Sepsis-induced lung injury is a common type of sepsis complicated with multiple organ dysfunction syndrome， whose uncontrolled inflammatory response and oxidative stress are the key pathological mechanisms. As an important pathway of anti-inflammatory and anti-oxidative stress， the nuclear factor-erythroid 2-related factor 2 （Nrf2） signaling pathway is very important in the occurrence and development of sepsis-induced lung injury. This review summarizes relevant research conducted over the past decade on the regulation of the Nrf2 signaling pathway by traditional Chinese medicine （TCM） to ameliorate sepsis- induced lung injury. It has been found that 14 kinds of TCM effective ingredients （including five types of compounds： flavonoids， terpenes， alkaloids， saponins， phenols） and 6 kinds of compound preparations （including three types of formulas： heat-clearing and detoxifying formulas， purgative formulas for promoting bowel movement， and formulas for reinforcing vital qi and consolidating the constitution） can inhibit inflammatory responses and oxidative stress by activating Nrf2 signaling pathway and intervening in related pathways such as those involving Kelch-like ECH-associated protein 1， heme oxygenase-1， antioxidant response element and AMP-activated protein kinase， thereby alleviating sepsis-induced lung injury.

The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR-CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, via functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR-CYP1A1 axis. Following screening of a compound library, LAC-7 was identified as an efficacious activator of the AhR-CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR-CYP1A1 axis as novel anti-inflammatory agents.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Sensorineural hearing loss (SNHL), the most commonly-occurring form of hearing loss, is caused mainly by injury to or the loss of hair cells and spiral ganglion neurons in the cochlea. Numerous environmental and physiological factors have been shown to cause acquired SNHL, such as ototoxic drugs, noise exposure, aging, infections, and diseases. Several programmed cell death (PCD) pathways have been reported to be involved in SNHL, especially some novel PCD pathways that have only recently been reported, such as ferroptosis, necroptosis, and pyroptosis. Here we summarize these PCD pathways and their roles and mechanisms in SNHL, aiming to provide new insights and potential therapeutic strategies for SNHL by targeting these PCD pathways.
Humans ; Hearing Loss, Sensorineural/metabolism* ; Necroptosis/drug effects* ; Pyroptosis/drug effects* ; Ferroptosis/drug effects* ; Animals

Objective To explore the relationship between the polymorphism of excision repair cross-complementation group 1 (ERCC1) C8092A locus and the efficacy and prognosis of platinum-based chemotherapy for lung cancer (LC), and to provide a theoretical basis for precision treatment of LC. Methods From January 2014 to October 2017, 120 patients from two tertiary hospitals in Haikou City, and with pathologically confirmed lung cancer treated with platinum-based chemotherapy were selected as the research objects. After informed consent was obtained, peripheral blood samples were collected for DNA extraction, and the genotype of ERCC1 C8092A locus was detected by mass spectrometry. WHO's Response Evaluation Criteria in Solid Tumours (RECIST) was used to judge patients' chemotherapy efficacy and patients' survival status was obtained by telephone follow-up and other means. Results Among the 120 LC patients, the genotype frequencies of ERCC1 C8092A locus were 67 cases of CC wildtype (55.8%), 45 cases of CA heterozygous type (37.5%), and 8 cases of AA rare mutation type (6.7%), which conformed to Hardy-Weinberg equilibrium (χ2=0.140, P>0.05). The total effective rate of chemotherapy was 32.5%, with the highest effective rate in patients with the CA genotype (42.2%) at the ERCC1 C8092A locus and the lowest in patients with the CC genotype (25.4%). The overall one-year survival rate was 68.3% and the three-year survival rate was 35.8%. The patients with ERCC1 C8092A AA genotype had the lowest survival rate, with a one-year survival rate of 50.0% and three-year survival rate of only 25.0%. However, there were no statistical differences in the overall survival rate among the three genotypes of carriers of ERCC1 C8092A (χ2=0.328, P=0.849). Conclusions The polymorphism of ERCC1 C8092A locus is associated with the efficacy of platinum-based chemotherapy for LC, and patients with CA genotype have the highest efficacy. The one-year and three-year survival rates of patients with CC genotype are significantly higher than those of CA and AA genotypes.

