Pulmonary endothelial cell (EC) activation is a key factor in acute respiratory distress syndrome (ARDS). In sepsis, increased glycolysis leads to lactate buildup, which induces lysine lactylation (Kla) on histones and other proteins. However, the role of protein lactylation in EC dysfunction during sepsis-induced ARDS remains unclear. Integrative lactylome and proteome analyses were performed to identify the global lactylome profile in the lung tissues of septic mice. Cut&Tag analysis was used to identify the transcriptional targets of histone H3 lysine 14 lactylation (H3K14la) in ECs. Septic mice presented elevated levels of lactate and H3K14la in lung tissues, particularly in pulmonary ECs. Suppressing glycolysis reduced both H3K14la and EC activation, suggesting a link between glycolysis and lactylation. Moreover, H3K14la was enriched at promoter regions of ferroptosis-related genes such as transferrin receptor (TFRC) and solute carrier family 40 member 1 (SLC40A1), which contributed to EC activation and lung injury under septic conditions. For the first time, we reported the role of lactate-dependent H3K14 lactylation in regulating EC ferroptosis to promote vascular dysfunction during sepsis-induced lung injury. Our findings suggest that manipulation of the glycolysis/H3K14la/ferroptosis axis may provide novel therapeutic approaches for sepsis-associated ARDS.

Moyamoya disease (MMD) is a type of cerebrovascular disease characterized by occlusion of the distal end of the internal carotid artery and the formation of collateral blood vessels. Over the past 20 years, the landscape of research on MMD has significantly transformed. In this review, we provide insights into the pathogenesis, diagnosis, and therapeutic interventions in MMD. The development of high-throughput sequencing technology has expanded our understanding of genetic susceptibility, identifying MMD-related genes beyond RNF213, such as ACTA2, DIAPH1, HLA, and others. The genetic susceptibility of MMD to its pathological mechanism was summarized and discussed. Based on the second-hit theory, the influences of inflammation, immunity, and environmental factors on MMD were also appropriately summarized. Despite these advancements, revascularization surgery remains the primary treatment for MMD largely because of the lack of effective in vivo and in vitro models. In this study, 16 imaging diagnostic methods for MMD were summarized. Regarding therapeutic intervention, the influences of drugs, endovascular procedures, and revascularization surgeries on patients with MMD were discussed. Future research on the central MMD vascular abnormalities and peripheral circulating factors will provide a more comprehensive understanding of the pathogenic mechanisms of MMD.

Rapid advances in vaccine technology are becoming increasingly important in tackling global health crises caused by respiratory virus infections. While traditional vaccines, primarily administered by intramuscular injection, have proven effective, they often fail to provide the broad upper respiratory tract mucosal immunity, which is urgently needed for first-line control of respiratory viral infections. Furthermore, traditional intramuscular vaccines may not adequately address the immune escape of emerging virus variants. In contrast, respiratory mucosal vaccines developed using the body’s mucosal immune response mechanism can simultaneously establish both systemic and mucosal immunity. This dual action effectively allows the respiratory mucosal immune system to function as the first line of defense, preventing infections at the entry points. This review highlights the efficacy of respiratory mucosal vaccines, including innovative delivery methods such as nasal and oral formulations, in enhancing local and systemic immune barriers. Notably, respiratory mucosal vaccines offer potential advantages in protecting against emerging virus variants and maintaining long-term and multidimensional immune memory in the upper respiratory tract. In addition, a combination of intramuscular and respiratory mucosal delivery of vaccines largely improves their coverage and effectiveness, providing valuable insights for future vaccine development and public inoculation strategies.

Vascular endothelial cells form a single layer of flat cells that line the inner surface of blood vessels, extending from large vessels to the microvasculature of various organs. These cells are crucial metabolic and endocrine components of the body, playing vital roles in maintaining circulatory stability, regulating vascular tone, and preventing coagulation and thrombosis. Endothelial cell injury is regarded as a pivotal initiating factor in the pathogenesis of various diseases, triggered by multiple factors, including infection, inflammation, and hemodynamic changes, which significantly compromise vascular integrity and function. This review examines the causes, underlying molecular mechanisms, and potential therapeutic approaches for endothelial cell injury, focusing specifically on endothelial damage in cardiac ischemia/reperfusion (I/R) injury, sepsis, and diabetes. It delves into the intricate signaling pathways involved in endothelial cell injury, emphasizing the roles of oxidative stress, mitochondrial dysfunction, inflammatory mediators, and barrier damage. Current treatment strategies—ranging from pharmacological interventions to regenerative approaches and lifestyle modifications—face ongoing challenges and limitations. Overall, this review highlights the importance of understanding endothelial cell injury within the context of various diseases and the necessity for innovative therapeutic methods to improve patient outcomes.

