OBJECTIVES: To determine the pharmacological impact of hesperidin, the main component of Citri Reticulatae Pericarpium, on depressive behavior and elucidate the mechanism by which hesperidin treats depression, focusing on the gut-brain axis. METHODS: Fifty-four Sprague Dawley male rats were randomly allocated to 6 groups using a random number table, including control, model, hesperidin, probiotics, fluoxetine, and Citri Reticulatae Pericarpium groups. Except for the control group, rats in the remaining 5 groups were challenged with chronic unpredictable mild stress (CUMS) for 21 days and housed in single cages. The sucrose preference test (SPT), immobility time in the forced swim test (FST), and number in the open field test (OFT) were performed to measure the behavioral changes in the rats. Enzyme-linked immunosorbent assay was used to determine the levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) in brain tissue, and the histopathology was performed to evaluate the changes of colon tissue, together with sequencing of the V3-V4 regions of 16S rRNA gene on feces to explore the changes of intestinal flora in the rats. RESULTS: Compared to the control group, the rats in the model group showed notable reductions in body weight, SPF, and number in OFT (P<0.01). Hesperidin was found to ameliorate depression induced by CUMS, as seen by improvements in body weight, SPT, immobility time in FST, and number in OFT (P<0.05 or P<0.01). Regarding neurotransmitters, it was found that at a dose of 50 mg/kg hesperidin treatment upregulated the levels of 5-HT and BDNF in depressed rats (P<0.05). Compared to the control group, the colon tissue of the model group exhibited greater inflammatory cell infiltration, with markedly reduced numbers of goblet cells and crypts and were significantly improved following treatment with hesperidin. Simultaneously, the administration of hesperidin demonstrated a positive impact on the gut microbiome of rats treated with CUMS, such as Shannon index increased and Simpson index decreased (P<0.01), while the abundance of Pseudomonadota and Bacteroidota increased in the hesperidin-treated group (P<0.05). CONCLUSION The mechanism responsible for the beneficial effects of hesperidin on depressive behavior in rats may be related to inhibition of the expressions of BDNF and 5-HT and preservation of the gut microbiota.
Animals ; Hesperidin/therapeutic use* ; Rats, Sprague-Dawley ; Depression/drug therapy* ; Male ; Stress, Psychological/drug therapy* ; Brain/metabolism* ; Brain-Derived Neurotrophic Factor/metabolism* ; Serotonin/metabolism* ; Gastrointestinal Microbiome/drug effects* ; Behavior, Animal/drug effects* ; Rats ; Brain-Gut Axis/drug effects* ; Chronic Disease ; Colon/drug effects*

ObjectiveHuman Ku70 protein mainly involves the non-homologous end joining (NHEJ) repair of double-stranded DNA breaks (DSB) through its DNA-binding properties, and it is recently reported having an RNA-binding ability. This paper is to explore whether Ku70 has RNA helicase activity and affects miRNA maturation. MethodsRNAs bound to Ku protein were analyzed by RNA immunoprecipitation sequencing (RIP-seq) and bioinfomatic anaylsis. The expression relationship between Ku protein and miRNAs was verified by Western blot (WB) and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) assays. Binding ability of Ku protein to the RNAs was tested by biolayer interferometry (BLI) assay. RNA helicase activity of Ku protein was identified with EMSA assay. The effect of Ku70 regulated miR-124 on neuronal differentiation was performed by morphology analysis, WB and immunofluorescence assays with or without Zika virus (ZIKV) infection. ResultsWe revealed that the Ku70 protein had RNA helicase activity and affected miRNA maturation. Deficiency of Ku70 led to the up-regulation of a large number of mature miRNAs, especially neuronal specific miRNAs like miR-124. The knockdown of Ku70 promoted neuronal differentiation in human neural progenitor cells (hNPCs) and SH-SY5Y cells by boosting miR-124 maturation. Importantly, ZIKV infection reduced the expression of Ku70 whereas increased expression of miR-124 in hNPCs, and led to morphologically neuronal differentiation. ConclusionOur study revealed a novel function of Ku70 as an RNA helicase and regulating miRNA maturation. The reduced expression of Ku70 with ZIKV infection increased the expression of miR-124 and led to the premature differentiation of embryonic neural progenitor cells, which might be one of the causes of microcephaly.

