Objective To investigate the potential therapeutic effects,targets,and pathways of wogonoside in hypertension-induced renal injury using the Gene Expression Omnibus(GEO)database and network pharmacology,and to validate the effects of wogonoside intervention on the renal tissues of spontaneously hypertensive rats(SHR),angiotensin Ⅱ(Ang Ⅱ)-stimulated NRK-52E cell apoptosis,and the regulation of relevant pathways through in vivo and in vitro experiments.Methods GEO dataset and network pharmacology analyses were performed to investigate the key therapeutic targets of wogonoside for hypertensive nephropathy.The STRING database was used to analyze protein-protein interactions.Biological functions were annotated via Gene Ontology(GO),and the potential signaling pathways were enriched using the Kyoto Encyclopedia of Genes and Genomes(KEGG).SHR were randomly divided into groups and given low,medium,or high doses of wogonoside(0.075,0.75,and 7.5 mg/kg)via gastric gavage for 10 weeks.Morphological changes in the kidney tissue were assessed by hematoxylin-eosin(HE)staining.Serum levels of inflammatory cytokines,including tumor necrosis factor α(TNF-α),interleukin(IL)-1 β,and IL-6,were measured using ELISA.Apoptosis rates were evaluated by TUNEL staining,and Western blot was performed to determine the expression of Bax,Bcl-2,cleaved caspase-3,and caspase-3,and the expression of phosphorylated and total extracellular signal-regulated kinases(ERK)and p38 mitogen-activated protein kinase(MAPK)proteins.An in vitro model of Ang Ⅱ-stimulated NRK-52E cells was constructed and was treated with wogonoside at different concentrations(25,50,or 100 μmol/L)for 24 h.The apoptosis rates were then assessed by Annexin V staining,and Western blot was performed to validate the expression of apoptosis-related and pathway-associated proteins.Results Analysis of dataset GSE41453 revealed 11673 upregulated and 5902 downregulated genes in the renal tissues of SHR compared to the Wistar Kyoto(WKY)rats,or the WKY control group.Through the analysis of multiple databases,371 potential targets of wogonoside were identified,resulting in 98 overlapping targets.From these,45 core therapeutic targets were identified through further analysis,including TNF,CASP3,etc.GO analysis significantly enriched processes such as the negative regulation of apoptosis.KEGG pathway enrichment analysis highlighted the apoptosis pathway,IL-17 signaling pathway,and MAPK signaling pathway as being significantly enriched.Wogonoside treatment effectively mitigated pathological damage in SHR kidney tissues and significantly inhibited the expression of inflammatory cytokines,including TNF-α,IL-1 β,and IL-6(P＜0.05).It also decreased cell apoptosis rates in SHR kidney tissues and Ang Ⅱ-stimulated NRK-52E cells,downregulated the expression of Bax and cleaved caspase-3,and upregulated Bcl-2 expression(P＜0.05).Furthermore,wogonoside treatment inhibited the phosphorylation of ERK and p38 MAPK in SHR kidney tissues and Ang Ⅱ-stimulated NRK-52E cells(P＜0.05).Conclusion Wogonoside may exert its protective effects against hypertension-induced renal injury by suppressing the inflammatory response and cell apoptosis,potentially through the regulation of the MAPK signaling pathway.

Objective To investigate the potential therapeutic effects of trifolin on hypertension-induced renal injury,as well as the key targets and pathways involved.Methods The mRNA transcriptional profiles of peripheral blood clinical samples from hypertensive patients were analyzed using Gene Expression Omnibus(GEO),a high-throughput gene expression database.The network pharmacology method was employed to screen key targets of trifolin in treating hypertension-induced renal injury.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were conducted.NRK-52E cells,a rat renal proximal tubular cell line,were used to construct an angiotensin Ⅱ(Ang Ⅱ)-stimulated cell model.Flow cytometry was performed to assess cell apoptosis rates and Western blotting was performed to determine the expression levels of apoptosis-related proteins,including Bax,Bcl-2,cleaved caspase-3,and caspase-3,and the phosphorylation and total protein levels of the key MAPK pathway proteins,including ERK,p38 MAPK,and JNK.Results Analysis of the dataset GSE75360 revealed that,compared with healthy controls,3 331 genes were upregulated and 3 197 genes were downregulated in peripheral blood mononuclear cells of hypertensive patients.According to network pharmacology analysis,472 potential targets of trifolin were identified,including CASP3 and MAPK1.Protein-protein interaction network analysis showed that these targets were closely associated with apoptosis regulatory signaling pathways.GO and KEGG pathway enrichment analyses indicated that trifolin was significantly enriched in pathways associated with negative regulation of apoptosis,apoptotic signaling pathways,and the MAPK signaling pathway.The in vitro experiments confirmed that,compared with the Ang Ⅱ group,trifolin intervention inhibited apoptosis in Ang Ⅱ-stimulated NRK-52E cells,suppressed the expression of Bax and cleaved caspase-3,promoted Bcl-2 expression,and inhibited the phosphorylation of p38 MAPK,ERK,and JNK(P<0.05).Conclusion Trifolin may exert its protective effect against hypertension-induced renal injury by inhibiting Ang Ⅱ-induced NRK-52E cell apoptosis and regulating the MAPK signaling pathway,representing an important mechanism underlying its therapeutic action.

