Tailored lipid nanoparticles (LNPs)-mediated small interfering RNA (siRNA) nanomedicines show promise in treating liver disease, such as acute liver injury (ALI) and non-alcoholic steatohepatitis (NASH). However, constructing LNPs that address biosafety concerns, ensure efficient delivery, and target specific hepatic subcellular fractions has been challenging. To evade above obstacles, we develop three novel self-degradable "gemini-like" ionizable lipids (SS-MA, SS-DC, SS-MH) by incorporating disulfide bonds and modifying the length of ester bond and tertiary amino head. Our findings reveal that the disulfide-bond-bridged LNPs exhibit reduction-responsive drug release, improving both biosafety and siRNA delivery efficiency. Furthermore, the distance of ester bond and tertiary amino head significantly influences the LNPs' pK _a, thereby affecting endosomal escape, hemolytic efficiency, absorption capacity of ApoE, uptake efficiency of hepatocytes and liver accumulation. We also develop the modified-mannose LNPs (M-LNP) to target liver macrophages specifically. The optimized M-MH_LNP@TNFα exhibits potential in preventing ALI by decreasing tumor necrosis factor α (TNFα) levels in the macrophages, while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol O-acyltransferase 2 (DGAT2) in the hepatocytes. Our findings provide new insights into developing novel highly effective and low-toxic "gemini-like" ionizable lipids for constructing LNPs, potentially achieving more effective treatment for hepatic diseases.

Acute kidney injury (AKI) has high morbidity and mortality, but effective clinical drugs and management are lacking. Previous studies have suggested that macrophages play a crucial role in the inflammatory response to AKI and may serve as potential therapeutic targets. Emerging evidence has highlighted the importance of forkhead box protein O1 (FoxO1) in mediating macrophage activation and polarization in various diseases, but the specific mechanisms by which FoxO1 regulates macrophages during AKI remain unclear. The present study aimed to investigate the role of FoxO1 in macrophages in the pathogenesis of AKI. We observed a significant upregulation of FoxO1 in kidney macrophages following ischemia-reperfusion (I/R) injury. Additionally, our findings demonstrated that the administration of FoxO1 inhibitor AS1842856-encapsulated liposome (AS-Lipo), mainly acting on macrophages, effectively mitigated renal injury induced by I/R injury in mice. By generating myeloid-specific FoxO1-knockout mice, we further observed that the deficiency of FoxO1 in myeloid cells protected against I/R injury-induced AKI. Furthermore, our study provided evidence of FoxO1's pivotal role in macrophage chemotaxis, inflammation, and migration. Moreover, the impact of FoxO1 on the regulation of macrophage migration was mediated through RhoA guanine nucleotide exchange factor 1 (ARHGEF1), indicating that ARHGEF1 may serve as a potential intermediary between FoxO1 and the activity of the RhoA pathway. Consequently, our findings propose that FoxO1 plays a crucial role as a mediator and biomarker in the context of AKI. Targeting macrophage FoxO1 pharmacologically could potentially offer a promising therapeutic approach for AKI.

Objective:To discuss the clinical curative effect and feasibility of the combination therapy of the minimally invasive percutaneous quantitative suture technique eight times and Kirschner wire elastic fixation in the treatment of mallet finger.Methods:A retrospective analysis was performed on patients with tendon zone Ⅰ rupture of tendinous mallet fingers who underwent surgery in the Department of Hand and Foot Microsurgery of Nanjing Jiangbei Hospital from July 2021 to June 2023. During the procedure, firstly, the extensor digitalis tendon in the zone Ⅰ was sutured percutaneous with 3-0 thread monofilament sutures in the "quantitative 8-stitch method " according to the pre-marked number sequence of 1 to 8, and fixed at the base of the distal phalanx via a constructed bone tunnel. Secondly, the distal interphalangeal joint (DIPJ) was fixed elastically with Kirschner wire, without damage to the articular surface. Four to five weeks after the operation, the Kirschner wire was removed, and flexion and extension of the affected finger were gradually increased. At the last follow-up, the range of motion (ROM) and the total action motion (TAM) of the finger were recorded, and the healthy side of the ROM and TAM slightly differed. Finger function was evaluated following the American Association of Hand Surgeons TAM system. It was divided into four grades: excellent, good, fair and poor. SPSS 15.0 software was used for statistical analysis. Measurement data conforming to normal distribution were expressed as Mean±SD, and a paired sample t-test was used for comparison between the affected finger and the corresponding healthy finger. Results:A total of 30 patients (30 digits) were enrolled, including 19 males and 11 females with the age of (38.5±4.3) years (14 to 71 years). All were single closed injuries. Time from injury to operation was (1.1±0.4) d (3 h to 7 d). The distance of tendon break was (8.4±0.5) mm (4 to 12 mm). Mallet finger deformities were all corrected postoperatively. There were no complications such as scar, exposed suture, nail tract infection, or nail removal on the dorsal side of the affected finger. All patients were followed up for (7.5±1.3) months (6-13 months). At the last follow-up, the ROM of DIPJ of the affected finger and the corresponding healthy finger were 43.28°±2.03° and 44.15°±1.12°, respectively, with no statistical significance ( t=1.32, P=0.084). TAM of the affected finger and the corresponding healthy finger were 240.15°±5.13° and 242.13°±3.11°, respectively, with no significant difference ( t=2.12, P=0.135). According to TAM system evaluation criteria, excellent in 27 cases, good in 3 cases, excellent and good rate was 100% (30/30). Conclusion:The combination of the minimally invasive percutaneous quantitative suture technique eight times and Kirschner wire elastic fixation has a satisfactory treatment outcome in the mallet finger, and there is no damage to the DIPJ surface. It is a simple, safe, effective method with minimal invasion.