Objective To investigate the patterns of traditional Chinese medicine(TCM)syndrome differentiation and treatment for dengue fever by using R language data visualization technology,so as to provide reference for TCM syndrome differentiation and treatment of dengue fever.Methods The related literature of dengue fever treated by Chinese medicine was retrieved from CNKI,Wanfang Data,and VIP.R-Studio software was used to conduct descriptive statistical analysis of the TCM syndromes,treatment methods,prescriptions and Chinese medicine in the literature of dengue fever treated by oral use of Chinese medicine.Based on Apriori algorithm,association rule mining and cluster analysis were carried out to explore the TCM syndrome and treatment patters of dengue fever.Results A total of 176 prescriptions for effective cases were extracted,and the included literature involved 29 syndromes,73 TCM treatment methods,56 classical prescriptions and 35 self-formulated prescriptions,and 179 Chinese medicinals.The syndrome of comorbidity of defense phase and qi phase and the syndrome of blazing of both qi phase and nutrient phase were the high-frequency syndromes of dengue fever treated by oral use of Chinese medicine.The high-frequency treatment methods covered heat-clearing therapy,toxin-removing therapy,blood-cooling therapy and dampness-resolving therapy.Qingwen Baidu Decoction was the most frequently-used prescription.Glycyrrhizae Radix et Rhizoma,Forsythiae Fructus,Scutellariae Radix,Gypsum Fibrosum,and Lonicerae Japonicae Flos were the frequently-used Chinese medinals.There were three drug combinations containing Paeoniae Radix Rubra,Moutan Cortex,and Rehmanniae Radix,and their correlation of association rules was the highest.Bubali Cornu,Moutan Cortex,Paeoniae Radix Rubra,Rehmanniae Radix,Lonicerae Japonicae Flos,Forsythiae Fructus,Gypsum Fibrosum,Scutellariae Radix,Anemarrhenae Rhizoma,and Glycyrrhizae Radix et Rhizoma were the core Chinese medicinals for the treatment of dengue fever.Conclusion The TCM syndromes of dengue fever are predominated by the syndrome of comorbidity of defense phase and qi phase and the syndrome of blazing of both qi phase and nutrient phase.The treatment of dengue fever with TCM is based on the principle of clearing heat toxin from the qi phase,cooling the nutrient-blood excess heat,resolving pathogenic dampness,and nourishing qi and yin.The treatment focuses on clearing qi phase and blood phase,and the application of removing stasis in febrile diseases should be stressed,thus to block the progression of the disease in time.

Objective:To investigate the clinical efficacy and safety of ferric derisomaltose injection versus iron sucrose injection in the treatment of iron deficiency anemia (IDA) .Methods:A total of 120 patients with iron deficiency anemia admitted from June 2021 to March 2023 were given intravenous iron supplementation with ferric derisomaltose to assess the efficacy and safety of hemoglobin (HGB) elevation before and after treatment. Simultaneously, the clinical effects of iron supplementation with iron sucrose were compared to those of inpatient patients during the same period.Results:Baseline values were comparable in both groups. Within 12 weeks of treatment, the elevated HGB level in the ferric derisomaltose group was higher than that of the iron sucrose group, with a statistical difference at all time points, and the proportion of HGB increased over 20 g/L in the patients treated for 4 weeks was higher (98.7%, 75.9% ). During the treatment with ferric derisomaltose and iron sucrose, the proportion of mild adverse reactions in the ferric derisomaltose group was slightly lower than that of the iron sucrose group, and neither group experienced any serious adverse reactions. The patients responded well to the infusion treatment, with no reports of pain or pigmentation at the injection site.Conclusion:The treatment of IDA patients with ferric derisomaltose has a satisfactory curative effect, with the advantages of rapidity, accuracy, and safety. Therefore, it is worthy of widespread clinical use.