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

Objective:To observe the clinical efficacy of manual therapy based on the Discovery of Posture Secret (DPS) in treating adolescent idiopathic scoliosis (AIS).Methods:Thirty-six AIS patients were randomly divided into an observation group of 17 and a control group of 16. In addition to 10 minutes of side-shift training each week, the control group was given 20 minutes of sling exercise training (SET), while the observation group underwent weekly 20-minute manual therapy sessions based on DPS on the days without SET. Before and after the 4 weeks of treatment spine curvature (Cobb angle), clavicular angle (CA), angle of trunk rotation (ATR) and vertebral rotation (VR) were measured, and the Scoliosis Research Society′s patient questionnaire 22 (SRS-22) was administered.Results:After the treatment the average Cobb angle, CA, ATR and SRS-22 score of the observation group had improved significantly compared with before the treatment. The average Cobb angle, ATR and SRS-22 score of the control group were also significantly higher, but the improvements were not as great as in the observation group. There was no significant difference in VR improvement between the two groups.Conclusion:Manual therapy based on the DPS can effectively ameliorate the scoliosis and shoulder imbalance of AIS patients.

Objective:To investigate mechanism of phosphodiesterase 5(PDE5)inhibitor Sildenafil in treatment of pain and inflammation in chronic pelvic pain mediated by macrophage polarization.Methods:A total of 32 adult Wistar rats were divided into 4 groups:Sham group,Experimental autoimmune prostatitis(EAP)group,Sildenafil+EAP group,MET+Sildenafil+EAP group,with 8 rats in each group.EAP model was induced by subcutaneous injection of prostate antigen(PAg)and complete Fredrin adjuvant,Sham group was injected with equivalent normal saline.EAP rats were treated with Sildenafil.Metformin was injected on basis of Silde-nafil+EAP.HE staining was used to analyze pathological changes of prostate.Response rate of pelvic pain in rats was measured by von Frey fiber method.Serum cytokines IL-10 and TNF-α levels were determined by ELISA.Numbers of iNOS+and CD16/32+macrophages and CD206+and CD10+macrophages in serum were detected by flow cytometry.Results:Compared with Sham group,EAP group showed obvious focal or multifocal inflammation in ventral prostate gland tissues,pelvic pain response rate,serum inflammatory factor TNF-α level,and number of M1-type polarization characteristic iNOS+and CD16/32+cells in EAP group were significantly increased(all P<0.05),while M2-type polarization characteristics of macrophages,IL-10 level and number of CD206+and CD10+macrophages were significantly decreased(all P<0.05).Compared with EAP group,pelvic pain response rate,TNF-α level,iNOS+and CD16/32+cell number in Sildenafil+EAP group were significantly decreased(all P<0.05),while IL-10 level and CD206+and CD10+macrophage number were significantly increased(all P<0.05).Compared with Sildenafil+EAP group,pelvic pain response rate,TNF-α level,iNOS+and CD16/32+cells in MET+Sildenafil+EAP group were significantly increased(all P<0.05),while IL-10 level and number of CD206+and CD10+macrophages were significantly decreased(all P<0.05).Conclusion:Sildenafil,a PDE5 inhibitor,blocks chronic pelvic pain and inflammation by promoting polarization of M2 macrophages.

