OBJECTIVE To investigate the effects of multiple doses of Shugan jieyu capsules on the pharmacokinetics of voriconazole， rivaroxaban and apixaban in rats. METHODS Male SD rats were randomly divided into voriconazole group （30 mg/kg）， rivaroxaban group （2 mg/kg）， apixaban group （0.5 mg/kg）， Shugan jieyu capsules+voriconazole group （145 mg/kg+30 mg/kg）， Shugan jieyu capsules+rivaroxaban group （145 mg/kg+2 mg/kg）， Shugan jieyu capsules+apixaban group （145 mg/kg+0.5 mg/kg）， with 6 rats in each group. After the rats in each group were consecutively administered solvent （0.5% sodium carboxymethyl cellulose solution） or Shugan jieyu capsules by intragastric gavage for 8 days， they were respectively given voriconazole， rivaroxaban and apixaban solution by intragastric gavage on the 8th day. Blood samples were then collected at different time points （in voriconazole group， rivaroxaban group and corresponding drug combination groups， blood was collected before administration and at 0.17， 0.34， 0.5， 0.75， 1， 1.5， 2， 3， 4， 5， 6， 8， 10 and 12 hours post-administration； in apixaban group and corresponding drug combination group， blood was collected before administration and at 0.08， 0.17， 0.25， 0.34， 0.5， 0.75， 1， 3， 5， 7， 10 and 12 hours post-administration）. Ultra-high performance liquid chromatography-tandem mass spectrometry method was employed to determine the mass concentrations of voriconazole， rivaroxaban and apixaban in rat plasma. The main pharmacokinetic parameters of these drugs were calculated using a non-compartmental model， and the comparisons were made between groups. RESULTS Compared with single drug group， after multiple administrations of Shugan jieyu capsules， AUC0－t， AUC0－∞ and cmax of voriconazole were significantly decreased， while CLz/F was significantly increased， and tmax was also significantly prolonged （P＜0.05）. For rivaroxaban and apixaban， their tmax values were both significantly prolonged （P＜0.05）. However， there were no statistically significant differences in the other pharmacokinetic parameters between the two groups （P＞0.05）. CONCLUSIONS The combination of Shugan jieyu capsules can decrease the exposure， increase the clearance， and delay the peak concentration of oral voriconazole. However， it does not affect the exposure levels of rivaroxaban and apixaban， but it does delay the time to reach peak concentration for both drugs.

Microalgae possess high photosynthetic efficiency, robust adaptability, and substantial biomass, serving as excellent biological resources for large-scale cultivation. Malic enzyme (ME), a ubiquitous metabolic enzyme in living organisms, catalyzes the decarboxylation of malate to produce pyruvate, CO₂, and NAD(P)H, playing a role in multiple metabolic pathways including energy metabolism, photosynthesis, respiration, and biosynthesis. In this study, we identified the Scenedesmus quadricauda malic enzyme gene (SqME) and its biological functions, aiming to provide excellent target genes for the genetic improvement of higher plants. Based on the RNA-seq data from S. quadricauda under the biofilm cultivation mode with high CO₂ and light energy transfer efficiency and small water use, a highly expressed gene (SqME) functionally annotated as ME was cloned. The physicochemical properties of the SqME-encoded protein were systematically analyzed by bioinformatics tools. The subcellular localization of SqME was determined via transient transformation in Nicotiana benthamiana leaves. The biological functions of SqME were identified via genetic transformation in Nicotiana tabacum, and the potential of SqME in the genetic improvement of higher plants was evaluated. The ORF of SqME was 1 770 bp, encoding 590 amino acid residues, and the encoded protein was located in chloroplasts. SqME was a NADP-ME, with the typical structural characteristics of ME. The ME activity in the transgenic N. tabacum plant was 1.8 folds of that in the wild-type control. Heterologous expression of SqME increased the content of chlorophyll a, chlorophyll b, and total chlorophyll by 20.9%, 26.9%, and 25.2%, respectively, compared with the control. The transgenic tobacco leaves showed an increase of 54.0% in the fluorescence parameter NPQ and a decrease of 30.1% in Fo compared with the control. Moreover, the biomass, total lipids, and soluble sugars in the transgenic tobacco leaves enhanced by 20.5%, 25.7%, and 9.5%, respectively. On the contrary, the starch and protein content in the transgenic tobacco leaves decreased by 22.4% and 12.2%, respectively. Collectively, the SqME-encoded protein exhibited a strong enzymatic activity. Heterologous expressing of SqME could significantly enhance photosynthetic protection, photosynthesis, and biomass accumulation in the host. Additionally, SqME can facilitate carbon metabolism remodeling in the host, driving more carbon flux towards lipid synthesis. Therefore, SqME can be applied in the genetic improvement of higher plants for enhancing photosynthetic carbon fixation and lipid accumulation. These findings provide scientific references for mining of functional genes from S. quadricauda and application of these genes in the genetic engineering of higher plants.
Nicotiana/genetics* ; Photosynthesis/physiology* ; Malate Dehydrogenase/biosynthesis* ; Plant Leaves/genetics* ; Scenedesmus/enzymology* ; Carbon Cycle/genetics* ; Lipid Metabolism/genetics* ; Plants, Genetically Modified/metabolism*