Objective:This study aimed at investigating the efficacy and safety of eltrombopag in the treatment of adult primary immune thrombocytopenia (ITP) and evaluated the factors influencing its efficacy and side effects.Methods:A total of 198 patients with adult ITP who were admitted to Tianjin Medical University General Hospital between January 2018 and March 2022 were retrospectively analyzed. The efficacy of each starting dose of eltrombopag was evaluated, and adverse events were analyzed. The factors influencing efficacy were investigated, including sex, age, adult ITP type, platelet antibodies, and combined drug treatments.Results:Of the 198 patients, 70 males and 128 females with a median age of 45 years (18-88 years) were included; 130 (65.7%) had newly diagnosed adult ITP, 25 (12.6%) had persistent adult ITP, and 43 (21.7%) had chronic adult ITP. The bleeding event scores at baseline were assessed; 84.3% had scores of<4 and 15.7% had scores of ≥4. The eltrombopag response rate (initial response) at 6 weeks was 78.8% (complete response [CR]: 49.0%; CR1: 14.6%; CR2: 15.2%). The median response time to eltrombopag was 7 (7, 14) days. The initial response rates to 25, 50, and 75 mg eltrombopag were 74.1%, 85.9%, and 60.0%, respectively ( P=0.031). The initial response rate to the 50 mg dose was significantly higher than that of the 25-mg and 75-mg doses. Two patients received 100 mg as the starting dose, and their initial response was 0. Regarding dose adjustment, 70.7% of the patients remained on the starting dose, 8.6% underwent dose adjustment to 50 mg, and 6.1% underwent dose adjustment to 75 mg. Another two patients underwent dose adjustment to 100 mg. After dose adjustment, the persistent response rates were 83.6%, 85.3%, and 85.7% for the 25-, 50-, and 75-mg doses, respectively, with no significant difference. After dose adjustment, the sustained efficacy rate for the 100-mg dose (4 patients) was 100.0%. After 6 weeks of treatment with eltrombopag, the overall bleeding score of patients with ITP decreased. The number of patients with a score of ≥4 decreased to 0, the number of patients with a score of<4 decreased, and there was no significant change in the number of patients with a score of 1-2. The most common adverse event associated with eltrombopag was impaired liver function (7.7%). No thrombosis events or other adverse events were observed. ITP type and number of megakaryocytes significantly affected the initial response to eltrombopag. The initial response rates to eltrombopag for newly diagnosed adult ITP, persistent adult ITP, and chronic adult ITP were 85.3%, 56.0%, and 76.2%, respectively ( P=0.003). For megakaryocytes, the initial response rates were 61.8%, 87.1%, and 84.3% ( P=0.009) for the decreased, normal, and increased megakaryocyte groups, respectively. Conclusion:Eltrombopag, as a second-line or higher treatment for adult ITP, has a rapid onset of action and good safety. The initial response rate is significantly higher with a dose of 50 mg than with a dose of 25 mg. Patients with newly diagnosed ITP and those with normal or increased megakaryocyte numbers have a higher initial response rate to eltrombopag.

Objective:To analyze the level and clinical significance of IL-18 and IL-18-binding protein (BP) in the bone marrow of patients with myelodysplastic syndrome (MDS) .Methods:A total of 43 newly diagnosed patients with MDS who were admitted to the Department of Hematology, Tianjin Medical University General Hospital, from July 2020 to February 2021 were randomly selected. The control group consisted of 14 patients with acute myeloid leukemia (AML) and 25 patients with iron-deficiency anemia (IDA). The levels of IL-18 and IL-18 BP in the bone marrow supernatant were measured, and their correlations with MDS severity, as well as the functionality of CD8 + T cells and natural killer cells, was analyzed. Results:The levels of IL-18, IL-18 BP, and free IL-18 (fIL-18) in the bone marrow supernatant of patients with MDS were higher than in the IDA group. The level of fIL-18 was linearly and negatively correlated with the MDS-International Prognostic Scoring System (IPSS) score. IL-18 receptor (IL-18Rα) expression on CD8 + T cells in the MDS group was lower than in the IDA group, and the levels of fIL-18 and IL-18Rα were positively correlated with CD8 + T-cell function in the MDS group. Conclusion:IL-18 BP antagonizes IL-18, leading to a decrease in fIL-18 in the bone marrow microenvironment of patients with MDS, affecting CD8 + T-cell function, which is closely related to MDS severity; therefore, it may become a new target for MDS treatment.