Disseminated intravascular coagulation (DIC) is a complex and serious condition characterized by widespread activation of the coagulation cascade, resulting in both thrombosis and bleeding. This review aims to provide a comprehensive overview of DIC, emphasizing its clinical significance and the need for improved management strategies. We explore the primary causes of DIC, including sepsis, trauma, malignancies, and obstetric complications, which trigger an overactive coagulation response. At the molecular level, DIC is marked by excessive thrombin generation, leading to platelet and fibrinogen activation while simultaneously depleting clotting factors, creating a paradoxical bleeding tendency. Diagnosing DIC is challenging and relies on a combination of existing diagnostic criteria and laboratory tests. Treatment strategies focus on addressing the underlying causes and may involve supportive care, anticoagulation therapy, and other supportive measures. Recent advances in understanding the pathophysiology of DIC are paving the way for more targeted therapeutic approaches. This review highlights the critical need for ongoing research to enhance diagnostic accuracy and treatment efficacy, ultimately improving patient outcomes in those affected by DIC.

The patient-derived xenograft (PDX) model is a crucial in vivo model extensively employed in cancer research that has been shown to maintain the genomic characteristics and pathological structure of patients across various subtypes, metastatic, and diverse treatment histories. Various treatment strategies utilized in PDX models can offer valuable insights into the mechanisms of tumor progression, drug resistance, and the development of novel therapies. This review provides a comprehensive overview of the establishment and applications of PDX models. We present an overview of the history and current status of PDX models, elucidate the diverse construction methodologies employed for different tumors, and conduct a comparative analysis to highlight the distinct advantages and limitations of this model in relation to other in vivo models. The applications are elucidated in the domain of comprehending the mechanisms underlying tumor development and cancer therapy, which highlights broad applications in the fields of chemotherapy, targeted therapy, delivery systems, combination therapy, antibody–drug conjugates and radiotherapy. Furthermore, the combination of the PDX model with multiomics and single-cell analyses for cancer research has also been emphasized. The application of the PDX model in clinical treatment and personalized medicine is additionally emphasized.

Head and neck squamous cell carcinoma (HNSCC) develops and advances because of the accumulation of somatic mutations located in orthosteric and allosteric areas. However, the biological effects of allosteric driver mutations during tumorigenesis are mostly unknown. Here, we mapped somatic mutations generated from 10 tumor-normal matched HNSCC samples into allosteric sites to prioritize the mutated allosteric proteins via whole-exome sequencing and AlloDriver, identifying the specific mutation H351Q in β-glucuronidase (GUSB), a lysosomal enzyme, as a novel allosteric driver mutation, which considerably encouraged HNSCC progression both in vitro and in vivo. Mechanistically, the allosteric mutation of H351Q remarkably attenuated protein trafficking from the endoplasmic reticulum (ER) to lysosomes, leading to ER retention, in which GUSB-H351Q facilitated the aberrant N-glycosylation of PD-L1 through increasing protein stability and mRNA transcripts of the STT3 oligosaccharyltransferase complex catalytic subunit B, an oligosaccharyltransferase complex. Moreover, GUSB-H351Q reshaped a more immunosuppressive microenvironment featuring increased infiltration of exhausted CD8⁺ T cells and remodeled tumor metabolism, characterized by increased activity of the purine metabolism pathways and pyruvic acid accumulation. This study provides a mechanism-driven approach to overcoming HNSCC progression and immune evasion and identifies novel druggable targets based on the presence of GUSB allosteric driver mutation.

Neutrophils, the most abundant circulating leukocytes, have long been recognized as key players in innate immunity and inflammation. However, recent discoveries unveil their remarkable heterogeneity and plasticity, challenging the traditional view of neutrophils as a homogeneous population with a limited functional repertoire. Advances in single-cell technologies and functional assays have revealed distinct neutrophil subsets with diverse phenotypes and functions and their ability to adapt to microenvironmental cues. This review provides a comprehensive overview of the multidimensional landscape of neutrophil heterogeneity, discussing the various axes along which diversity manifests, including maturation state, density, surface marker expression, and functional polarization. We highlight the molecular mechanisms underpinning neutrophil plasticity, focusing on the complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications that shape neutrophil responses. Furthermore, we explore the implications of neutrophil heterogeneity and plasticity in physiological processes and pathological conditions, including host defense, inflammation, tissue repair, and cancer. By integrating insights from cutting-edge research, this review aims to provide a framework for understanding the multifaceted roles of neutrophils and their potential as therapeutic targets in a wide range of diseases.