Purpose To investigate the clinicopathological features,immunophenotypes,molecular characteristics,treat-ment and prognosis of nodal follicular helper T cell lymphoma,angioimmunoblastic type(nTFHL-AI)with B cell clonal hyper-plasia.Methods The clinicopathological data of 10 nTFHL-AI patients with B cell clonal hyperplasia were collected from medi-cal records,with HE and immunohistochemical staining and gene rearrangement analysis.Related literature was also re-viewed.Results The included 10 patients were 5 males and 5 females with a median age of 73 years.The clinical manifesta-tions were mainly systemic lymphadenopathy,splenomegaly and B symptoms.8 patients were categorized as stage Ⅳ and 2 pa-tients were staged as Ⅰ+Ⅱ according to Ann Arbor staging cri-teria.Major laboratory results were increased β2 microglobulin,lactate dehydrogenase and decreased hemoglobin,erythrocytes and thrombocytes.Plasma Epstein-Barr virus(EBV)nucleic acid quantification was positive in 8 cases.Microscopically,the morphological patterns were nodular aggregation or scattered clear cells,branched high endothelial vessels and disorderly"wind-blown"like follicular dendritic cells(FDC).The num-ber of infiltrated eosinophils was 0-5/HPF in 7 cases,5-10/HPF in 2 cases,and＞50/HPF in 1 case.Plasma cell count was≤5％in 6 cases,10％in 1 case,20％in 1 case,and the rest 2 had relative higher count of 30％.The tumor cells of 7 ca-ses coexisted with marked hyperplasia of histiocytes,and in only one case Reed-Sternberg(RS)-like large cells were found 5 ca-ses showed abundant background B cells while the other 5 cases had limited background B cells.All tumor cells expressed T cell markers,6 were positive for CD10,BCL6,CXCL13 and PD-1 simultaneously and all of 10 were positive for BCL6,CXCL13 and PD-1.8 cases were positive for EBV-encoded small RNA(EBER)by in situ hybridization.Clonal TCR gene rearrange-ments and IG gene rearrangement were detected in all 10 pa-tients.After diagnosis,all patients were treated with chemother-apy,and three of them died due to disease progression.Conclu-sion B cell clonal hyperplasia,the status of EBV infection and the number of EBV-positive cells may be related with disease progression,individualized treatment and prognosis of patients with nTFHL-AI.