Objective To evaluate the short-term clinical efficacy of unilateral biportal endoscopic(UBE)technique in the treatment of adjacent segment disease after lumbar interbody fusion.Methods The clinical data of 21 patients with adjacent segment disease after lumbar interbody fusion who treated with UBE technique and followed up for more than 3 months in our hospital from March 2020 to January 2023 were retrospectively analyzed.The operation time,decrease value of hemoglobin 1 day before and after operation,drainage volume of the operation area,time of bed rest and complications were recorded.The Japanese Orthopaedic Association(JOA)score was used to evaluate lumbar function 1 day before operation,3 days and 3 months after operation to determine the improvement.The visual analogue scale(VAS)score was used to evaluate the pain 1 day before operation,3 days and 3 months after operation.Results The operation time was 60～175 minutes,with an average of(95.38±18.64)minutes;the decrease value of hemoglobin was 2～6 g/L,with an average of(1.42±0.18)g/L;the time of bed rest was 27～88 hours,with an average of(36.42±15.33)hours;the drainage volume of the operation area was 50～315 mL,with an average of(85.56±15.65)mL;and one case of dural tear occurred during the operation,who was converted to open surgery for repairing dural sac.There was statistically significant difference in VAS score before operation compared with that 3 days and 3 months after operation(P<0.05).There was statistically significant difference in the JOA score before operation compared with that 3 days and 3 months after surgery(P<0.05).Conclusion UBE technique is effective in the treatment of adjacent segment disease after lumbar interbody fusion,with the advantages of small trauma,little bleeding and short time of bed rest.However,patients with the serious adjacent segment degeneration and severe spinal stenosis may have dural tear during operation.Once it occurs,active repair should be performed to avoid cauda equina herniation and necrosis,or switch to open surgery,if necessary.

Objective:To evaluate the efficacy and safety of dupilumab in the treatment of prurigo nodularis (PN) in the real world.Methods:PN patients who were subcutaneously injected with dupilumab for over 12 weeks were collected from the China Type Ⅱ Inflammatory Skin Disease Clinical Research and Standardized Diagnosis and Treatment Project Database from June 2021 to October 2022. Their clinical data were retrospectively analyzed, which included demographic data, and changes in pruritus numeric rating scale (NRS), investigator global assessment for PN-Stage (IGA PN-S), dermatology life quality index (DLQI) and hospital anxiety and depression scale (HADS) scores before and after treatment. Differences in scores before and after treatment, as well as in efficacy between patients with and without a history of atopic diseases, were analyzed using Wilcoxon signed-rank test, paired t-test or chi-square test. Results:A total of 66 PN patients were collected, including 42 males and 24 females, and they were aged 8 to 89 (44.12 ± 24.17) years. Thirty-six patients had a history of atopic diseases, and 27 had a family history of atopic diseases. After 12-week treatment with dupilumab, the pruritus NRS, IGA PN-S and DLQI scores in the 66 patients significantly decreased from the baseline scores (7.00 [5.00, 8.00], 3.00 [3.00, 4.00], 12.00 [7.75, 20.25], respectively) to 3.00 [2.00, 4.25], 2.00 [2.00, 3.00], 5.00 [1.75, 8.25], respectively (all P < 0.001). Among the 66 patients, 39 continued the regular treatment with dupilumab after 12 weeks and were followed up to 16 weeks; their pruritus NRS and IGA PN-S scores at week 16 further decreased compared with those at week 12 (both P < 0.05). There were no significant differences in the proportion of patients showing an improvement of ≥ 4 points in the NRS score or the proportion of patients achieving IGA 0/1 at week 12 between the patients with history of atopic diseases and those without (both P > 0.05). Before treatment, 32 PN patients were accompanied by mild to severe anxiety and/or depression; after 12-week treatment, the HADS-A scores in the 28 patients with anxiety (HADS-A scores > 7 points) and the HADS-D scores in the 20 patients with depression (HADS-D scores > 7 points) significantly decreased compared with their baseline scores (both P < 0.001) ; 18 (56.52%) patients achieved remission in anxiety and depression (both HADS-A and HADS-D scores < 7 points). Among the 66 PN patients, there were 13 minor patients, including 7 males and 6 females, and they were aged 8 to 17 (13.77 ± 3.09) years; after 12-week treatment, their pruritus NRS, IGA PN-S, and DLQI scores significantly decreased compared with the corresponding baseline scores (all P < 0.05) ; 8 minor patients continued dupilumab treatment for 16 weeks, with a further decrease in the IGA PN-S score compared with that at week 12 ( P < 0.05), but without significant differences between the pruritus NRS and DLQI scores at week 16 and those at week 12 (both P > 0.05). Adverse reactions were observed in 7 adult patients, including eye pruritus, local injection reactions, and systemic erythema accompanied by pruritus on the day of injection. No adverse reactions were reported in minor patients. Conclusion:In the real world, dupilumab could markedly alleviate pruritus, skin lesions, anxiety and depression symptoms in PN, improve the quality of life, and exhibited a good safety profile.