Objective:To investigate the efficacy of fruquintinib in the treatment of advanced colorectal cancer, and to analyze the risk factors for all-cause death of fruquintinib.Methods:The clinical data of 82 patients with advanced colorectal cancer in the First Affiliated Hospital of Bengbu Medical College from December 2020 to April 2022 were retrospectively analyzed. The basic clinical data, efficacy and adverse reactions were recorded. The patients were followed up to October 2022, and all-cause death was recorded. Multivariate Logistic regression was used to analyze the risk factors of all-cause death in patients with advanced colorectal cancer treated with fruquintinib.Results:After treatment, partial remission was found in 9 cases, stable disease in 42 cases, disease progression in 31 cases. The objective remission rate was 10.98% (9/82), and the disease control rate was 62.20% (51/82). The incidence of adverse reactions was 75.61% (62/82), mainly hypertension and hand-foot syndrome. By the end of follow-up, 19 patients died and 63 survived. The incidences of body mass index (BMI)≥24 kg/m 2, lymph node metastasis, tumor located in the right colon and lactate dehydrogenase >200 U/L in all-cause death patients were significantly higher than those in survival patients: 36.51% (23/63) vs. 16/19, 39.68% (25/63) vs. 13/19, 44.44% (28/63) vs. 15/19 and 41.27% (26/63) vs. 14/19, and there were statistical differences ( P<0.01 or <0.05); there were no statistical differences in gender composition, age, smoking history, hypertension and postoperative complications between the two groups ( P>0.05). Multivariate Logistic regression analysis result showed that BMI≥24 kg/m 2, lymph node metastasis, tumor located in the right colon and lactate dehydrogenase >200 U/L were independent risk factors for all-cause death in patients with advanced colorectal cancer treated with fruquintinib ( OR = 9.275, 3.293, 4.687 and 3.985; 95% CI 2.440 to 35.265, 1.106 to 9.806, 1.398 to 15.715 and 1.277 to 12.430; P<0.01 or <0.05). Conclusions:Fruquintinib is effective in the treatment of advanced colorectal cancer. The BMI≥24 kg/m 2, lymph node metastasis, tumor located in the right colon and lactate dehydrogenase >200 U/L are independent risk factors for all-cause death in patients with advanced colorectal cancer treated with fruquintinib.

Objective:To investigate the clinical significance of cc-chemokine receptor 7 (CCR7) as a potential diagnostic or differential marker for chronic lymphocytic leukemia (CLL).Methods:A total number of 643 patients with B-cell chronic lymphoproliferative diseases (B-CLPD) admitted to the First Affiliated Hospital of Nanjing Medical University from January 2015 to December 2018 were enrolled. The patients included 327 cases of CLL, 58 cases of mantle cell lymphoma (MCL), 34 cases of follicular lymphoma (FL), 36 cases of marginal zone lymphoma (MZL), 10 cases of hair-cell leukemia or its variants (HCL/HCLV-v), 40 cases of Waldorf′s macroglobulinemia (WM), 48 cases of CD5 +B-cell chronic lymphoproliferative disease unclassified (B-CLPD-U) and 90 cases of CD5 -B-CLPD-U. At the same time, 20 samples from healthy people from the medical examination center of our hospital were used as normal controls. Flow cytometry was used to detect the immune-phenotype and CCR7 expression level in B-CLPD patients, and Fluorescence in situ hybridization (FISH) was used to analyze the genomic alterations: the ataxia telangiectasia mutant gene (ATM) deletion, the 13q14 deletion, the P53 deletion and trisomy 12. Sanger sequencing was used to analyze gene mutations of splicing factor 3B subunit 1 (SF3B1), NOTCH1, tumor protein 53 (TP53) and immunoglobulin heavy chain variable region (IGHV). Measurement data were compared by Mann-Whitney test, and the positive rates were compared by chi-square test. The diagnostic value and optimal positive cutoff value of CCR7 were calculated using receiver operating characteristic (ROC) curve. Results:The positive rates of CCR7 expression in typical CLL and atypical CLL were 90.8% (257/283) and 84.1% (37/44), respectively, and there was no significant difference of the positive rates (χ 2=1.228, P=0.268) between groups. The positive expression rates of CCR7 in CLL, MCL, CD5 +B-CLPD-U, CD5 -B-CLPD-U, FL, WM, HCL/HCL-v and MZL were 89.9% (294/327), 10.3% (6/58), 6.3% (3/48), 8.9% (8/90), 0, 0, 0 and 13.9% (5/36) respectively, and the median mean fluorescence intensity (MFI) was 278 (246, 307), 114 (106, 128), 112 (106, 117), 110 (104, 121), 108 (105, 119), 111 (105, 124), 112 (108, 115) and 109 (105, 120) respectively. Compared with CLL, the positive expression rates of CCR7 in other types of B-CLPDs were lower significantly (χ 2=181.3, 177.8, 232, 164.7, 180.8, 62.6, 129, P<0.01). In addition, the sensitivity, specificity and accuracy of CCR7 for distinguishing CLL from other types of B-CLPD were 89.9%, 93.0% and 92.3%, respectively. The positive expression rate of CD49d in CCR7 +CLL patients was 13.9%, which was significantly lower than that in CCR7 -CLL patients (42.1%) (χ 2=7.6, P=0.01). The coincidence rate of 13q14 deletion was 50.3% in CCR7 +CLL patients, which was significantly higher than that in CCR7 -CLL patients (20%) (χ 2=6.56, P=0.01). Conclusions:The CC-chemokine receptor 7 (CCR7) antigen is an effective marker for the diagnosis and identification of chronic lymphocytic leukemia (CLL). The expression level of CCR7 in clinical specimens can distinguish CLL from other pathological subtypes of B-CLPDs.