Diabetic peripheral neuropathy (DPN) is the common chronic complication of diabetes, which can lead to foot ulcers, gangrene, and amputation in severe cases, seriously affecting their quality of life. DPN belongs to the category of "arthralgia", "hemorrhoids" and other categories of TCM, and the main pathogenesis is the deficiency of qi and blood, yin and yang, and the obstruction of the meridians by phlegm and stasis. Clinically, DPN is more common with qi deficiency and blood stasis syndrome. Based on the theory of "qi meridian constant communication" in the Huang Di Nei Jing, this article proposed that for patients with DPN with qi deficiency and blood stasis syndrome, the treatment should be based on the principle of "invigorating qi and activating blood circulation, dissolving stasis and arthralgia", so that the patients' qi meridian can be accessible, delay the disease progression, and provide reference for the TCM treatment of DPN.

Objective:To evaluate the efficacy and safety of oliceridine for treatment of moderate to severe pain after surgery with general anesthesia in patients.Methods:The patients with moderate to severe pain (numeric pain rating scale ≥4) after abdominal surgery with general anesthesia from 14 hospitals between July 6, 2021 and November 9, 2021 were included in this study. The patients were assigned to either experiment group or control group using a random number table method. Experiment group received oliceridine, while control group received morphine, and both groups were treated with a loading dose plus patient-controlled analgesia and supplemental doses for 24 h. The primary efficacy endpoint was the drug response rate within 24 h after giving the loading dose. Secondary efficacy endpoints included early (within 1 h after giving the loading dose) drug response rates and use of rescue medication. Safety endpoints encompassed the development of respiratory depression and other adverse reactions during treatment.Results:After randomization, both the full analysis set and safety analysis set comprised 180 cases, with 92 in experiment group and 88 in control group. The per-protocol set included 170 cases, with 86 in experiment group and 84 in control group. There were no statistically significant differences between the two groups in 24-h drug response rates, rescue analgesia rates, respiratory depression, and incidence of other adverse reactions ( P>0.05). The analysis of full analysis set showed that the experiment group had a higher drug response rate at 5-30 min after giving the loading dose compared to control group ( P<0.05). The per-protocol set analysis indicated that experiment group had a higher drug response rate at 5-15 min after giving the loading dose than control group ( P<0.05). Conclusions:When used for treatment of moderate to severe pain after surgery with general anesthesia in patients, oliceridine provides comparable analgesic efficacy to morphine, with a faster onset.

Small interfering RNA (siRNA) has a promising future in the treatment of ocular diseases due to its high efficiency, specificity, and low toxicity in inhibiting the expression of target genes and proteins. However, due to the unique anatomical structure of the eye and various barriers, delivering nucleic acids to the retina remains a significant challenge. In this study, we rationally design PACD, an A-B-C type non-viral vector copolymer composed of a hydrophilic PEG block (A), a siRNA binding block (B) and a pH-responsive block (C). PACDs can self-assemble into nanosized polymeric micelles that compact siRNAs into polyplexes through simple mixing. By evaluating its pH-responsive activity, gene silencing efficiency in retinal cells, intraocular distribution, and anti-angiogenesis therapy in a mouse model of hypoxia-induced angiogenesis, we demonstrate the efficiency and safety of PACD in delivering siRNA in the retina. We are surprised to discover that, the PACD/siRNA polyplexes exhibit remarkable intracellular endosomal escape efficiency, excellent gene silencing, and inhibit retinal angiogenesis. Our study provides design guidance for developing efficient nonviral ocular nucleic acid delivery systems.