Background Non-occupational carbon monoxide (CO) poisoning is a public health problem that seriously affect people’s health and lives. Objective To describe the prevalence of non-occupational CO poisoning during 2007—2018 in Shanghai, analyze its epidemiological characteristics and potential influencing factors, and explore effective prevention and control measures. Methods Daily reported non-occupational CO poisoning cases and meteorological factors from 2007 to 2018 were collected in Shanghai, epidemiological characteristics were analyzed by descriptive epidemiology methods, and a distributed lag nonlinear model was used to assess the association between temperature and non-occupational CO poisoning. Results A total of 2264 non-occupational CO poisoning events and 3866 cases from 2007 to 2018 were reported in Shanghai, including 59 death cases. More than half of the poisoning cases were female (56.3%), and young adults accounted for more cases than any other age group (54.8%). The poisoning events mainly occurred in winter (from December to next February); however, cases reported in summer increased in recent years. The peak period of the events was from 20:00 to 24:00. Households (85.2%) and restaurants (8.0%) were the common places of non-occupational CO poisoning events, and the main cause was improper use of gas water heater (36.9%). A nonlinear curve was found between daily average temperature of current day and the occurrence of non-occupational CO poisoning. Temperature was negatively associated with the risk of non-occupational CO poisoning when the temperature was lower than 9.6 ℃, while a positive association was found during 9.7-26.0 ℃. Conclusion Winter is a high season for non-occupational CO poisoning in Shanghai, rising cases reported in summer is also worthy of attention. Supervision should be strengthened to ban sales of unqualified gas water heaters, and health education on CO poisoning prevention and control should be conducted through multiple channels, in order to reduce the incidence of CO poisoning.

Macular edema is formed by the accumulation of extracellular fluid or intracellular fluid in the macular area of the retina. In a physiological state, the retina is kept relatively dehydrated and transparent, thereby ensuring the transmission of optical signals. This process requires multiple active or passive liquid transport systems to be performed together, and any of these process anomalies can disrupt the retinal water ion homeostasis, causing an imbalance between fluid entry and exit processes, leading to fluid formation. Macular edema is not an independent disease, it can occur in the process of many retinal diseases. It is the main cause of serious damage to the central vision, the main causes of diabetes, retinal vein occlusion, choroidal angiogenesis, uveitis, postoperative inflammation and tumor. This review mainly discusses the complex mechanism of macular edema caused by retinal barrier dysfunction when retinal water ion homeostasis is abnormal at the cellular and molecular levels. The purpose of this review is to provide a deeper overview of macular edema and its mechanisms of development, opening up new prospects for new prevention and treatment strategies for macular edema, a serious threat to vision.

To evaluate effects of reinfusion of the remaining blood filtered by leukocyte depletion filter on postoperative cellular immune function after cardiopulmonary bypass (CPB). Methods Forty patients who underwent selective cardiac valve replacement surgery with CPB in department of anesthesiology of Haikou Municipal Hospital from January to June in 2018 were enrolled. All the patients were divided into the control group and experimental group according to the random number table method, with 20 patients in each group. In the experimental group, patients received residual pump blood transfusion which had been filtered by leukocyte depletion filter and stored in sterile blood collection bags. In the control group, patients received residual pump blood transfusion which was stored in sterile blood collection bags without being filtered. The remaining blood was reinfused after CPB in two groups. Blood samples were taken before CPB (T1), 2 hours following CPB (T2), and 1, 3, 5 days after reinfusion of the remaining blood (T3, T4, T5), the levels of T lymphocyte subsets CD3+, CD4+, CD8+ and natural killer cells (NK cells) were detected by flow cytometer, and CD4+/CD8+ ratio was calculated. The levels of plasma tumor necrosis factor-α (TNF-α), interleukins (IL-2, IL-6, IL-8) were measured by enzyme linked immunosorbent essay (ELISA). The duration of mechanical ventilation, the length of intensive care unit (ICU) stay, the length of hospital stay, and incidence of wound and pulmonary infection after surgery were compared between two groups. Results Among 40 patients, there were 22 males and 18 females; with an age of (47.88±12.29) years old; and with 25 cases of American Society of Anesthesiologists (ASA) physical status Ⅱ, and 15 cases of ASAⅢ. There was no statistical difference in the volume of the remaining blood between the two groups (mL: 959.00±116.84 vs. 971.50±115.68, P > 0.05). Compared with T1, the levels of T lymphocyte subsets CD3+, CD4+, CD8+, NK cells and plasma levels of IL-2 were significantly decreased from T2, the CD4+/CD8+ ratio was significantly decreased from T3 in two groups, but there was no statistical difference in CD3+, CD4+, CD8+, NK cells, CD4+/CD8+ ratio or plasma level of IL-2 at each time between the two groups. Compared with T1, the plasma levels of TNF-α, IL-6 and IL-8 were significantly increased at T2 in two groups and then decreased gradually. The plasma levels of TNF-α, IL-6 and IL-8 from T3 in experimental group were lower than those in control group [TNF-α (ng/L): 28.49±4.66 vs. 33.82±4.30, IL-6 (ng/L): 25.98±4.51 vs. 31.38±5.42, IL-8 (ng/L):38.98±4.67 vs. 45.76±5.33, all P < 0.05], they restored to the level of T1 at T5. In addition, compared with control group, the duration of mechanical ventilation, the length of ICU stay in experimental group were significantly decreased (hours: 8.07±1.30 vs. 9.16±1.52, 28.22±2.78 vs. 31.25±3.18, both P < 0.05), and there was no statistical difference in the length of hospital stay (days: 20.65±2.76 vs. 22.45±3.22), incidence of wound and pulmonary infection (25.0% vs. 15.0%, 5.0% vs. 15.0%) between the two groups (all P > 0.05). Conclusion Reinfusion of the remaining blood filtered by leukocyte depletion filtercan inhibit inflammatory responses and don't affect the function of cellular immunity, and don't increase the incidence of infection.