Objective:To explore the correlation of CD49d expression patterns with molecular genetics and hotspot gene mutants in patients with chronic lymphocytic leukemia.Methods:The expression of CD49d was detected by flow cytometry and grouped into homogeneous, bimodal, negative and positive expression. Panel fluorescence in situ hybridization (FISH) was used for molecular genetics analysis and next-generation sequencing (NGS) was conducted for gene mutation detection.Results:There were 43 patients (23.89% ) with positive CD49d expression, 137 patients (76.11% ) with negative CD49d expression, 96 patients (53.33% ) with homogeneous CD49d expression and 84 patients (46.67% ) with bimodal CD49d expression. Compared with patients in the CD49d negative group, patients in the CD49d positive group had higher Rai stage ( P=0.048) and higher proportion of spleen enlargement ( P=0.030) . Compared with patients with homogeneous expression of CD49d, patients with bimodal expression of CD49d had a higher proportion of spleen enlargement ( P=0.009) . The expression rate of 11q22- in bimodal CD49d - group was significantly higher than that in homogeneous CD49d - group (24.29% vs 10.45% , P=0.043) . The incidence of +12 in homogeneous CD49d group was higher than that in bimodal CD49d group (16.67% vs 5.95% , P=0.035) . The incidence of +12 in homogeneous CD49d + group was higher than that in bimodal CD49d - group (17.24% vs 4.29% , P=0.045) . The incidence of +12 in homogeneous CD49d - group was higher than that in bimodal CD49d - group (16.42% vs 4.29% , P=0.024) . BIRC3 mutation rate in CD49d positive group was higher than that in CD49d negative group (11.63% vs 2.92% , P=0.037) . Conclusion:There were significant correlations between CD49d and 11q22-, +12 and BIRC3 gene mutation. Patients with bimodal CD49d were more correlated with poor prognosis indexes.

Objective:To analyze the differences in immunophenotype, cytogenetics, and molecular biology between typical and atypical immunophenotype chronic lymphocytic leukemia (CLL) , and explore the correlation of cytogenetic anomalies with gene mutations.Methods:This study included 488 patients diagnosed in the First Affiliated Hospital of Nanjing Medical University between November 2014 and May 2021. Of these, 382 patients scored 4-5 points, which was typical CLL (tCLL) , and 106 scored 3 points, which was atypical CLL (aCLL) as per the Royal Marsden Hospital Immunomarker Integral System. Peripheral blood cells were collected for immunophenotype by multiparameter flow cytometry in 488 patients, fluorescence in situ hybridization (FISH) was employed to detect cytogenetic anomalies in 359 patients, and gene mutations were detected by next-generation sequencing (NGS) in 330 patients.Results:The positive rates of CD10, CD22, CD49d, CD81, and FMC7 were significantly higher in the aCLL compared with the tCLL group ( P=0.020, P<0.001, P<0.001, P=0.027, and P<0.001, respectively) , while the positive rates of CD5, CD23, CD148, and CD200 were lower in the former compared to the latter ( P<0.001, P=0.017, P=0.041, and P<0.001, respectively) . aCLL exhibited a higher frequency of trisomy 12 and lower frequency of del (13q14) compared to the tCLL group ( P<0.001 and P<0.001, respectively) . Moreover, aCLL patients also showed a higher incidence of NOTCH1 mutations than the tCLL patients ( P=0.038) , while no statistically significant differences in other gene mutations occurred between the two groups. No significant differences in overall survival (OS) and treatment-free survival (TFS) occurred between aCLL and tCLL using Kaplan-Meier analysis ( P>0.05) . Conclusion:aCLL has characteristic immunophenotype, cytogenetic, and somatic mutation that differ from tCLL, and this can provide reliable information for the diagnosis and differential diagnosis between the two groups.