2025年 · 第138卷第08期

Intestinal fibrosis is a major complication of inflammatory bowel disease (IBD), leading to a high incidence of surgical interventions and significant disability. Despite its clinical relevance, no targeted pharmacological therapies are currently available. This review aims to explore the underlying mechanisms driving intestinal fibrosis and address unresolved scientific questions, offering insights into potential future therapeutic strategies. We conducted a literature review using data from PubMed up to October 2024, focusing on studies related to IBD and fibrosis. Intestinal fibrosis results from a complex network involving stromal cells, immune cells, epithelial cells, and the gut microbiota. Chronic inflammation, driven by factors such as dysbiosis, epithelial injury, and immune activation, leads to the production of cytokines like interleukin (IL)-1β, IL-17, and transforming growth factor (TGF)-β. These mediators activate various stromal cell populations, including fibroblasts, pericytes, and smooth muscle cells. The activated stromal cells secrete excessive extracellular matrix components, thereby promoting fibrosis. Additionally, stromal cells influence the immune microenvironment through cytokine production. Future research would focus on elucidating the temporal and spatial relationships between immune cell-driven inflammation and stromal cell-mediated fibrosis. Additionally, investigations are needed to clarify the differentiation origins of excessive extracellular matrix-producing cells, particularly fibroblast activation protein (FAP)⁺ fibroblasts, in the context of intestinal fibrosis. In conclusion, aberrant stromal cell activation, triggered by upstream immune signals, is a key mechanism underlying intestinal fibrosis. Further investigations into immune–stromal cell interactions and stromal cell activation are essential for the development of therapeutic strategies to prevent, alleviate, and potentially reverse fibrosis.

Organ transplantation, particularly pediatric liver transplantation (LT), has transformed medical practice over the past six decades, providing life-saving interventions for children with end-stage liver disease. This review demonstrated the historical milestones of pediatric organ transplantation, emphasizing Japan’s contributions, mainly through the National Center for Child Health and Development. While early transplantation efforts in the 1950s and 1960s faced significant challenges, breakthroughs in preservation methods, immunosuppressive therapies, surgical techniques, and innovations such as living donor LT in Asia have greatly improved success rates. Japan’s pediatric LT landscape is distinct, primarily due to its reliance on living donor LT, shaped by cultural and religious influences that have traditionally restricted deceased donor organ donation. This review manuscript discusses Japan’s pioneering role in expanding the indications for pediatric LT to include rare conditions such as inherited metabolic disorders and hepatoblastoma. It highlights recent innovations such as hyper-reduced lateral segment grafts, machine perfusion, and minimally invasive surgery that have further improved outcomes. International collaboration has facilitated the sharing of expertise, advancing pediatric liver transplantation practice worldwide. Despite these achievements, challenges remain, particularly in light of Japan’s declining birth rate, which threatens the sustainability of pediatric transplant services. This review emphasizes the need for centralized transplant facilities, greater awareness of brain-dead organ donation, and continued medical advances to ensure that pediatric LT remains a viable, life-saving option for future generations.

Lung cancer is one of the most lethal tumors in the world with a 5-year overall survival rate of less than 20%, mainly including lung adenocarcinoma (LUAD). Tumor microenvironment (TME) has become a new research focus in the treatment of lung cancer. The TME is heterogeneous in composition and consists of cellular components, growth factors, proteases, and extracellular matrix. The various cellular components exert a different role in apoptosis, metastasis, or proliferation of lung cancer cells through different pathways, thus contributing to the treatment of adenocarcinoma and potentially facilitating novel therapeutic methods. This review summarizes the research progress on different cellular components with cell–cell interactions in the TME of LUAD, along with their corresponding drug candidates, suggesting that targeting cellular components in the TME of LUAD holds great promise for future theraputic development.