Objective: To explore the efficacy of chemotherapy re-challenge in the third-line setting for patients with metastatic colorectal cancer (mCRC) in the real world. Methods: The clinicopathological data, treatment information, recent treatment efficacy, adverse events and survival data of mCRC patients who had disease progression after treatment with oxaliplatin-based and/or irinotecan-based chemotherapy and received third-line chemotherapy re-challenge from January 2013 to December 2020 at Tianjin Medical University Cancer Institute and Hospital were retrospectively collected. Survival curves were plotted with the Kaplan-Meier method, and the Cox proportional hazard model was used to analyze the prognostic factors. Results: A total of 95 mCRC patients were included. Among them, 32 patients (33.7%) received chemotherapy alone and 63 patients (66.3%) received chemotherapy combined with targeted drugs. Eighty-three patients were treated with dual-drug chemotherapy (87.4%), including oxaliplatin re-challenge in 35 patients and irinotecan re-challenge in 48 patients. The remaining 12 patients were treated with triplet chemotherapy regimens (12.6%). Among them, as 5 patients had sequential application of oxaliplatin and irinotecan in front-line treatments, their third-line therapy re-challenged both oxaliplatin and irinotecan; 7 patients only had oxaliplatin prescription before, and these patients re-challenged oxaliplatin in the third-line treatment. The overall response rate (ORR) and disease control rate (DCR) reached 8.6% (8/93) and 61.3% (57/93), respectively. The median progression free survival (mPFS) and median overall survival (mOS) were 4.9 months and 13.0 months, respectively. The most common adverse events were leukopenia (34.7%) and neutropenia (34.7%), followed by gastrointestinal adverse reactions such as nausea (32.6%) and vomiting (31.6%). Grade 3-4 adverse events were mostly hematological toxicity. Cox multivariate analysis showed that gender (HR=1.609, 95% CI: 1.016-2.548) and the PFS of front-line treatments (HR=0.598, 95% CI: 0.378-0.947) were independent prognostic factors. Conclusion: The results suggested that it is safe and effective for mCRC patients to choose third-line chemotherapy re-challenge, especially for patients with a PFS of more than one year in front-line treatments.
Humans ; Irinotecan/therapeutic use* ; Oxaliplatin/therapeutic use* ; Colorectal Neoplasms/pathology* ; Retrospective Studies ; Fluorouracil ; Colonic Neoplasms/chemically induced* ; Rectal Neoplasms/drug therapy* ; Antineoplastic Combined Chemotherapy Protocols/adverse effects* ; Camptothecin/adverse effects*

Abstract: Objective To investigate the impact of SARS-CoV-2 virus infection on the risk of thrombosis in COVID-19 outpatient patients with mild and regular symptoms. Methods Outpatient patients during the SARS-CoV-2 large-scale infection period after the policy adjustment for COVID-19 in Beijing in 2022 were selected as the observation group, and the dynamic zero-clearing period before the policy adjustment and outpatient patients during the 2022/2021/2020 period were taken as the three control groups. The patients with physiological factors that may increase the risk of coagulation, such as thrombotic diseases, malignant tumors, female pregnancy and other physiological factors, were excluded. Pediatric patients under 14 years old were also excluded. Age was expressed as median (interquartile). The changes in blood routine, fibrin/fibrinogen degradation products, and D-Dimer in Beijing outpatient patients were studied with statistical method and data analysis techniques. Results Compared with the control groups, the observation group showed a statistically significant decrease in red blood cells (RBC), hemoglobin (Hb), and hematocrit (HCT) levels, and an increase in monocytes (MONO) and platelet (PLT) counts, all showed statistically significant differences (P<0.0001). The proportion of fibrinogen degradation product (FDP) and D-Dimer of observation group exceeding the range increased significantly. Compared with the three control groups, the number of outpatient fibrinogen degradation products (FDP) in the observation group of patients aged 50 years and verage number of patients under 50 years old in the observation group with D-Dimer exceeding the threshold increased by more than 48.98%, and the monthly average number of patients with D-Dimer exceeding the threshold in patients aged 50 or older increased by 346%-998%. Conclusions The results of this study suggest that outpatient patients with mild or regular SARS-CoV-2 infection are also at risk for thrombotic events, and monitoring blood coagulation indicators such as D-dimer is recommended to avoid the sudden onset of thrombosis-related fatal complications .