Chronic kidney disease (CKD) is a disease that affects more than 850 million people. Acute kidney injury (AKI) is a common cause of CKD, and blocking the AKI–CKD transition shows promising therapeutic potential. Herein, we found that butyrolactone I (BLI), a natural product, exerts significant nephroprotective effects, including maintenance of kidney function, inhibition of inflammatory response, and prevention of fibrosis, in both folic acid- and ureteral obstruction-induced AKI–CKD transition mouse models. Notably, BLI showed greater blood urea nitrogen reduction and anti-inflammatory effects than telmisartan. Bioinformatics analysis and target confirmation assays suggested that BLI directly binds to JAK1, and kinase inhibition assay confirmed it is a potent JAK1inhibitor with an IC₅₀ of 0.376 µM. Experiments in JAK1-knockdown mice also proved that BLI targets JAK1 to work. Furthermore, BLI demonstrated nephroprotective effects and safety comparable to ivarmacitinib, the well-known JAK1 inhibitor. Mechanistically, BLI targets JAK1 and inhibits its phosphorylation and JAK-STAT activation, subsequently regulating the downstream signaling pathways to inhibit reactive oxygen species production, inflammation, and ferroptosis, thereby preventing the occurrence of kidney fibrosis and blocking the AKI–CKD transition process. This study demonstrates for the first time that BLI is a JAK1 inhibitor and a promising candidate for delaying CKD progression, which warrants further investigation.

This study aimed to evaluate the prognostic value of plasma circulating tumor DNA (ctDNA) level in patients with resectable gastric cancer (GC). A total of 59 patients were prospectively enrolled, with their ctDNA detected and paired tumor tissue collected at various peri-operative time points. Patients with higher 1-month post-operative ctDNA levels demonstrated shorter overall survival status (hazard ratio [HR] = 5.30, p = 0.0022) and a higher risk of recurrence (HR = 3.85, p = 0.011). The model combining ctDNA with conventional serum tumor markers for GC, including carcinoembryonic antigen, carbohydrate antigen 19-9, and CA72-4, shows high predictive effectiveness for GC prognosis with an area under the curve of 0.940 (p = 0.002), which is higher than net ctDNA and other models without ctDNA. Patients with lower ctDNA levels were more likely to have positive stromal programmed cell death ligand 1 expression (p = 0.046). Additionally, DCAF4L2 mutation was identified as the crucial gene mutation in ctDNA suggesting poor prognosis of patients with GC. Overall, this study highlights that post-operative ctDNA can serve as an effective biomarker for prognostic prediction and recurrence surveillance in resectable GC.

Chimeric antigen receptor T-cell (CAR-T) therapy is a revolutionary approach in cancer treatment. More than 10 CAR-T products have already approved on market worldly wide, and they use either gamma retroviral vectors or lentiviral vectors to deliver the CAR gene. Both vectors have the ability to effectively and persistently integrate the CAR gene into T cells. Despite the advancements in CAR-T therapy, the potential risks associated with the vectors, particularly the risks of the secondary malignancies, still remain as a concern. This article compares the characteristics of gamma retroviral and lentiviral vectors, discusses the development of vector packaging systems, and examines the design of self-inactivating (SIN) vectors. It also addresses the risks of secondary malignancies that might possibly be associated with the retroviral vectors, and the strategies to decrease the risks and increase the safer clinical use of the vectors. This article also discusses the current regulatory landscape and management approaches aiming to mitigate these risks through stringent safety measures and ongoing monitoring. Future perspectives focus on improving the safety profiles of the vectors and broadening their scope of use. The article provides a thorough overview of the most recent research discoveries and regulatory updates in the field of CAR-T therapy, highlighting the significance of a balanced strategy that strikes a balance between innovation and patient safety in the development and implementation of CAR-T therapy.

Proteolysis targeting chimeras (PROTACs) are pivotal in cancer therapy for their ability to degrade specific proteins. However, their non-specificity can lead to systemic toxicity due to protein degradation in normal cells. To address this, we have integrated a nanobody into the PROTACs framework and leveraged the tumor microenvironment to enhance drug specificity. In this study, we engineered BumPeD, a novel bispecific nanobody-targeted PROTACs-like platform, by fusing two nanobodies with a Furin protease cleavage site (RVRR) and a degron sequence (ALAPYIP or KIGLGRQKPPKATK), enabling the tumor microenvironment to direct the degradation of intracellular proteins. We utilized KN035 and Nb4A to target PD-L1 (programmed death ligand 1) on the cell surface and intracellular Survivin, respectively. In vitro experiments showed that BumPeD triggers Survivin degradation via the ubiquitin-proteasome pathway, inducing tumor apoptosis and suppressing bladder tumor cell proliferation and migration. In vivo experiments further confirmed BumPeD’s robust anti-tumor efficacy, underscoring its potential as a precise protein degradation strategy for cancer therapy. Our platform provides a systematic approach to developing effective and practical protein degraders, offering a targeted theoretical basis and experimental support for the development of novel degradative drugs, as well as new directions for cancer therapy.