Objective:To explore the clinical features of chronic atrophic gastritis (CAG) without Helicobacter pylori ( H. pylori) infection and its correlation with metabolic syndrome. Methods:From June 1, 2022 to March 31, 2023, a total of 966 patients diagnosed with CAG at Army Medical Center of PLA (Chongqing Daping Hospital) were enrolled. All the patients underwent 14C-urea breath test and gastroscopy. The patients were divided into infected group (461 patients with H. pylori-positive CAG) and uninfected group (505 patients with H. pylori-negative CAG). Relevant data including age, body mass index, degree of gastric atrophy (Kimura-Takemoto classification), metabolic syndrome, diabetes mellitus, and hyperlipidemia were collected and compared between the 2 groups. Independent sample t-test and chi-square test were used for statistical analysis. Multiple linear regression analysis was performed to investigate the correlation between relevant indicators and the degree of gastric atrophy in the uninfected group patients. Results:The proportion of patients aged 71 to 80 years old in the uninfected group was higher than that in the infected group (17.0%, 86/505 vs.10.4%, 48/461), and the difference was statistically significant ( χ2=9.62, P=0.002). The degree of gastric atrophy was compared between the 2 groups, the proportions of C1 and C2 patients in the uninfected group were higher than those in the infected group (53.5%, 270/505 vs. 46.4%, 214/461; 34.1%, 172/505 vs. 26.24%, 121/461), and the differences were statistically significant ( χ2=4.78 and 6.96, both P<0.05). The proportions of patients with metabolic syndrome, diabetes mellitus, hyperlipidemia and obesity in the uninfected group were higher than those in the infected group (31.2%, 20/64 vs.14.8%, 9/61; 33.5%, 62/185 vs. 21.5%, 34/158; 31.3%, 67/214 vs. 7.8%, 36/461; 36.7%, 22/60 vs.19.7%, 12/61), and the differences were statistically significant ( χ2=4.77, 6.08, 4.95, and 4.32, all P<0.05). The results of multiple linear regression analysis showed that high density lipoprotein-cholesterol, blood glucose, and body mass index were all correlated with the degree of gastric atrophy ( r=-0.15, 0.20, and 0.31, all P<0.05). Conclusion:CAG without H. pylori infection may be related to physiological aging, and the degree of gastric atrophy is C1 and C2, which is related to metabolic syndrome.

Objective:To investigate the efficacy and adverse reactions of whole-lung low-dose radiotherapy (LDRT) in patients with severe/critical coronavirus disease 2019 (COVID-19).Methods:Eight patients with severe/critical COVID-19 treated in the Jiangyin Hospital Affiliated to Nantong University from January to June 2023 who were treated with whole-lung LDRT after deteriorating or failing to improve post-medical treatment were enrolled in this single-arm phase I clinical trial. They received anterior-posterior penetrating radiation in a supine or prone position, with a total dose range from 0.5 to 1.5 Gy and a dose weight ratio of 1∶1. The oxygenation status, inflammatory markers, and imaging changes before and after radiotherapy were analyzed, and patients were followed up for acute radiation-induced adverse reactions.Results:One week after LDRT, the SaO 2/FiO 2 or PaO 2/FiO 2 indices increased in seven patients (87.5%), inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) decreased in seven patients (87.5%), and chest CT/chest radiographs revealed a significant reduction in the extent of pneumonia involvement in 5 patients (62.5%). No evident acute radiation-related adverse reactions were observed. Conclusions:Whole-lung LDRT with a dose range from 0.5 to 1.5 Gy can reduce inflammatory markers, improve clinical symptoms, and promote inflammatory absorption in patients with severe/critical COVID-19 who responded poorly to medical treatment while not inducing acute adverse reactions.