Epigenomic imbalance drives abnormal transcriptional processes,promoting the onset and progression of cancer.Although defective gene regulation generally affects carcinogenesis and tumor suppression networks,tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes,which may have significant implications for the development and application of epigenetic therapy,cancer immunotherapy,and their combinations.Herein,we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes,DNA methylation,histone post-translational modification,and chromatin structure in tumor immunogenicity,and introduce these epigenetic research methods.We emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immuno-therapy through the complex interaction between cancer epigenetics and cancer immunology.

Objective:To discuss the clinical curative effect and feasibility of the combination therapy of the minimally invasive percutaneous quantitative suture technique eight times and Kirschner wire elastic fixation in the treatment of mallet finger.Methods:A retrospective analysis was performed on patients with tendon zone Ⅰ rupture of tendinous mallet fingers who underwent surgery in the Department of Hand and Foot Microsurgery of Nanjing Jiangbei Hospital from July 2021 to June 2023. During the procedure, firstly, the extensor digitalis tendon in the zone Ⅰ was sutured percutaneous with 3-0 thread monofilament sutures in the "quantitative 8-stitch method " according to the pre-marked number sequence of 1 to 8, and fixed at the base of the distal phalanx via a constructed bone tunnel. Secondly, the distal interphalangeal joint (DIPJ) was fixed elastically with Kirschner wire, without damage to the articular surface. Four to five weeks after the operation, the Kirschner wire was removed, and flexion and extension of the affected finger were gradually increased. At the last follow-up, the range of motion (ROM) and the total action motion (TAM) of the finger were recorded, and the healthy side of the ROM and TAM slightly differed. Finger function was evaluated following the American Association of Hand Surgeons TAM system. It was divided into four grades: excellent, good, fair and poor. SPSS 15.0 software was used for statistical analysis. Measurement data conforming to normal distribution were expressed as Mean±SD, and a paired sample t-test was used for comparison between the affected finger and the corresponding healthy finger. Results:A total of 30 patients (30 digits) were enrolled, including 19 males and 11 females with the age of (38.5±4.3) years (14 to 71 years). All were single closed injuries. Time from injury to operation was (1.1±0.4) d (3 h to 7 d). The distance of tendon break was (8.4±0.5) mm (4 to 12 mm). Mallet finger deformities were all corrected postoperatively. There were no complications such as scar, exposed suture, nail tract infection, or nail removal on the dorsal side of the affected finger. All patients were followed up for (7.5±1.3) months (6-13 months). At the last follow-up, the ROM of DIPJ of the affected finger and the corresponding healthy finger were 43.28°±2.03° and 44.15°±1.12°, respectively, with no statistical significance ( t=1.32, P=0.084). TAM of the affected finger and the corresponding healthy finger were 240.15°±5.13° and 242.13°±3.11°, respectively, with no significant difference ( t=2.12, P=0.135). According to TAM system evaluation criteria, excellent in 27 cases, good in 3 cases, excellent and good rate was 100% (30/30). Conclusion:The combination of the minimally invasive percutaneous quantitative suture technique eight times and Kirschner wire elastic fixation has a satisfactory treatment outcome in the mallet finger, and there is no damage to the DIPJ surface. It is a simple, safe, effective method with minimal invasion.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic inflammation and excessive proliferation of the synovium. Currently, treatment options focus on either reducing inflammation or inhibiting synovial hyperplasia. However, these modalities are unsatisfactory in achieving the desired therapeutic outcomes. Halofuginone hydrobromide (HF), an herbal active ingredient, has demonstrated pharmacological effects of both anti-inflammation and inhibition of synovial hyperplasia proliferation. However, HF's medical efficacy is limited due to its poor water solubility, short half-life (t _1/2), and non-target toxicity. In the current study, by using the advantages of nanotechnology, we presented a novel dual-targeted nanocomplex, termed HA-M@P@HF NPs, which consisted of a hyaluronic acid (HA)-modified hybrid membrane (M)-camouflaged poly lactic-co-glycolic acid (PLGA) nanosystem for HF delivery. These nanocomplexes not only overcame the limitations of HF but also achieved simultaneous targeting of inflammatory macrophages and human fibroblast-like synoviocytes-RA (HFLS-RA). In vivo experiments demonstrated that these nanocomplexes effectively suppressed immune-mediated inflammation and synovial hyperplasia, safeguarding against bone destruction in rats with adjuvant-induced arthritis (AIA). Remarkable anti-arthritic effects of these nanocomplexes were accomplished through promoting repolarization of M1-to-M2 macrophages and apoptosis of HFLS-RA, thereby offering a promising therapeutic strategy for RA.