Historically considered downstream effects of tumorigenesis—arising from changes in DNA content or chromatin organization—nuclear alterations have long been seen as mere prognostic markers within a genome-centric model of cancer. However, recent findings have placed the nuclear envelope (NE) at the forefront of tumor progression, highlighting its active role in mediating cellular responses to mechanical forces. Despite significant progress, the precise interplay between NE components and cancer progression remains under debate. In this review, we provide a comprehensive and up-to-date overview of how changes in NE composition affect nuclear mechanics and facilitate malignant transformation, grounded in the latest molecular and functional studies. We also review recent research that uses advanced technologies, including artificial intelligence, to predict malignancy risk and treatment outcomes by analyzing nuclear morphology. Finally, we discuss how progress in understanding nuclear mechanics has paved the way for mechanotherapy—a promising cancer treatment approach that exploits the mechanical differences between cancerous and healthy cells. Shifting the perspective on NE alterations from mere diagnostic markers to potential therapeutic targets, this review calls for further investigation into the evolving role of the NE in cancer, highlighting the potential for innovative strategies to transform conventional cancer therapies.

Acute respiratory distress syndrome (ARDS) is a clinical syndrome of acute hypoxic respiratory failure caused by diffuse lung inflammation and edema. ARDS can be precipitated by intrapulmonary factors or extrapulmonary factors, which can lead to severe hypoxemia. Patients suffering from ARDS have high mortality rates, including a 28-day mortality rate of 34.8% and an overall in-hospital mortality rate of 40.0%. The pathophysiology of ARDS is complex and involves the activation and dysregulation of multiple overlapping and interacting pathways of systemic inflammation and coagulation, including the respiratory system, circulatory system, and immune system. In general, the treatment of inflammatory injuries is a coordinated process that involves the downregulation of proinflammatory pathways and the upregulation of anti-inflammatory pathways. Given the complexity of the underlying disease, treatment needs to be tailored to the problem. Hence, we discuss the pathogenesis and treatment methods of affected organs, including 2019 coronavirus disease (COVID-19)-related pneumonia, drowning, trauma, blood transfusion, severe acute pancreatitis, and sepsis. This review is intended to provide a new perspective concerning ARDS and offer novel insight into future therapeutic interventions.

Airway stenosis (AS) is a fibroinflammatory disease characterized by abnormal activation of fibroblasts and excessive synthesis of extracellular matrix, which has puzzled many doctors despite its relatively low prevalence. Traditional treatment such as endoscopic surgery, open surgery, and adjuvant therapy have many disadvantages and are limited in the treatment of patients with recurrent AS. Therefore, it is urgent to reveal the pathogenesis of AS and accelerate its clinical transformation. Based on the discovered pathogenesis, including fibrosis, inflammation, epithelial–mesenchymal transition, metabolic reprogramming, microbiome, genetic susceptibility, and other mechanisms, researchers have developed a series of treatments, such as drug therapy, gene therapy, stem cell therapy, growth factor therapy, protein therapy, and photodynamic therapy. This review introduces the classification of AS, explores the existing pathogenesis and preclinical treatments developed based on the pathogenesis, and finally summarizes the current clinical management. In addition, the prospect of exploring the interaction between different types of cells and between microorganisms and cells to identify the intersection of multiple mechanisms based on single-cell RNA sequencing, 16S rRNA gene sequencing and shotgun metagenomic sequencing is worth looking forward to.

Hepatic ischemia–reperfusion (I/R) injury frequently occurs during the perioperative phase of liver surgery. Inappropriate activation of STING signaling can trigger excessive inflammation response to aggravate hepatic I/R injury. Dimethyl fumarate (DMF) is an FDA-approved immunomodulatory drug used to treat multiple sclerosis and psoriasis due to its notable anti-inflammation properties. However, the mechanism and targets of DMF in immunomodulation remain unclear. Here, we found that DMF suppresses cGAS-STING activation induced by HSV-1, hering testis DNA, and mitochondrial DNA in a variety of cells. DMF significantly reduces hepatic I/R injury and inhibits cGAS-STING pathway activation in mice. The alleviating effect of DMF on hepatic I/R injury was negligible in STING-knockout mice. Mechanistically, DMF directly inhibits STING activation via an autophagy-independent pathway, and the immunocoprecipitation experiment showed that DMF inhibited STING recruitment of downstream TBK1 and IRF3. Our study found that DMF protects liver I/R injury by inhibiting the STING pathway and may be a potential target of this disease.