Acute kidney injury (AKI) is a common clinically critical syndrome in hospitalized patients with high morbidity and mortality. At present, the mechanism of AKI has not been fully elucidated, and no therapeutic drugs exist. As known, glycolytic product lactate is a key metabolite in physiological and pathological processes. The kidney is an important gluconeogenic organ, where lactate is the primary substrate of renal gluconeogenesis in physiological conditions. During AKI, altered glycolysis and gluconeogenesis in kidneys significantly disturb the lactate metabolic balance, which exert impacts on the severity and prognosis of AKI. Additionally, lactate-derived posttranslational modification, namely lactylation, is novel to AKI as it could regulate gene transcription of metabolic enzymes involved in glycolysis or Warburg effect. Protein lactylation widely exists in human tissues and may severely affect non-histone functions. Moreover, the strategies of intervening lactate metabolic pathways are expected to bring a new dawn for the treatment of AKI. This review focused on renal lactate metabolism, especially in proximal renal tubules after AKI, and updated recent advances of lactylation modification, which may help to explore potential therapeutic targets against AKI.

Angiotensin receptor neprilysin inhibitors (ARNIs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) are the cornerstones in treating heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) are included in HFrEF treatment guidelines. However, the effect of SGLT-2i and the five drugs on HFrEF have not yet been systematically evaluated.

PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) from inception dates to September 23, 2022. Additional trials from previous relevant reviews and references were also included. The primary outcomes were changes in left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter/dimension (LVEDD), left ventricular end-systolic diameter/dimension (LVESD), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV), left ventricular end-systolic volume index (LVESVI), and left ventricular end-diastolic volume index (LVEDVI). Secondary outcomes were New York Heart Association (NYHA) class, 6-min walking distance (6MWD), B-type natriuretic peptide (BNP) level, and N-terminal pro-BNP (NT-proBNP) level. The effect sizes were presented as the mean difference (MD) with 95% confidence interval (CI).

We included 68 RCTs involving 16,425 patients. Compared with placebo, ARNI + BB + MRA + SGLT-2i was the most effective combination to improve LVEF (15.63%, 95% CI: 9.91% to 21.68%). ARNI + BB + MRA + SGLT-2i (5.83%, 95% CI: 0.53% to 11.14%) and ARNI + BB + MRA (3.83%, 95% CI: 0.72% to 6.90%) were superior to the traditional golden triangle ACEI + BB + MRA in improving LVEF. ACEI + BB + MRA + SGLT-2i was better than ACEI + BB + MRA (–8.05 mL/m², 95% CI: –14.88 to –1.23 mL/m²) and ACEI + BB + SGLT-2i (–18.94 mL/m², 95% CI: –36.97 to –0.61 mL/m²) in improving LVEDVI. ACEI + BB + MRA + SGLT-2i (–3254.21 pg/mL, 95% CI: –6242.19 to –560.47 pg/mL) was superior to ARB + BB + MRA in reducing NT-proBNP.

Adding SGLT-2i to ARNI/ACEI + BB + MRA is beneficial for reversing cardiac remodeling. The new quadruple drug "ARNI + BB + MRA + SGLT-2i" is superior to the golden triangle "ACEI + BB + MRA" in improving LVEF.

PROSPERO; No. CRD42022354792.

Organs are fundamental anatomical entities within the human body, each performing distinct physiological functions and serving as sites for various pathological conditions. Current medical research and treatment focus primarily on the individual as a whole or on cellular and genetic levels. However, due to the absence of well-establishedin vitroorgan culture techniques and models, research at the mesoscopic level of organs significantly lags behind microscopic and macroscopic investigations. This lag restricts the efficient translation of research outcomes and constrains the potential for regional research and precise treatment of diseased organs. Although murine models and cell lines contribute to the understanding of organ biology and associated diseases, they fail to replicate crucial aspects of human organ complexity and metabolic functions. Notably, failures in clinical trials have often been attributed to inaccurate modeling, particularly in animal models.

Valvular heart disease (VHD) has become increasingly common with the aging in China. This study aimed to evaluate regional differences in the clinical features, management strategies, and outcomes of patients with VHD across different regions in China.