OBJECTIVE: To derive the Chinese medicine (CM) syndrome classification and subgroup syndrome characteristics of ischemic stroke patients. METHODS: By extracting the CM clinical electronic medical records (EMRs) of 7,170 hospitalized patients with ischemic stroke from 2016 to 2018 at Weifang Hospital of Traditional Chinese Medicine, Shandong Province, China, a patient similarity network (PSN) was constructed based on the symptomatic phenotype of the patients. Thereafter the efficient community detection method BGLL was used to identify subgroups of patients. Finally, subgroups with a large number of cases were selected to analyze the specific manifestations of clinical symptoms and CM syndromes in each subgroup. RESULTS: Seven main subgroups of patients with specific symptom characteristics were identified, including M3, M2, M1, M5, M0, M29 and M4. M3 and M0 subgroups had prominent posterior circulatory symptoms, while M3 was associated with autonomic disorders, and M4 manifested as anxiety; M2 and M4 had motor and motor coordination disorders; M1 had sensory disorders; M5 had more obvious lung infections; M29 had a disorder of consciousness. The specificity of CM syndromes of each subgroup was as follows. M3, M2, M1, M0, M29 and M4 all had the same syndrome as wind phlegm pattern; M3 and M0 both showed hyperactivity of Gan (Liver) yang pattern; M2 and M29 had similar syndromes, which corresponded to intertwined phlegm and blood stasis pattern and phlegm-stasis obstructing meridians pattern, respectively. The manifestations of CM syndromes often appeared in a combination of 2 or more syndrome elements. The most common combination of these 7 subgroups was wind-phlegm. The 7 subgroups of CM syndrome elements were specifically manifested as pathogenic wind, pathogenic phlegm, and deficiency pathogens. CONCLUSIONS There were 7 main symptom similarity-based subgroups in ischemic stroke patients, and their specific characteristics were obvious. The main syndromes were wind phlegm pattern and hyperactivity of Gan yang pattern.
Humans ; Syndrome ; Ischemic Stroke ; Medicine, Chinese Traditional ; Liver ; Phenotype

