) and cardiovascular mortality (HR 0.38, 95% CI 0.22–0.67) compared with those in the lowest quartile (<1.33). A similar pattern was also found when Na/Cl was dealt with continuous variables. Initial levels of Na/Cl at the start of PD were negatively correlated with all-cause mortality and cardiovascular mortality in PD patients.

RNA modifications are emerging as critical cancer regulators that influence tumorigenesis and progression. Key modifications, such as N6-methyladenosine (m⁶A) and 5-methylcytosine (m⁵C), are implicated in various cellular processes. These modifications are regulated by proteins that write, erase, and read RNA and modulate RNA stability, splicing, translation, and degradation. Recent studies have highlighted their roles in metabolic reprogramming, signaling pathways, and cell cycle control, which are essential for tumor proliferation and survival. Despite these scientific advances, the precise mechanisms by which RNA modifications affect cancer remain inadequately understood. This review comprehensively examines the role RNA modifications play in cancer proliferation, metastasis, and programmed cell death, including apoptosis, autophagy, and ferroptosis. It explores their effects on epithelial–mesenchymal transition (EMT) and the immune microenvironment, particularly in cancer metastasis. Furthermore, RNA modifications’ potential in cancer therapies, including conventional treatments, immunotherapy, and targeted therapies, is discussed. By addressing these aspects, this review aims to bridge current research gaps and underscore the therapeutic potential of targeting RNA modifications to improve cancer treatment strategies and patient outcomes.

Respiratory diseases pose a significant global health burden, with challenges in early and accurate diagnosis due to overlapping clinical symptoms, which often leads to misdiagnosis or delayed treatment. To address this issue, we developed LungDiag, an artificial intelligence (AI)-based diagnostic system that utilizes natural language processing (NLP) to extract key clinical features from electronic health records (EHRs) for the accurate classification of respiratory diseases. This study employed a large cohort of 31,267 EHRs from multiple centers for model training and internal testing. Additionally, prospective real-world validation was conducted using 1142 EHRs from three external centers. LungDiag demonstrated superior diagnostic performance, achieving an F1 score of 0.711 for top 1 diagnosis and 0.927 for top 3 diagnoses. In real-world testing, LungDiag outperformed both human experts and ChatGPT 4.0, achieving an F1 score of 0.651 for top 1 diagnosis. The study emphasizes the potential of LungDiag as an effective tool to support physicians in diagnosing respiratory diseases more accurately and efficiently. Despite the promising results, further large-scale multicenter validation with larger sample sizes is still needed to confirm its clinical utility and generalizability.

The optimal strategy for improving cardiometabolic factors (CMFs) in young obese individuals through diet and exercise remains unclear, as do the potential mechanisms. We conducted an 8-week randomized controlled trial to compare the effects of different interventions in youth with overweight/obesity. Gut microbes and serum metabolites were examined to identify regulating mechanisms. A total of 129 undergraduates were randomly assigned to fiber-rich (FR) diet, rope-skipping (RS), combined FR–RS and control groups. The results showed that single interventions were as effective as combined interventions in improving weight, waist circumference, body fat, and lipid profile compared with control group. Notably, the FR group further reduced low-density lipoprotein (LDL-C) and uric acid (UA) (all p < 0.05). Mediation analysis revealed four gut microbiota–metabolite–host axes in improving CMFs. Additionally, we used machine learning algorithms to further predict individual responses based on baseline gut microbiota composition, with specific microbial genera guiding targeted intervention selection. In conclusion, FR diet and/or RS were effective in improving CMFs, with the FR diet particular effectiveness in reducing LDL-C and UA levels. These benefits may drive by gut microbiome–metabolite–host interactions. Moreover, the predictability of gut microbiota composition supports making targeted decisions in selecting interventions. Trial Registration: NCT04834687.

Antigen uptake, processing, and presentation are crucial for the immune responses of protein-based vaccines. Herein, we introduced a reversible chemical cross-linking strategy to engineer protein antigens, which can be tracelessly removed upon antigen-presenting cell (APC) uptake and cellular reduction. The chemically cross-linked antigen proteins presented significantly enhanced uptake and epitope presentation by APC. We applied this strategy to monkeypox virus antigens A29L and A35R to construct dual-antigen subunit vaccines. Our results revealed that chemical cross-linking was robust enough to improve both proteins’ APC uptake and lymph node accumulation, with each protein being chemically cross-linked and administered separately. In vivo validation revealed that the chemical cross-linking of the two antigen proteins improved immune responses, with increases in antigen-specific antibody and live virus-neutralizing antibody production. Monkeypox virus challenge experiments revealed that dual-antigen vaccines prepared via the chemical cross-linking strategy mitigated tissue damage, reduced the virus load, and extended mouse survival, which proved that the chemical cross-linking strategy is valuable for protein-based subunit vaccine development. In consideration of the current threats from the monkeypox virus and potential future emerging pathogens, the chemical cross-linking strategy provide powerful tools.