Objective:To investigate the effects of modified endoscopic retrograde appendicitis therapy (mERAT) on the treatment of children with different severities of acute appendicitis.Methods:This study was a case-control study. A total of 586 children with acute appendicitis, who were admitted to the Pediatric Department of Second Affiliated Hospital of Air Force Medical University between January 2019 and November 2023, were selected as the research subjects. According to the severity of the disease, the patients were divided into simple appendicitis group, suppurative appendicitis group and perforated appendicitis group. The baseline data, hospitalization treatment and costs, outcomes, and recurrence in each group were analyzed, and the difference in the effectiveness of mERAT between the groups were compared by Kruskal-Wallis H test and χ2 test. Results:Among 586 children, there were 338 males and 248 females. The age at onset was 7.0 (4.6, 9.4) years. There were 475 cases of simple appendicitis, 78 cases of suppurative appendicitis, and 33 cases of perforated appendicitis. There were no significant differences in age and gender among the three groups ( F=0.59, χ2=3.31, both P>0.05). However, there were statistically significant differences in body temperature, white blood cell counts, neutrophil percentage, lymphocyte percentage, nausea or vomiting, right lower abdominal pain, umbilical pain, right lower abdominal tenderness, and right lower abdominal rebound pain ( H=7.56, 161.52, 169.11, and 169.61, χ2=12.05, 13.82, 12.05, 7.74, 20.35, and 94.61, all P<0.05). Also, the treatment time, postoperative hospital stay, total hospital stay, and cost showed statistically significant differences ( H=4.70, 33.66, 34.99, 30.37, all P<0.05). There was no significant difference in the initial treatment success rate (98.1% (466/475) vs. 98.7% (77/78) vs. 90.9% (30/33), P=0.057). During the 30 (23, 36) months of follow-up, the recurrence rate was 7.9% (35/433) in the simple appendicitis group, 20.8% (15/72) in the suppurative appendicitis group, and 30.0% (9/30) in the perforated appendicitis group, with a statistically significant difference ( χ2=23.56, P<0.001). Among the children with recurrent appendicitis, 15 cases still chose mERAT, of them 11 cases (31.2%) had simple appendicitis, 2 cases (2/15) had suppurative appendicitis, and 2 cases (2/9) had perforated appendicitis.The latest time to recurrence in the 3 groups was 32, 35 and 10 months, respectively. Conclusion:Treatment with mERAT has a good effect in pediatric simple appendicitis, but has a higher recurrence rate despite a better initial treatment success rate in suppurative appendicitis and perforated appendicitis.

OBJECTIVE Amyotrophic lateral sclerosis(ALS)is a fetal neurodegenerative disease characterized by the progressive loss of upper and lower motor neu-rons,leading to skeletal muscle atrophy,weakness,and paralysis.Oxidative stress plays a crucial role in ALS pathogenesis,including the familial forms of the disease arising from mutations in the gene coding for superox-ide dismutase(SOD1).Additionally,the abnormal accu-mulation of TAR DNA-binding protein of 43 ku(TDP-43)is a pathological feature present in almost all patients,even though the pathogenesis of ALS is unclear.Current-ly,there is no drug that can cure ALS/FTLD.Tetramethyl-pyrazine nitrone(TBN)is a derivative of tetramethylapyr-azine,derived from traditional Chinese medicine Ligusti-cum chuanxiong,which has been extensively proven to have therapeutic effects on various models of neurode-generative diseases.METHODS We investigated the therapeutic effect of TBN in the SOD1G93A and TDP-43M337V ALS mouse models.In the SOD1G93A trans-genic mouse model,TBN was administered to mice via intraperitoneal or intragastric injection after the onset of motor deficits.We injected the TDP-43M337V virus into the striatum of mice unilaterally and bilaterally,and then administered TBN 30 mg·kg-1 intragastrically to observe changes in behavior and survival rate of mice.RESULTS TBN slowed the progression of motor neuron disease,as evidenced by improved motor performance,reduced spi-nal motor neuron loss and associated glial response,and decreased skeletal muscle fiber denervation and fibrosis.TBN treatment activated mitochondrial antioxidant activity through the PGC-1α/Nrf2/HO-1 pathway and decreased the expression of human SOD1.In the mice with unilateral injection of TDP-43M337V into the striatum,TBN improved motor deficits and cognitive impairment in the early stages of disease progression.In mice with bilateral injection of TDP-43M337V into the striatum,TBN not only improved motor function but also prolonged survival.Moreover,we demonstrate that its therapeutic effect may be through activation of the Akt/mTOR/GSK-3β and AMPK/PGC-1α/Nrf2 signaling pathways.CONCLUSION TBN shows promise as an agent for the treatment of ALS/FTLD.TBN is currently undergoing clinical investigation for several indications,including a Phase Ⅱ trial for ALS.