Metabonomics analysis of aqueous humor samples from cataract patients with branch retinal vein occlusion.

Cataract (CAT) has a very high incidence rate among the middle-aged and elderly, with most patients complicated by branch retinal vein occlusion (BRVO), a key cause of blindness. In this study, through metabolomic analysis of aqueous humor samples from CAT patients with BRVO, a total of 319 different metabolites were found, most of which belonged to the categories of carboxylic acids and derivatives, fatty acyls, and organooxygen compounds. The most typical metabolites were 3-methylhistidine and biliverdin, which were up-regulated, as well as the down-regulated beta-glycerophosphoric acid. Tricosanoic acid showed the most significant correlation with CAT+BRVO. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the most commonly related keywords for differentially expressed metabolites were biosynthesis of unsaturated fatty acids and synaptic vesicle cycle. These results can not only help to further understand the pathogenesis of CAT complicated by BRVO in clinical practice, but also provide some new therapeutic research directions.

SP1 promotes high glucose-induced lens epithelial cell viability, migration and epithelial-mesenchymal transition via regulating FGF7 and PI3K/AKT pathway.

BACKGROUND: Diabetic cataract (DC) is a common complication of diabetes and its etiology and progression are multi-factorial. In this study, the roles of specific protein 1 (SP1) and fibroblast growth factor 7 (FGF7) in DC development were explored. METHODS: DC cell model was established by treating SRA01/04 cells with high glucose (HG). MTT assay was conducted to evaluate cell viability. Transwell assay and wound-healing assay were performed to assess cell migration and invasion. Western blot assay and qRT-PCR assay were conducted to measure the expression of N-cadherin, E-cadherin, Collagen I, Fibronectin, SP1 and FGF7 expression. CHIP assay and dual-luciferase reporter assay were conducted to analyze the combination between FGF7 and SP1. RESULTS: FGF7 was upregulated in DC patients and HG-induced SRA01/04 cells. HG treatment promoted SRA01/04 cell viability, migration, invasion and epithelial-mesenchymal transition (EMT), while FGF7 knockdown abated the effects. Transcription factor SP1 activated the transcription level of FGF7 and SP1 overexpression aggravated HG-induced SRA01/04 cell injury. SP1 silencing repressed HG-induced SRA01/04 cell viability, migration, invasion and EMT, but these effects were ameliorated by upregulating FGF7. Additionally, SP1 knockdown inhibited the PI3K/AKT pathway by regulating the transcription level of FGF7. CONCLUSION: Transcription factor SP1 activated the transcription level of FGF7 and the PI3K/AKT pathway to regulate HG-induced SRA01/04 cell viability, migration, invasion and EMT.

Circular RNA HIPK3 regulates human lens epithelial cell dysfunction by targeting the miR-221-3p/PI3K/AKT pathway in age-related cataract.

Circular RNA Homeodomain Interacting Protein Kinase 3 (circHIPK3) was found to involve in the pathogenesis of age-related cataract (ARC). Here, we further disclosed the related target genes and molecular mechanism of circHIPK3 in the ARC progression. The expression of circHIPK3, microRNA (miR)-221-3p was detected using the quantitative real-time polymerase chain reaction. Human lens epithelial cell (HLEC) proliferation and apoptosis were measured by 3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-di-phenytetrazoliumromide (MTT) assay and flow cytometry, respectively. Western blot was used to detect the levels of apoptosis-related proteins, and phosphoinositide 3-kinase (PI3K)/p-protein kinase B (AKT) pathway-related proteins. Levels of malondialdehyde (MDA) and glutathione peroxidase (GSH-PX) were measured by kits. The interaction between miR-221-3p and circHIPK3 was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assay. CircHIPK3 was down-regulated while miR-221-3p was up-regulated in human lens epithelium samples of ARC patients. CircHIPK3 up-regulation or miR-221-3p down-regulation mediated the promotion of proliferation, inhibition of apoptosis, decrease of MDA level as well as increase of GSH-PX level in HLECs. MiR-221-3p was a target of circHIPK3, and miR-221-3p overexpression reversed the protective action of circHIPK in HLEC functions. In addition, circHIPK3 activated PI3K/AKT pathway via regulating miR-221-3p, and silencing miR-221-3p protected HLECs from dysfunction by activating PI3K/AKT pathway. We demonstrated that circHIPK3 protected HLECs from dysfunction by regulating miR-221-3p/PI3K/AKT pathway, indicating a new insight into the pathogenesis of ARC and providing a potential therapeutic target for ARC.