Objective To evaluate the lung protection of residual pump blood processed by microaggregate blood filter-reinfusion in patients undergoing cardiac surgery under cardiopulmonary bypass (CPB).Methods A total of 40 patients,aged 28-55 yr,weighing 46-66 kg,of American Society of Anesthesiologists physical status Ⅱ or Ⅲ,with New York Heart Association of Ⅱ or Ⅲ,with left ventricular ejection fraction＞50％,scheduled for elective cardiac valve replacement under general anesthesia,were divided into 2 groups (n =20 each) using a random number table method:residual pump blood reinfusion group (group C) and residual pump blood processed by microaggregate blood filter-reinfusion group (group M).Residual pump blood was collected immediately after the end of CPB.The residual pump blood was stored in sterile blood collection bags without being filtered in group C.The residual pump blood was stored in sterile blood collection bags after being processed by microaggregte blood filter in group M.Residual pump blood was intravenously reinfused after the CPB pipe was removed.At 10 min before CPB (T1),immediately after the end ofCPB (T2),immediately after processing (T3) and at 12 and 24 h after residual pump blood reinfusion (T4,5),blood samples were collected to measure blood components and serum tumor necrosis factor-alpha and intedeukin-6 concentrations (by enzyme-linked immunosorbent assay).Airway plateau pressure was recorded,arterial blood samples were collected for blood gas analysis,and static lung compliance,oxygenation index and respiratory index were calculated at T1.5.The postoperative mechanical ventilation time,duration of intensive care unit stay,length of hospital stay,and incidence of hypoxemia and pulmonary infection were recorded.Results Compared with group C,white blood cell count was significantly decreased at T3-5,and static lung compliance and oxygenation index were increased,respiratory index was decreased,serum tumor necrosis factor-alpha and interleukin-6 concentrations were decreased,postoperative mechanical ventilation time and duration of intensive care unit stay were shortened,and the incidence of hypoxemia was decreased at T4.5 in group M (P＜0.05).Conclusion Residual pump blood proccessed by microaggregate blood filter-reinfusion can reduce systemic inflammatory responses and exerts lung protection to some extent in the patients undergoing cardiac surgery under CPB.

Objective To observe the changes of subfoveal choroidal thickness (SFCT) in diabetic patients with non-proliferative diabetic retinopathy (NPDR) and clinically significant macular edema(CSME),and then investigate diabetic SFCT and the relationship of diabetic CT with diabetic retinopathy (DR).Methods The patients were divided into 2 groups according to clinical guidelines of DR in China in 2014,including NPDR CSME + group(21 eyes) and NPDR CSME-group(36 eyes).All patients were underwent best corrected visual acuity (BCVA),intraocular pressure,axial length,slit lamp microscope,indirect ophthalmoscope,EDI-OCT examination,and mean arterial blood pressure measurement.The differences of BCVA,central retinal thickness (CRT) and SFCT between NPDR CSME + group and NPDR CSME-group were studied as well by means of using SPSS 18.0 for data statistics.Results There was no significant difference in gender,age,eye axis and intraocular pressure between NPDR CSME + group and NPDR CSME-group (all P ＞ 0.05).There was significant difference in BCVA between the two groups (P =0.001).The mean SFCT were (328.24 ± 101.92) μm in the NPDR CSME + group and (235.31 ± 66.98) μm in the NPDR CSME-group,and the difference was statistically significant (t =4.156,P=0.000).And plotting changes in CRT against changes in SFCT in patients with CSME revealed a positive correlation(r =0.473,P =0.000).Conclusion SFCT in NPDR CSME + patient is thicker than that in NPDR CSME-patient.And plotting changes in CRT against changes in SFCT in patients with CSME reveals a positive correlation.