Data were collected from the China-VHD Study. From April 2018 to June 2018, 12,347 patients who presented with moderate or severe native VHD with a median of 2 years of follow-up from 46 centers at certified tertiary hospitals across 31 provinces, autonomous regions, and municipalities in Chinese mainland were included in this study. According to the locations of the research centers, patients were divided into five regional groups: eastern, southern, western, northern, and central China. The clinical features of VHD patients were compared among the five geographical regions. The primary outcome was all-cause mortality or rehospitalization for heart failure. Kaplan–Meier survival analysis was used to compare the cumulative incidence rate.

Among the enrolled patients (mean age, 61.96 years; 6877 [55.70%] male), multiple VHD was the most frequent type (4042, 32.74%), which was mainly found in eastern China, followed by isolated mitral regurgitation (3044, 24.65%), which was mainly found in northern China. The etiology of VHD varied significantly across different regions of China. The overall rate of valve interventions was 32.67% (4008/12,268), with the highest rate in southern China at 48.46% (205/423). In terms of procedure, the proportion of transcatheter valve intervention was relatively low compared to that of surgical treatment. Patients with VHD in western China had the highest incidence of all-cause mortality or rehospitalization for heart failure. Valve intervention significantly improved the outcome of patients with VHD in all five regions (all P <0.05).

This study revealed that patients with VHD in China are characterized by significant geographic disparities in clinical features, treatment, and clinical outcomes. Targeted efforts are needed to improve the management and prognosis of patients with VHD in China according to differences in geographical characteristics.

ClinicalTrials.gov, NCT03484806.

The correlation between the morphological structure of the patellofemoral joint (PFJ) and the severity of knee joint osteoarthritis (KOA) remains uncertain. This study aims to investigate the correlation between the severity of knee joint osteoarthritis and the alignment of patellofemoral and patellar height on radiographs.

This multi-center, retrospective study analyzed the magnetic resonance imaging (MRI) scans and anteroposterior radiographs of 534 adult outpatients with KOA. To evaluate the radiographic severity of KOA, anteroposterior radiographs of the knee and the Kellgren-Lawrence (K-L) grade were used. Knee MRI scans were used to measure the patellar length ratio (PLR), sulcus angle (SA), lateral patellar tilt angle (LPTA), and the distance between tibial tuberosity and trochlear groove (TT-TG). We examined the association between the configuration of the PFJ, arrangement, and harshness of the KOA. Information on participants’ demographics, such as age, sex, side, height, and weight, was collected. A chi-squared test was used for the correlation of radiographic severity of KOA with sex and the affected side. Spearman correlation was used for patellofemoral alignment or morphology and the radiographic severity of lateral KOA. Multiple linear regression models were used for the association between LPTA, SA, TT-TG, and severity of KOA after accounting for demographic variables.

The study comprised of 534 patients; of these, 339 (63%) were female. A total of 586 knees were evaluated in this study. Age showed a strong positive correlation with KOA severity (r = 0.516, P <0.01), whereas LPTA showed a strong negative correlation (r = –0.662, P <0.01). Additionally, SA (r = 0.616, P <0.05), and TT-TG showed a strong positive correlation (r = 0.770, P <0.01) with tibiofemoral osteoarthritis (TFOA) severity. Multiple linear regression analysis indicated that knee osteoarthritis severity (β = –2.946, P <0.001) and side (β = –0.839, P = 0.001) was associated with LPTA; knee osteoarthritis severity (β = 5.032, P <0.001) and age (β = –0.095, P <0.001) was associated with SA; knee osteoarthritis severity (β = 2.445, P <0.001), sex (β = –0.326, P = 0.041), body mass index (β = –0.061, P = 0.017) and age (β = –0.025, P <0.001) was associated with TT-TG.

Radiographic severity of KOA was positively associated with age, SA, and TT-TG but negatively associated with LPTA.

