Objective To investigate the relationship between the therapeutic effect of anti-vascular endothelial growth factor(VEGF)and cytokines in aqueous humor in patients with diabetic retinopathy(DR).Methods From July 2023 to December 2023,50 DR patients(56 eyes)who were treated with anti-VEGF drugs in the Department of Ophthal-mology,the Third Affiliated Hospital of Xinxiang Medical University were included in this study.The patients were divided into the diabetic macular edema(DME)group(30 patients,36 eyes)and the proliferative DR(PDR)group(20 patients,20 eyes).Patients in the DME group received an intravitreal injection of aflibercept once a month for three consecutive times,with aqueous humor extracted before each injection.Patients in the PDR group received an intravitreal injection of aflibercept one week before vitrectomy,with aqueous humor extracted before injection and during vitrectomy,respective-ly.The concentrations of vascular endothelial growth factor A(VEGF-A),placental growth factor(PLGF),interleukin(IL)-1β,IL-23,IL-17A,and tumor necrosis factor-α(TNF-α)in the aqueous humor were detected using the Luminex as-say.Before injection therapy,all patients underwent best corrected visual acuity(BCVA)and central macular thickness(CMT)examinations,and their correlations with cytokine concentrations in DR patients before injection therapy were ana-lyzed.Results Compared to before injection therapy,the concentrations of VEGF-A,PLGF,and IL-23 in the aqueous humor of patients in the DME group decreased significantly after treatment(all P＜0.05);additionally,the CMT de-creased,and the BCVA increased(both P＜0.05).After injection therapy,the concentrations of VEGF,PLGF,IL-1β,IL-23,IL-17A,and TNF-α in the aqueous humor of patients in the PDR group significantly decreased compared to before injec-tion therapy(all P＜0.05).Before injection therapy,the levels of VEGF-A,PLGF,and IL-23 in the aqueous humor of pa-tients in the DME group were higher than those in the PDR group,and the differences were statistically significant(all P＜0.05).The correlation analysis results showed that before injection therapy,VEGF was negatively correlated with BCVA(r=-0.767,P=0.004)and was positively correlated with CMT(r=0.662,P=0.019)and IL-23(r=0.765,P=0.004)in the DME group.There was no correlation between the cytokines in the aqueous humor of patients in the PDR group be-fore injection therapy(all P＞0.05).Conclusion Changes in the concentration of VEGF-A,PLGF,and IL-23 are closely related to the occurrence and development of DR.Anti-VEGF treatment can improve BCVA and decrease CMT in DME pa-tients.The expression level of IL-23 in aqueous humor can serve as a predictive factor for the anti-VEGF efficacy in DR pa-tients,providing new targets for early diagnosis and treatment of DR.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unclear etiology and limited treatment options. The median survival time for IPF patients is approximately 2-3 years and there is no effective intervention to treat IPF other than lung transplantation. As important components of lung tissue, endothelial cells (ECs) are associated with pulmonary diseases. However, the role of endothelial dysfunction in pulmonary fibrosis (PF) is incompletely understood. Sphingosine-1-phosphate receptor 1 (S1PR1) is a G protein-coupled receptor highly expressed in lung ECs. Its expression is markedly reduced in patients with IPF. Herein, we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin (BLM) challenge. Selective activation of S1PR1 with an S1PR1 agonist, IMMH002, exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier. These results suggest that S1PR1 might be a promising drug target for IPF therapy.

[This corrects the article DOI: 10.1016/j.apsb.2022.02.031.].

The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections. Herein we discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AZD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity. The hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase (GyrB, IC₅₀ = 49 nmol/L) and a modest inhibitory effect on Topo IV (ParE, IC₅₀ = 1.513 μmol/L) of Staphylococcus aureus. It also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration (MIC) of less than 0.03 μg/mL, which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against S. aureus. Compound 28 had better protective effects than the positive control drugs such as DS-2969 ( 5) and AZD5099 ( 6) in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) infection. It also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection models. Moreover, compound 28 has much lower mitochondrial toxicity than AZD5099 ( 6) as well as excellent therapeutic indexes and pharmacokinetic properties. At present, compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial infection. On the other hand, compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli (MIC = 1 μg/mL), which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported recently. In addition, the structure-activity relationships of the compounds were also studied.

PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients, and their indications are expanding incessantly. Currently, most PD-1/PD-L1 agents are administered intravenously, which may be uncomfortable for some cancer patients. Herein, we develop a novel oral-delivered small molecular, YPD-29B, which specifically targets human PD-L1. Our data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1, but did not inhibit any other immune checkpoints. Mechanistically, YPD-29B induced human PD-L1 dimerization and internalization, which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in vitro. YDP-29B was modified as the YPD-30 prodrug to improve druggability. Using humanized mice with human PD-1 xenografts of human PD-L1 knock-in mouse MC38 cancer cells, we demonstrated that YPD-30 exhibited significant antitumor activity and was well tolerated in vivo. Taken together, our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy.