A high-risk papillomavirus 18 E7 affibody-enabled in vivo imaging and targeted therapy of cervical cancer.

High-risk papillomavirus (HPV) is one of the major reasons for cervical cancer, causing most lethal gynecologic malignancies worldwide. For cervical cancer progression, oncogene E7 plays vital roles and is used as one of the major targets for cervical tumor diagnosis and treatment. In the clinic, successful treatment of cervical cancer relies on diagnosing the disease at an early stage, where a late-stage diagnosis usually led to treatment failure. In this work, we designed and purified an HPV18 E7 oncogene targeting affibody, named as ZHPV18E7, for in vitro and in vivo imaging and targeted treatment of cervical cancer. In vitro, ZHPV18E7 showed a specific targeting effect against an HPV18 positive cell line; as a contrast, the affibody did not target the HPV18 negative cell line. In vivo, we tested the bio-distribution of the affibody in mice bearing cervical cancer. The whole animal imaging analysis indicated the affibody-targeted tumor tissue specifically with 10 min after injection, and the affibody reached the highest level at tumor tissues 45 min after injection. At the 24th hour after injection, the affibody still maintained a certain level in tumor tissues compared to other organs. To test the therapeutic effect of this affibody, we modified the affibody (i.e., ZHPV18E7) with a clinically used anti-cancer agent (i.e., Pseudomonas exotoxin). In a mice cervical cancer model, ZHPV18E7 was able to deliver Pseudomonas exotoxin to tumor tissues effectively, showing great potential for cancer treatment. This study indicated that ZHPV18E7 could be employed for in vitro imaging and targeted treatment of cervical cancer. Beyond the chemotherapeutic agent used in this work, the affibody could be extended for carrying other therapeutic agents for cervical cancer treatment.

Effect of Fine Particulate Matter (PM2.5) on Rat Placenta Pathology and Perinatal Outcomes.

BACKGROUND Fine particulate matter with aerodynamic diameters smaller than 2.5 µm (PM2.5) has been reported to cause adverse effects on human health. Evidence has shown the association between PM2.5 exposure and adverse perinatal outcomes, and the most common method is epidemiological investigation. We wished to investigate the impact of PM2.5 on placenta and prenatal outcomes and its related mechanisms in a rat model. MATERIAL AND METHODS Pregnant rats were exposed to a low PM2.5 dose (15 mg/kg) with intratracheal instillation at pregnant day 10 and day 18, while the controls received an equivalent volume normal saline. All rats received cesarean section 24 h after the last intratracheal instillation and were sacrificed with anesthesia. Blood routine tests (BRT) and interleukin-6 (IL-6) were detected for analyzing inflammation and blood coagulation. Placenta tissue sections underwent pathologic examination, and the levels of homogenate glutathione peroxidase (GSH-Px) and methane dicarboxylic aldehyde (MDA) were determined for oxidative stress estimation. RESULTS Increased absorbed blastocysts, and lower maternal weight gain and fetal weight were found in the PM2.5 exposure group compared to controls (p<0.05). Exposure to PM2.5 caused a significant increase of blood mononuclear cells (PBMC), platelets, and IL-6 levels (P<0.01). There were no differences in GSH-Px and MDA of placenta homogenate between the 2 groups (P>0.05). Placenta pathological examination demonstrated thrombus and chorioamnionitis in the PM2.5 exposure group. CONCLUSIONS PM2.5 exposure can result in placental pathological changes and adverse perinatal outcomes. The placental inflammation and hypercoagulability with vascular thrombosis may play important roles in placental impairment, but oxidative stress appears to be less important.

Synthesis and Anti-gastric Cancer Activity by Targeting FGFR1 Pathway of Novel Asymmetric Bis-chalcone Compounds.