Generalized pustular psoriasis (GPP), a rare and recurrent autoinflammatory disease, imposes a substantial burden on patients and society. Awareness of GPP in China remains limited.

This cross-sectional survey, conducted between September 2021 and May 2023 across 14 hospitals in China, included GPP patients of all ages and disease phases. Data collected encompassed demographics, clinical characteristics, economic impact, disease severity, quality of life, and treatment-related complications. Risk factors for GPP recurrence were analyzed.

Among 127 patients (female/male ratio = 1.35:1), the mean age of disease onset was 25 years (1st quartile [Q1]–3rd quartile [Q3]: 11–44 years); 29.2% had experienced GPP for more than 10 years. Recurrence occurred in 75.6% of patients, and nearly half reported no identifiable triggers. Younger age at disease onset (P = 0.021) and transitioning to plaque psoriasis (P = 0.022) were associated with higher recurrence rates. The median diagnostic delay was 8 months (Q1–Q3: 2–41 months), and 32.3% of patients reported misdiagnoses. Comorbidities were present in 53.5% of patients, whereas 51.1% experienced systemic complications during treatment. Depression and anxiety affected 84.5% and 95.6% of patients, respectively. During GPP flares, the median Dermatology Life Quality Index score was 19.0 (Q1–Q3: 13.0–23.5). This score showed significant differences between patients with and without systemic symptoms; it demonstrated correlations with both depression and anxiety scores. Treatment costs caused financial hardship in 55.9% of patients, underscoring the burden associated with GPP.

The substantial disease and economic burdens among Chinese GPP patients warrant increased attention. Patients with early onset disease and those transitioning to plaque psoriasis require targeted interventions to mitigate the high recurrence risk.

Most studies have evaluated disability-adjusted life years (DALYs) of colorectal cancer (CRC) patients based on a set of generic disability weights (DWs). This study aimed to apply local CRC-stage-specific DWs to estimate the burden of DALYs for CRC (CRC-DALYs) in populations in China and consider the influence of local screening coverage of CRC.

A prevalence-based model was constructed using data from various sources. Years lived with disability (YLDs) were estimated mainly via cumulative prevalence data (based on CRC incidence rates, population numbers, and survival rates), stage-specific proportions of CRC, and DWs of the local population. Years of life lost (YLLs) were calculated based on the CRC mortality rates and standard life expectancies. CRC incidence and mortality rates for the years 2020, 2025, and 2030 were estimated by joinpoint regression, and the corresponding DALYs were predicted. The main assumption was made for CRC screening coverage. Sensitivity analyses were used to assess the impact of population, DWs, and coverage.

In 2017, among the Chinese population, the estimated number of CRC-DALYs was 4,303,314 (11.9% for YLDs). If CRC screening coverage rate in China (2.3%) remains unchanged, the overall DALYs in 2030 are predicted to increase by 37.2% (45.1% of those aged ≥65 years). More optimistically, the DALYs would then decrease by 0.7% in 2030 (from 5,902,454 to 5,860,200) if the coverage could be increased to 25.0%. A sensitivity analysis revealed that using local DWs would change the base-case values by 5.7%.

The estimated CRC-DALYs in China using population-specific DWs were considerably lower (with a higher percentage of YLDs) than the global burden of disease (GBD) estimates (5,865,004, of 4.6% for YLDs), suggesting the impact extent of applying local parameters. Sustainable scale-up CRC screening needs to be in place to moderate the growth trend of CRC-DALYs in China.

Diabetic foot is a complex condition with high incidence, recurrence, mortality, and disability rates. Current treatments for diabetic foot ulcers are often insufficient. This study was conducted to identify potential therapeutic targets for diabetic foot.

Datasets related to diabetic foot and diabetic skin were retrieved from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified using R software. Enrichment analysis was conducted to screen for critical gene functions and pathways. A protein interaction network was constructed to identify node genes corresponding to key proteins. The DEGs and node genes were overlapped to pinpoint target genes. Plasma and chronic ulcer samples from diabetic and non-diabetic individuals were collected. Western blotting, immunohistochemistry, and enzyme-linked immunosorbent assays were performed to verify the S100 calcium binding protein A9 (S100A9), inflammatory cytokine, and related pathway protein levels. Hematoxylin and eosin staining was used to measure epidermal layer thickness.