Interleukin (IL)-17-producing γδ-T cells (γδT-17) are a major source of IL-17 within the tumor microenvironment and have been shown to influence tumor development and therapy outcomes in various cancers. However, the role and presence of γδT-17 cells in nasopharyngeal carcinoma (NPC) remain poorly understood. It is also unclear how these cells might affect radiotherapy, the primary treatment for NPC patients. In this study, we discovered that NPC tumor tissues were rich in γδT-17 cells. Exosomes released from NPC cells (NPC-Exos) could direct γδ-T cells to differentiate into γδT-17 cells. These NPC-Exos-induced γδT-17 cells were found to enhance radioresistance in NPC, both in vitro and in vivo. Blocking IL-17 secreted by NPC-Exos-induced γδT-17 cells restored NPC cell sensitivity to radiation and elevated radiation-induced cell death. Mechanistic studies revealed that NPC-Exos not only increased the release of IL-17-promoting cytokines IL-1β, IL-6, and IL-23 from dendritic cells, but also suppressed CD25/IL-2 signaling in γδ-T cells, facilitating γδT-17 differentiation. The suppression of CD25/IL-2 signaling was driven by microRNA-15a (miR-15a) carried by NPC exosomes. Furthermore, miR-15a inhibitors were able to prevent γδT-17 induction by NPC-Exos. Our findings reveal a novel immunoregulatory role of NPC-Exos and offer potential strategies to combat NPC radioresistance.

Circular RNA (circRNA), a subtype of noncoding RNA, has emerged as a significant focus in RNA research due to its distinctive covalently closed loop structure. CircRNAs play pivotal roles in diverse physiological and pathological processes, functioning through mechanisms such as miRNAs or proteins sponging, regulation of splicing and gene expression, and serving as translation templates, particularly in the context of various cancers. The hallmarks of cancer comprise functional capabilities acquired during carcinogenesis and tumor progression, providing a conceptual framework that elucidates the nature of the malignant transformation. Although numerous studies have elucidated the role of circRNAs in the hallmarks of cancers, their functions in the development of chemoradiotherapy resistance remain unexplored and the clinical applications of circRNA-based translational therapeutics are still in their infancy. This review provides a comprehensive overview of circRNAs, covering their biogenesis, unique characteristics, functions, and turnover mechanisms. We also summarize the involvement of circRNAs in cancer hallmarks and their clinical relevance as biomarkers and therapeutic targets, especially in thyroid cancer (TC). Considering the potential of circRNAs as biomarkers and the fascination of circRNA-based therapeutics, the “Ying-Yang” dynamic regulations of circRNAs in TC warrant vastly dedicated investigations.

Prostate cancer is a common male genitourinary malignancy with bone metastasis posing challenges for prognosis and treatment. This study aimed to investigate the role of SHC protein SH2 structural domain binding protein 1 (SHCBP1) in prostate cancer bone metastasis. Whole transcriptome sequencing of prostate cancer samples was conducted to identify oncogene expression, specifically focusing on SHCBP1. In vivo and in vitro models were used to study SHCBP1’s impact on bone metastasis. Through co-immunoprecipitation, mass spectrometry, and Western blot assays, the interaction between SHCBP1 and cell cycle-related proteins was elucidated, along with analysis of downstream protein partners. SHCBP1 was found to enhance prostate cancer cell development, metastasis, and mitosis, with the SHCBP1—polo-like kinase 1 (PLK1)—CDC25C axis playing a key role in promoting tumorigenesis. Therapeutic inhibition of SHCBP1 increased docetaxel sensitivity. Clinical data showed elevated SHCBP1 expression in advanced prostate cancer stages. These findings offer insights into potential therapeutic strategies for prostate cancer bone metastasis and highlight the significance of the SHCBP1-PLK1-CDC25C axis in docetaxel sensitivity.