Objective:To investigate the safety and feasibility of the CHESS endoscpic ruler (CHESS ruler), and the consistency between the measured values and the interpretation values by endoscopic physician experience.Methods:From January 2021 to January 2022, a total of 105 liver cirrhosis patients with portal hypertension were prospectively enrolled from General Hospital, Xixia Branch Hospital, Ningnan Hospital of People′s Hospital of Ningxia Hui Autonomous Region (29 cases), and the First People′s Hospital of Yinchuan (25 cases), General Hospital of Ningxia Medical University (18 cases), Wuzhong People′s Hospital (10 cases), the Fifth People′s Hospital of Ningxia Hui Autonomous Region (10 cases), Shizuishan Second People′s Hospital (6 cases), Yinchuan Second People′s Hospital (5 cases), and Zhongwei People′s Hospital (2 cases) 8 hospitals. The clinical characteristics of all the patients, including gender, age, nationality, etiolog of liver cirrhosis, and Child-Pugh classification of liver function were recorded. A big gastroesophageal varices was defined as diameter of varices ≥5 mm. Endoscopist (associated chief physician) performed gastroscopy according to the routine gastroscopy procedures, and the diameter of the biggest esophageal varices was measured by experience and images were collected, and then objective measurement was with the CHESS ruler and images were collected. The diameter of esophageal varices of 10 randomly selected patients (random number table method) was determined by 6 endoscopists (attending physician or associated chief physician) with experience or measured by CHESS ruler. Kappa test was used to test the consistency in the diameter of esophageal varices between measured values by CHESS ruler and the interpretation values by endoscopic physician experience.Results:Among 105 liver cirrhosis patients with portal hypertension, male 65 cases and female 40 cases, aged (54.8±12.2) years old, Han nationality 82 cases, Hui nationality 21 cases and Mongolian nationality 2 cases. The etiology of liver cirrhosis included chronic hepatitis B (79 cases), alcoholic liver disease (7 cases), autoimmune hepatitis (7 cases), chronic hepatitis C (2 cases), and other etiology (10 cases). Liver function of 32 cases was Child-Pugh A, Child-Pugh B 57 cases, and Child-Pugh C 16 cases. All 105 liver cirrhosis patients with cirrhotic portal hypertension were successfully measured the diameter of gastroesophageal varices by CHESS ruler, and the success rate of application of CHESS ruler was 100.0% (105/105). The procedure time from the CHESS ruler into the body to the exit of the body after measurement was (3.50±2.55) min. No complications happened in all the patients during measurement. Among 105 liver cirrhosis patients with cirrhotic portal hypertension, 96 cases (91.4%) were recognized as big gastroesophageal varices by the endoscopists. Totally 93 cases (88.6%) were considered as big gastroesophageal varices by CHESS ruler. Eight cases were recognized as big gastroesophageal varices by the endoscopist, however not by the CHESS ruler; 5 cases were recognized as big gastroesophageal varices by the CHESS ruler, but not by the endoscopists; 4 cases were not recognized as big gastroesophageal varices both by the endoscopists and CHESS ruler; 88 cases were recognized as big gastroesophageal varices both by the endoscopists and CHESS ruler. The missed diagnostic rate of big gastroesophageal varices by the endoscopists experience was 5.4% (5/93), and the Kappa value of consistency coefficient between the measurement by the CHESS ruler and the interpretation by endoscopists experience was 0.31 (95% confidence interval 0.03 to 0.60). The overall Kappa value of consistency coefficient by 6 endoscopists measured by CHESS ruler in big gastroesophageal varices diagnosis was 0.77 (95% confidence interval 0.61 to 0.93).Conclusion:As an objective measurement tool, CHESS ruler can make up for the deficiency of subjective judgment by endoscopists, accurately measure the diameter of gastroesophageal varices, and is highly feasible and safe.

Conventional wisdom holds that the onset of chronic obstructive pulmonary disease (COPD) is usually in older people. However, with extended follow-up in large cohort studies, the trajectory of lung function development has been gradually delineated, indicating that the decline of lung function may originate early in life. In addition, a large number of studies have shown that people with chronic respiratory symptoms, pulmonary imaging changes and abnormal lung physiology, but not in line with pulmonary function diagnosis of COPD, tend to develop COPD in the future and may have a worse prognosis, suggesting the necessity of early intervention. The GOLD 2022 report proposes a series of terms related to COPD, including COPD in young people and pre-COPD, opening up new opportunities for the prevention, early diagnosis and treatment of COPD. These concepts also guide the study design of the biological mechanism of COPD and the trajectory of disease progression. This article reviews the research progress of COPD in young people and pre-COPD to attract more attention in clinical practice.
Humans ; Aged ; Adolescent ; Pulmonary Disease, Chronic Obstructive ; Lung ; Cohort Studies ; Research Design

Conventional wisdom holds that the onset of chronic obstructive pulmonary disease (COPD) is usually in older people. However, with extended follow-up in large cohort studies, the trajectory of lung function development has been gradually delineated, indicating that the decline of lung function may originate early in life. In addition, a large number of studies have shown that people with chronic respiratory symptoms, pulmonary imaging changes and abnormal lung physiology, but not in line with pulmonary function diagnosis of COPD, tend to develop COPD in the future and may have a worse prognosis, suggesting the necessity of early intervention. The GOLD 2022 report proposes a series of terms related to COPD, including COPD in young people and pre-COPD, opening up new opportunities for the prevention, early diagnosis and treatment of COPD. These concepts also guide the study design of the biological mechanism of COPD and the trajectory of disease progression. This article reviews the research progress of COPD in young people and pre-COPD to attract more attention in clinical practice.
Humans ; Aged ; Adolescent ; Pulmonary Disease, Chronic Obstructive ; Lung ; Cohort Studies ; Research Design