In total, 283 common DEGs and 42 node genes in diabetic foot ulcers were identified. Forty-three genes were differentially expressed in the skin of diabetic and non-diabetic individuals. The overlapping of the most significant DEGs and node genes led to the identification of S100A9 as a target gene. The S100A9 level was significantly higher in diabetic than in non-diabetic plasma (178.40 ± 44.65 ng/mL vs. 40.84 ± 18.86 ng/mL) and in chronic ulcers, and the wound healing time correlated positively with the plasma S100A9 level. The levels of inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1, and IL-6) and related pathway proteins (phospho-extracellular signal regulated kinase [ERK], phospho-p38, phospho-p65, and p-protein kinase B [Akt]) were also elevated. The epidermal layer was notably thinner in chronic diabetic ulcers than in non-diabetic skin (24.17 ± 25.60 µm vs. 412.00 ± 181.60 µm).

S100A9 was significantly upregulated in diabetic foot and was associated with prolonged wound healing. S100A9 may impair diabetic wound healing by disrupting local inflammatory responses and skin re-epithelialization.

Liver transplantation (LT) remains the primary treatment for irreversible liver failure. However, challenges in organ preservation, particularly ischemia-reperfusion injury and donor liver vulnerability, contribute to poor post-transplant outcomes.^[1,2]The accumulation of reactive oxygen species (ROS) exacerbates these issues, leading to inflammation, tissue damage, and impaired graft function.^[3]Ceria nanoparticles have gained attention for their antioxidant, antibacterial, and antifibrotic properties and exhibited multiple enzymatic activities, including those of superoxide dismutase and catalase.^[4]We developed an innovative system for organ preservation using dextran-coated ceria nanoparticles (CeO₂NPs) incorporated into the University of Wisconsin (UW) solution, aiming to enhance liver preservation by reducing oxidative stress and inflammation and adjusting macrophage polarization.

To the Editor: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but serious condition characterized by obstruction of the pulmonary arteries due to thromboembolic events and subsequent vascular remodeling, which leads to pulmonary hypertension (PH). Classified as Group 4 in the 2022 PH guidelines by the European Society of Cardiology and the European Respiratory Society, CTEPH poses significant risks, including progressive PH, right ventricular dysfunction, and mortality if left untreated. Despite established diagnostic and treatment guidelines, the exact national prevalence of CTEPH remains largely unknown due to the absence of organized registries, with estimates ranging from 3 to 30 cases per million people. Although CTEPH is commonly thought to follow acute pulmonary embolism (PE), epidemiological data reveal a discrepancy; studies suggest that only 0.1% to 3.8% of PE patients may develop CTEPH.^[1,2]Recent reports indicate that 65.6% of CTEPH patients have a history of acute PE, although this proportion varies across regions.^[3]Treatment options include pulmonary endarterectomy (PEA), riociguat, and balloon pulmonary angioplasty (BPA). CTEPH significantly impacts patients’ quality of life, causing symptoms such as shortness of breath and fatigue, which lead to increased healthcare utilization and economic burden. In China, limited awareness and delayed diagnosis further complicate the management of CTEPH, underscoring the need for studies that address the disease’s burden and enhance recognition among healthcare providers. Therefore, this systematic review aimed to estimate the prevalence of CTEPH using data from PE patients and to investigate the characteristics and management patterns of CTEPH in the Chinese population.