Resistance to radiotherapy remains a critical barrier in treating colorectal cancer (CRC), particularly in cases of locally advanced rectal cancer (LARC). To identify key kinases involved in CRC radioresistance, we employed a kinase-targeted CRISPR-Cas9 library screen. This approach aimed to identify potential kinase inhibitors as radiosensitizers. Our screening identified salt-inducible kinase 2 (SIK2) as a critical factor in CRC radioresistance. Increased SIK2 expression correlated with reduced tumor regression and poorer outcomes in LARC patients undergoing neoadjuvant chemoradiotherapy. The depletion of SIK2 significantly enhanced radiation-induced apoptosis and tumor regression. Mechanistically, SIK2 interacts with valosin-containing protein (VCP), promoting its hyperphosphorylation. This modification improves VCP’s capacity to extract K48-linked ubiquitin-conjugated proteins from chromatin, thus aiding the recruitment of RPA and RAD51 to DNA damage sites. This mechanism strengthens homologous recombination–mediated DNA repair, which contributes to radioresistance. Importantly, ARN-3236, a SIK2 inhibitor, markedly sensitized CRC cells to radiation both in vivo and in vitro, providing a potential strategy to overcome radioresistance. In summary, our findings reveal a novel mechanism by which SIK2 contributes to the radioresistance of CRC, proposing SIK2 as a potential therapeutic target with its inhibitor significantly enhancing CRC radiotherapy efficacy.

Pseudomonas aeruginosa is the predominant pathogen causing chronic infection in the airway of patients with bronchiectasis (BE), a chronic respiratory disease with high prevalence worldwide. Environmental factors are vital for bacterial successful colonization. Here, with sputa and bronchoalveolar lavage fluids, we determined that the concentration of airway antimicrobial peptide LL-37 and lactate was elevated in BE patients, especially in those infected with P. aeruginosa. The in vitro antibacterial assay revealed the bactericidal activity of LL-37 against the clinical P. aeruginosa isolates, which were dampened in the acidic condition. P. aeruginosa production of outer membrane vesicles (OMVs) enhanced in the lactate-adjusted acidic condition. Transcriptomic analysis suggested that OMVs induce the hyperproduction of the chemical compound 2-heptyl-4-quinolone (HHQ) in the bacterial population, which was verified by high-performance liquid chromatography. The positively charged HHQ interfered with the binding of LL-37 to bacterial cell membrane, potentiating the P. aeruginosa resistance to LL-37. To our knowledge, this is a new resistance mechanism of P. aeruginosa against antimicrobial peptides and may provide theoretical support for the development of new antibacterial therapies.

Inflammatory bowel diseases (IBDs), such as Crohn’s disease (CD) and ulcerative colitis (UC), represent a growing global health concern. Restoring the balance of the gut microbiota, a crucial factor in intestinal health, offers potential for treating IBD. DP7, a novel antimicrobial peptide with potent antibacterial activity, was investigated for its anti-inflammatory effects in a dextran sulfate sodium (DSS)-induced UC mouse model. DP7 significantly ameliorated key disease parameters, including disease activity index, weight loss, and shortened colon length, while preserving colonic epithelial integrity and reducing inflammatory infiltration. Further analysis revealed potential targets of DP7, highlighting the significant role of Muribaculaceae bacteria during inflammatory states. To further explore the role of the gut microbiota in DP7’s efficacy, fecal microbiota transplantation (FMT) was performed using feces from DP7-treated mice. FMT successfully ameliorated colitis in recipient mice, providing further evidence for the crucial role of the gut microbiome in IBD treatment and DP7’s ability to modulate the gut microbiota for therapeutic benefit. Moreover, our findings suggest that DP7’s modulation of the immune system is intricately linked to the complex microbial environment. Our findings demonstrate that DP7 effectively mitigates inflammation, attenuates barrier dysfunction, and shapes the gut microbiota, suggesting its potential as a therapeutic agent for UC.

Alcohol-associated liver disease (ALD) is a major cause of liver-related morbidity and mortality, yet clinically effective therapies for ALD remain lacking. Here, we demonstrate that alcohol intake and its metabolite, acetaldehyde (ACH), induce senescence in the liver and liver cells, respectively. To assess the therapeutic potential of targeting liver senescence in ALD, we treated ALD-affected mice with the senolytic compound ABT263 and the senomorphic NAD⁺ precursor, nicotinamide (NAM). The results show that ABT263 effectively clears senescent hepatocytes and stellate cells, and reduces liver triglyceride (TG), but increases plasma alanine aminotransferase and TG levels. Conversely, NAM efficiently suppresses senescence and the senescence-associated secretory phenotype (SASP), protecting the liver from alcohol-induced injury in ALD mice. RNA-sequencing analysis revealed that ABT263 treatment downregulated genes involved in adipogenesis while activating the complement pathway. In contrast, NAM upregulated metabolism-related genes, such as Sirt1, and downregulated DNA damage marker genes, including Rec8 and E2f1, in the liver. These findings suggest that cellular senescence plays a critical role in alcohol-induced liver injury. Compared with senescent cell clearance by ABT263, suppressing senescence and SASP by NAM may provide a safer and more effective therapeutic approach for ALD.