Psoriasis is characterized by abnormal proliferation of keratinocytes, as well as infiltration of immune cells into the dermis and epidermis, causing itchy, scaly and erythematous plaques of skin. The understanding of this chronic inflammatory skin disease remains unclear and all available treatments have their limitations currently. Here, we showed that IMMH002, a novel orally active S1P modulator, desensitized peripheral pathogenic lymphocytes to egress signal from secondary lymphoid organs and thymus. Using different psoriasis animal models, we demonstrated that IMMH002 could significantly relieve skin damage as revealed by PASI score and pathological injure evaluation. Mechanistically, IMMH002 regulated CD3 T lymphocytes re-distribution by inducing lymphocytes' homing, thus decreased T lymphocytes allocation in the peripheral blood and skin but increased in the thymus. Our results suggest that the novel S1P agonist, IMMH002, exert extraordinary capacity to rapidly modulate T lymphocytes distribution, representing a promising drug candidate for psoriasis treatment.

Objective To investigate the effect of different stimulants on the LAG3 expression and function of spleen lymphocytes in mice. Methods The spleen lymphocytes from mice were isolated by density centrifugation.The LAG3 expressions in T cell subsets after exposure to conA, PMA, PHA or anti-CD3/28 antibodies for 24 h or 72 h were analyzed by Flow cytometry.The IFN-γsecretions of conditional medium were detected by ELISA kit.The proliferation of lymphocytes was examined by MTT analysis.Results Treatment with conA for 24 h or 72 h dose-dependently increased LAG3 +CD3 +and LAG3 +CD4 +CD3 +T cell percentages.Similarly, an exposure of anti-CD3/28 antibodies for 72 h significantly increased LAG3 +CD3 +and LAG3 +CD4 +CD3 + T cell percentages.Meanwhile, conA and anti-CD3/28 antibodies increased the IFN-γsecretion of lymphocytes in a time-dependent manner.Furthermore, Treatment with conA, PMA, PHA or anti-CD3/28 antibodies for 72 h could enhance the proliferation of lymphocyte. Conclusion conA and anti-CD3/28 antibodies are effective activators of T cells, and both of them could promote the expression of LAG3 and IFN-γsecretion of lymphocytes.

Objective To invstigate the effect of ultrasound microbubble mediated miRNA delivery on mi-gration,invasion and cloning ability of human hepatoma HepG2 cells. Methods The migration,invasion and col-ony forming ability of HepG2 cells were measured after transfection with antisense miRNA-21/221 and miRNA-199a mimic via the optimal ultrasound microbubble transfection method. Results Compared with the control group ,the migration ,invasion and cloning ability of cells were significantly inhibited after transfection with miRNA mimics(P < 0.05,respectively),especially for miR-199a(relative cell migration rate was 31.05%,the number of invasive cells were 38.67 ± 4.51 and the number of clones were 105.67 ± 5.86). Conclusion The pres-ent study may provide new ideas and clues for gene therapy and prognosis of hepatocell ular carcinoma through ana-lyzing the effect of miRNAs on the biological characteristics of human hepatoma HepG2 cells.

Objective To evaluate the efficacy and safety of domestic human recombinant FSH (rhFSH) in women with anovulation of WHO groupⅡ. Methods A randomized, blind, parallel-controlled, non-inferiority and multicenter study was performed. A total of 534 admitted to 13 hospitals from May 2008 to August 2009. There were 531 women with ovulatory disorder was included in the statistical analysis, were randomly divided into test group (domestic rhFSH, n=352) and control group (imported rhFSH, n=179). Percentage of cycle with mature follicle, ovulation rate, clinical pregnancy rate, multiple pregnancy rate, ovarian hyperstimulation syndrome (OHSS) and adverse events were observed. Results No statistical significant differences (P>0.05) were observed between the two groups in terms of the efficiency on mature follicle [91.8%(323/352) versus 88.8%(159/179)], ovulation rate [91.3%(295/323) verus 90.6%(144/159)], clinical pregnancy rate [19.2%(62/323) verus 18.2%(29/159)], the number of the follicles<14 mm, the level of serum LH and progesterone, the thickness of endometrium on the day of hCG administration. The number of follicle≥18 mm and 14 mm≤follicle<18 mm and the level of serum estradiol on the day of hCG in the test group were significantly higher than those in the control group (P<0.05). The number of days of rhFSH administration in the test group was significantly less than that in the control group [(9.8±2.2) versus (11.4± 0.6) days, P<0.05], the dosage of rhFSH was significantly lower than that in the control group [(879 ± 419) versus (1 043 ± 663) U, P<0.05]. The multiple pregnancy rate in the test group was significantly higher than that in the control group [21% (13/62) versu 10% (3/29), P<0.05]. The incidence of OHSS and adverse events were similar between the two groups (P>0.05), and no other adverse events were observed in test group during treatment. Conclusion Ovarian stimulation with domestic rhFSH is effective, safe and economical in women with anovulation of WHO groupⅡ.

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor on hypoxia responses in mammalian tissues. HIF-1 plays as a positive factor in solid tumor and leads to hypoxia-driven responses that enhance its downstream gene expression for tumor growth and survival. LXY6099 was obtained by the structural modification and optimization of manassantin A (MA) as a high potent HIF-1 inhibitor. Antitumor activity of LXY6099 was observed in this study. LXY6099 with an IC50 value of 2.46 x 10(-10) mol x L(-1) showed more sensitive inhibition activity to HIF-1 than that of MA detected by reporter gene assay (> 100 folds). It showed strong inhibition on the growth of human solid tumor cell lines. Furthermore, LXY6099 exhibited significant antitumor activity against established human tumor xenografts in nu/nu mice with treatment of MX-1 breast cancer. Thus, LXY6099 as a novel HIF-1 inhibitor could be further developed into anti-cancer agents.