To the editor: Type 2 inflammation is a major driving factor in pediatric moderate-to-severe asthma, which may lead to the activation of downstream eosinophils, immunoglobulin E (IgE) production, increased fractional exhaled nitric oxide (FeNO), and airway mucus production.^[1]Despite adequate treatment with medium-high dose inhaled corticosteroids combined with long-acting β2-receptor agonists (ICS–LABAs) for pediatric moderate-to-severe asthma, symptoms persist or frequently worsen.^[2]Studies have shown that approximately 70–89% of children with moderate-to-severe asthma have type 2 inflammation, and a major endotype is type 2 asthma, characterized by the presence of elevated type 2 biomarkers, including blood or sputum eosinophils, total IgE with allergic sensitization, and FeNO.^[3]

To the Editor: Septate uterus is the most common congenital uterine malformation associated with an increased risk of miscarriage, preterm birth, and fetal malpresentation and reduced clinical pregnancy rates. The European classification defines septate uterus as having an internal fundal indentation exceeding 50% of the uterine wall thickness and an external indentation less than 50% of the uterine wall thickness.^[1]

To the Editor:Common respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma induce significant health burdens worldwide.^[1,2]Airway/lung microbiome and microbial metabolites have been proven to be closely related to multiple respiratory diseases.^[3]However, few relevant studies show characteristics and horizontal comparisons of metabolites of dominant bacteria in respiratory diseases. Additionally, most results are based on association analyses of microbiome sequences, especially those of the gut microbiome, and untargeted metabolomics, without evidence that the metabolites are directly produced and secreted by certain bacteria.^[4]In this context, our study aimed to analyze and compare the key metabolites and metabolic pathways of common bacteria involved in respiratory diseases.

To the Editor: Adiposity is a prominent global health issue, imposing a considerable burden on cardiometabolic diseases (CMDs, including cardiovascular diseases [CVDs] and diabetes). Beyond the focus on one single CMD, there has been a growing emphasis on their co-occurrence, termed cardiometabolic multimorbidity (CMM). The rising prevalence of CMM poses substantial risks to both individuals and healthcare systems. Notably, the prevalence of CMM has increased from 9% to 14% in the United States between 1999 and 2018, whereas in China, it has nearly tripled, from 2% to 6%, between 2010 and 2016.^[1,2]

To the Editor: Atopic dermatitis (AD) is a chronic inflammatory skin condition marked by recurrent eczematous lesions and intense pruritus, affecting approximately 15–20% of children and up to 10% of adults worldwide.^[1]The presence of AD significantly impairs patient quality of life and imposes substantial economic burdens on society. In recent years, the potential link between AD and lymphoma has attracted considerable attention from researchers and clinicians. Lymphoma, a malignancy of the lymphatic system, poses significant health risks due to its high mortality potential.^[2]However, observational studies investigating the potential correlation between AD and lymphoma have yielded inconsistent results. Consequently, the association between AD and lymphoma remains controversial and warrants further investigation.

To the Editor: Biologics have been used successfully for the treatment of psoriasis; however, some patients develop paradoxical reactions, particularly psoriasiform and eczematoid reactions. Eczematoid paradoxical reactions (EPRs) occur in 1%–6% of cases treated with tumor necrosis factor (TNF)-α inhibitors, 2.4% with interleukin (IL)-12/23 inhibitors, 3.5% with IL-17 inhibitors, and 0.01% with IL-23 inhibitors.^[1]In practice, the incidence of EPRs induced by IL-17A inhibitors varies widely^[2,3,4]and biologicals may have to be discontinued in some severe cases.^[5]

The proximal small intestine, encompassing the duodenum and jejunum, is widely recognized as the primary site for nutrient digestion and absorption in humans.^[1]Notably, its luminal environment exhibits diverse histological and physiological characteristics, including a longitudinal pH gradient, variations in oxygen pressure, and differing concentrations of antimicrobial peptides.^[2]In addition, the small intestine is a highly organized structure composed of repeated crypt-villous units. In mice, epithelial, immune, and mesenchymal cells have been identified to exhibit significant spatial variability in the gene expression patterns along the crypt-villus axis. However, the spatial expression heterogeneity of the small intestine in humans remains largely unexplored.