We aimed to compare the association of metabolic dysfunction-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), metabolic dysfunction and ALD (MetALD), and MASLD with viral hepatitis (MASLD-Viral) with risks of cirrhosis, liver cancer, and mortality. The data of 464,556 adults from the UK Biobank (UKB), 13,526 adults from the National Health and Nutrition Examination Survey (NHANES), and 2554 adults from BeijngFH Health Cohort Study (FHCS) were included. Adjusted hazard ratios (aHR) and odds ratios were calculated using Cox and Logistic regression models, respectively. Compared with non-SLD, the risk of liver cancer increased from MetALD (aHR 1.70 [95% CI 1.37, 2.09]), MASLD (1.91 [1.66, 2.21]), MAFLD (2.01 [1.76, 2.29]), ALD (3.16 [2.54, 3.93]), to MASLD-Viral (22.0 [10.8, 44.4]) in a stepwise manner in the UKB; the risk of all-cause mortality increased from MetALD, MASLD, MAFLD, ALD, to MASLD-Viral in the NHANES. The odds ratio of liver fibrosis increased from MASLD, MAFLD, to MASLD-Viral in the FHCS. In patients with diabetes, metformin plus other drugs were associated with higher risks of cirrhosis, liver cancer, and all-cause mortality in MASLD or MAFLD. Prevention rather than antiglycemic treatment is important for patients with diabetic MASLD or MAFLD.

SARS-CoV-2 variants are under continuous emergence carry numerous mutations within S1 subunit in spike protein and have escaped neutralization through many currently used vaccines and antibodies. The development of next-generation vaccines is a continuing and long-term need. In our prior research, the recombinant protein vaccine HR121 targeting the heptad repeat (HR) 1 domain of S2 subunit was constructed, which could evoke highly broad-spectrum neutralizing antibodies in vivo and confer efficient protective effect on several SARS-CoV-2 variants within multiple animal models. Compared with HR1, HR2 domain shows a more conservative degree within SARS-CoV-2 and related coronaviruses. Here, we designed a recombinant protein HR212 consisting of HR2–linker1–HR1–linker2–HR2. HR212 showed a high affinity with HR1 and was functionally analogous to HR2 within fusion intermediate in S2 subunit. Immunizing rabbits using HR212-mediated high nAbs for 28 pseudotyped SARS-CoV-2 variants, like currently circulating variants, such as BA.2.86 and JN.1. Transfer of rabbit anti-HR212 sera or immunization with HR212 offered efficient protective effect on SARS-CoV-2 ancestral strain and Omicron BA.2 variant infections of Syrian golden hamsters. According to our results, HR2 domain of S2 subunit is the novel target that can be used to develop broad-spectrum vaccines to resist SARS-CoV-2 variants.

The accumulation of lactate in tissue microenvironments is associated with atherosclerosis, but its precise role in atherogenesis remains largely unknown. This study demonstrated that lactate accumulation in aortic tissues and blood is correlated with increased monocarboxylate transporter 1 (Mct1) expression in endothelial cells (ECs) within atherosclerotic plaques. Lactate uptake via Mct1 triggers an inflammatory response in ECs. The administration of endothelial-targeting nanoparticles containing siRNA against Mct1 reduces endothelial inflammation and atherogenesis in Apoe–/– mice. Mechanistic studies revealed that the conversion of lactate to pyruvate, along with NADH production and oligomerization of the NADH-sensitive transcriptional corepressor C-terminal binding protein 1 (CtBP1), is necessary for the proinflammatory effects of lactate. Monomeric CtBP1 interacts with the transcriptional repressor forkhead box P1 (FOXP1) to suppress endothelial adhesion molecule expression. However, NADH-induced oligomerization of CtBP1 prevents its binding to FOXP1, significantly reducing FOXP1-mediated transrepression of endothelial adhesion molecules. Moreover, silencing Foxp1 in ECs negates the atheroprotective effect of endothelial Mct1 knockdown in Apoe–/– mice. These findings suggest that lactate/MCT1-induced epigenetic reprogramming represents a potential therapeutic target in atherosclerosis.