The increased prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and its biofilms poses a great threat to human health. Especially, S. aureus-related osteomyelitis was hardly cured even by conventional antibiotics combined with surgical treatment. The development of novel structural antibiotics is urgently needed. By high-throughput screening and rational design, we identified a small molecule C218-0546 and its optimized analog STK848198 with great antimicrobial potential against MRSA avoiding resistance occurrence. And significant synergistical antimicrobial effects were found between the molecules and conventional antibiotics. Mechanisms studies by transcriptomics, fluorescent probes, molecule dynamics, and plasma surface resonance indicated that the proton motive force as well as FtsH are the main potential targets of these molecules. The compounds exhibited excellent in vivo pharmacokinetics, toxicity profiles, and antimicrobial activities in the abscess model as well as the peritonitis-sepsis model. In addition, STK848198 was found to be effective against MRSA biofilms by interacting with the quorum sensing system. STK848198 also showed in vivo efficacy in the periprosthetic joint infection model. In all, our study identified a class of antimicrobials with novel scaffolds that could be potential alternatives for the treatment of MRSA and its biofilm-related infections.

Hepatic ischemia–reperfusion injury (IRI) poses a significant threat to clinical outcomes and graft survival during hemorrhagic shock, hepatic resection, and liver transplantation. Current pharmacological interventions for hepatic IRI are inadequate. In this study, we identified ginsenoside Rk2 (Rk2), a rare dehydroprotopanaxadiol saponin, as a promising agent against hepatic IRI through high-throughput screening. The pharmacological effects and molecular mechanisms of Rk2 on hepatic IRI were further evaluated and elucidated in vitro and in vivo. Rk2 significantly reduced inflammation and apoptosis caused by oxygen-glucose deprivation and reperfusion in hepatocytes and dose dependently protected against hepatic I/R-induced liver injury in mice. Integrated approaches, including network pharmacology, molecular docking, transcriptome analysis, and isothermal titration calorimetry, along with experimental validation, indicated that Rk2 protects against hepatic IRI by targeting and activating the AKT (RAC serine/threonine protein kinase) signaling pathway. Pharmacological inhibition of AKT pathway or knockdown of AKT1 effectively diminished protective effects of Rk2. Rk2 directly binds to AKT1, facilitating its translocation from the cytoplasm to plasma membrane. This process markedly enhanced AKT interaction with PDPK1, promoting the activation of AKT1 and its downstream signaling. Our findings demonstrate that Rk2 protects against hepatic IRI by activating AKT signaling through direct binding to AKT1 and facilitating its membrane translocation.

Cellular senescence is characterized by a stable cell cycle arrest and a hypersecretory, proinflammatory phenotype in response to various stress stimuli. Traditionally, this state has been viewed as a tumor-suppressing mechanism that prevents the proliferation of damaged cells while activating the immune response for their clearance. However, senescence is increasingly recognized as a contributing factor to tumor progression. This dual role necessitates a careful evaluation of the beneficial and detrimental aspects of senescence within the tumor microenvironment (TME). Specifically, senescent cells display a unique senescence-associated secretory phenotype that releases a diverse array of soluble factors affecting the TME. Furthermore, the impact of senescence on tumor–immune interaction is complex and often underappreciated. Senescent immune cells create an immunosuppressive TME favoring tumor progression. In contrast, senescent tumor cells could promote a transition from immune evasion to clearance. Given these intricate dynamics, therapies targeting senescence hold promise for advancing antitumor strategies. This review aims to summarize the dual effects of senescence on tumor progression, explore its influence on tumor–immune interactions, and discuss potential therapeutic strategies, alongside challenges and future directions. Understanding how senescence regulates antitumor immunity, along with new therapeutic interventions, is essential for managing tumor cell senescence and remodeling the immune microenvironment.

Chronic diseases have emerged as a paramount global health burden, accounting for 74% of global mortality and causing substantial economic losses. The oral cavity serves as a critical indicator of overall health and is inextricably linked to chronic disorders. Neglecting oral health can exacerbate localized pathologies and accelerate the progression of chronic conditions, whereas effective management has the potential to reduce their incidence and mortality. Nevertheless, limited resources and lack of awareness often impede timely dental intervention, delaying optimal therapeutic measures. This review provides a comprehensive analysis of the impact of prevalent chronic diseases—such as diabetes mellitus, rheumatoid arthritis, cardiovascular disorders, and chronic respiratory diseases—on oral health, along with an exploration of how changes in oral health affect these chronic conditions through both deterioration and intervention mechanisms. Additionally, novel insights into the underlying pathophysiological mechanisms governing these relationships are presented. By synthesizing these advancements, this review aims to illuminate the complex interrelationship between oral health and chronic diseases while emphasizing the urgent need for greater collaboration between dental practitioners and general healthcare providers to improve overall health outcomes.

Tissue-resident memory T (T_RM) cells are crucial components of the immune system that provide rapid, localized responses to recurrent pathogens at mucosal and epithelial barriers. Unlike circulating memory T cells, T_RM cells are located within peripheral tissues, and they play vital roles in antiviral, antibacterial, and antitumor immunity. Their unique retention and activation mechanisms, including interactions with local epithelial cells and the expression of adhesion molecules, enable their persistence and immediate functionality in diverse tissues. Recent advances have revealed their important roles in chronic inflammation, autoimmunity, and cancer, illuminating both their protective and their pathogenic potential. This review synthesizes current knowledge on T_RM cells’ molecular signatures, maintenance pathways, and functional dynamics across different tissues. We also explore the interactions of T_RM cells with other immune cells, such as B cells, macrophages, and dendritic cells, highlighting the complex network that underpins the efficacy of T_RM cells in immune surveillance and response. Understanding the nuanced regulation of T_RM cells is essential for developing targeted therapeutic strategies, including vaccines and immunotherapies, to enhance their protective roles while mitigating adverse effects. Insights into T_RM cells’ biology hold promise for innovative treatments for infectious diseases, cancer, and autoimmune conditions.