Diet rich in chicken protein has gained a widespread popularity for its profound effect on weight loss and glycemic control; however, its long-term effect on cardiovascular health and the underlying mechanisms remains obscure. Here, we demonstrated that higher intake of chicken protein was an independent risk factor for sub-clinical atherosclerosis. Adherence to high chicken protein diet (HCD) alleviated excessive weight gain and glycemic control regardless of the presence of gut microbiota in apolipoprotein E–deficient mice. In contrast, long-term HCD administration enhanced intestinal cholesterol absorption and accelerated atherosclerotic plaque formation in a gut microbiota-dependent manner. Integrative analysis of 16S rDNA sequencing and metabolomics profiling identified 3-Methyl-L-histidine (3-MH), resulting from an enrichment of Lachnospiraceae, as the key microbial effector to the atherogenic effect of HCD. Mechanistically, 3-MH facilitated the binding of hepatocyte nuclear factor 1A (HNF1A) to the promoter of NPC1-like intracellular cholesterol transporter 1 (NPC1L1), whereas inhibition of HNF1A–NPC1L1 axis abolished the atherogenic effect of 3-MH. Our findings uncovered a novel link between microbiota-derived 3-MH and disturbed cholesterol homeostasis, which ultimately accelerated atherosclerosis, and argued against the recommendation of HCD as weight loss regimens considering its adverse role in vascular health.

Genetic diseases constitute the majority of rare human diseases, resulting from abnormalities in an individual’s genetic composition. Traditional treatments offer limited relief for these challenging conditions. In contrast, the rapid advancement of gene therapy presents significant advantages by directly addressing the underlying causes of genetic diseases, thereby providing the potential for precision treatment and the possibility of curing these disorders. This review aims to delineate the mechanisms and outcomes of current gene therapy approaches in clinical applications across various genetic diseases affecting different body systems. Additionally, genetic muscular disorders will be examined as a case study to investigate innovative strategies of novel therapeutic approaches, including gene replacement, gene suppression, gene supplementation, and gene editing, along with their associated advantages and limitations at both clinical and preclinical levels. Finally, this review emphasizes the existing challenges of gene therapy, such as vector packaging limitations, immunotoxicity, therapy specificity, and the subcellular localization and immunogenicity of therapeutic cargos, while discussing potential optimization directions for future research. Achieving delivery specificity, as well as long-term effectiveness and safety, will be crucial for the future development of gene therapies targeting genetic diseases.

Bone marrow serves as the residence of hematopoietic stem cells and is recognized as one of the most radiosensitive tissues. Exposure to acute radiation leads to severe damage to bone marrow hematopoiesis which can be fatal, while few clinically applicable medication or specific therapeutic targets have been discovered. In this study, we found that the administration of cannabidiol significantly enhanced individual survival and restored the reconstitution capacity of bone marrow hematopoietic stem cells within 14 days after irradiation. Single-cell RNA sequencing analysis demonstrated that the expression levels of genes associated with stemness along with Wnt and BMP signaling pathways were restored by the cannabidiol treatment through the upregulation of Atf2, a transcription factor possessing multifunctional properties. Atf2 upregulation induced by cannabidiol treatment potentially upregulated the expression of Lrp6 to improve the stemness of hematopoietic stem cells. Further functional experiments validated the crucial role of Atf2 in regulating multilineage differentiation potential of bone marrow hematopoietic stem and progenitor cells. Overall, our findings provide evidence for a promising radioprotective function of cannabidiol and Atf2 as a candidate therapeutic target for acute radiation-induced hematopoietic injury, thereby paving the way for future research in the field.

This study aimed to determine the effects of polyethylene glycol loxenatide (PEG-Loxe), a glucagon-like peptide-1 receptor agonist, on a three-point major adverse cardiovascular event (3P-MACE) in patients with type 2 diabetes mellitus (T2DM). The study was conducted in six tertiary hospitals in three cities in China. Large language models were used to retrospectively screen and include 12,341 patients with T2DM who had either cardiovascular disease or cardiovascular risk factors. The patients were divided into the PEG-Loxe cohort (treated with PEG-Loxe, n = 1282) and the control cohort (treated with incretin glucose-lowering agents, n = 11,059). After a median follow-up of 4.0 years, 3P-MACE occurred in 51 (4.0%) and 1263 (11.4%) patients in PEG-Loxe and control cohorts, respectively (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.49–0.94; p = 0.019). In the PEG-Loxe versus control cohorts, 21 (1.6%) versus 476 (4.3%) patients experienced nonfatal stroke (HR 0.63; p = 0.041), whereas 22 (1.7%) versus 545 (4.9%) experienced nonfatal myocardial infarction (HR 0.66; p = 0.058), and the incidence of cardiovascular death was 8 (0.6%) versus 240 (2.2%), respectively (HR 0.56; p = 0.118). We found a significantly lower incidence of first nonfatal myocardial infarction, nonfatal stroke, or cardiovascular deaths in the PEG-Loxe cohort than the control cohort.