BACKGROUP: Bis-chalcone compounds with symmetrical structures, either isolated from natural products or chemically synthesized, have multiple pharmacological activities. Asymmetric Bis-chalcone compounds have not been reported before, which might be attributed to the synthetic challenges involved, and it remains unknown whether these compounds possess any potential pharmacological activities. AIMS: The aim of this study is to investigate the synthesis route of asymmetric bis-chalcone compounds and identify potential candidates with efficient anti-tumor activity. METHOD: The two-step structural optimization of the bis-chalcone compounds was carried out sequentially, guided by the screening of the compounds for their growth inhibitory activity against gastric cancer cells by MTT assay. The QSAR model of compounds was established through random forest (RF) algorithm. The activities of the optimal compound J3 on growth inhibition, apoptosis, and apoptosis-inducing protein expression in gastric cancer cells were investigated sequentially by colony formation assay, flow cytometry, and western blotting. Further, the inhibitory effects of J3 on the FGFR1 signaling pathway were explored by Wester Blotting, siRNA, and MTT assays. Finally, the in vivo anti-tumor activity and mechanism of J3 were studied through nude mouse xenograft assay, western blotting. RESULT: 27 asymmetric bis-chalcone compounds, including two types (N and J) were sequentially designed and synthesized. Some N-class compounds have good inhibitory activity on the growth of gastric cancer cells. The vast majority of J-class compounds optimized on the basis of N3 exhibit excellent inhibitory activity on gastric cancer cell growth. We established a QSAR model (R2 = 0.851627) by applying random forest algorithms. The optimal compound J3, which has better activity, concentration-dependently inhibited the formation of gastric cancer cell colonies and led to cell apoptosis by inducing the expression of the pro-apoptotic protein cleaved PARP. J3 may exert anti-gastric cancer effects by inhibiting the activation of FGFR1/ERK pathway. Moreover, at a dose of 10 mg/kg/day, J3 inhibited tumor growth in nude mice by nearly 70% in vivo with no significant toxic effect on body weight and organs. CONCLUSION: In summary, this study outlines a viable method for the synthesis of novel asymmetric bischalcone compounds. Furthermore, the compound J3 demonstrates substantial promise as a potential candidate for an anti-tumor drug.

Discovery of Pyroptosis-inducing Drugs and Antineoplastic Activity based on the ROS/ER Stress/Pyroptosis Axis.

BACKGROUND: Pyroptosis, a cell death process triggered by chemotherapy drugs, has emerged as a highly promising mechanism for combating tumors in recent years. As the lead of new drugs, natural products play an important role in the discovery of anticancer drugs. Compared to other natural products, the medicine food homologous natural products (MFHNP) exhibit a superior safety profile. Among a series of MFHNP molecular skeletons, this study found that only benzylideneacetophenone (1) could induce cancer cell pyroptosis. However, the anti-cancer activity of 1 remains to be improved. AIMS: This study aimed to find a pyroptosis inducer with highly effective antitumor activity by modifying the chalcone structure. METHODS: To examine the effect of the Michael receptor in compound 1 on the induction of pyroptosis, several analogs were synthesized by modifying the Michael acceptor. Subsequently, the anticancer activity was tested by MTT assay, and morphological indications of pyroptosis were observed in human lung carcinoma NCI-H460 and human ovarian cancer CP-70 cell lines. Furthermore, to improve the activity of the chalcone skeleton, the anticancer group 3,4,5- trimethoxyphenyl was incorporated into the phenyl ring. Subsequently, compounds 2-22 were designed, synthesized, and screened in human lung cancer cells (NCI-H460, H1975, and A549). Additionally, a quantitative structure-activity relationship (QSAR) model was established using the eXtreme Gradient Boosting (XGBoost) machine learning library to identify the pharmacophore. Furthermore, both in vitro and in vivo experiments were conducted to investigate the molecular mechanisms of pyroptosis induced by the active compound. RESULTS: α, ß-unsaturated ketone was the functional group of the chalcone skeleton and played a pivotal role in inducing cancer cell pyroptosis. QSAR models showed that the regression coefficients (R2) were 0.992 (A549 cells), 0.990 (NCI-H460 cells), and 0.998 (H1975 cells). Among these compounds, compound 7 was selected to be the active compound. Moreover, compound 7 was found to induce pyroptosis in lung cancer cells by upregulating the expression of CHOP by increasing the ROS level. Furthermore, it effectively suppressed the growth of lung cancer xenograft tumors. CONCLUSION: Compound 7 exhibits antineoplastic activity by regulating the ROS/ER stress/pyroptosis axis and is a kind of promising pyroptosis inducer.

Red Blood Cell Membrane-Coated Nanoparticles Enable Incompatible Blood Transfusions.

Blood transfusions save lives and improve health every day. Despite the matching of blood types being stricter than it ever has been, emergency transfusions among incompatible blood types are still inevitable in the clinic when there is a lack of acceptable blood types for recipients. Here to overcome this, a counter measure nanoplatform consisting of a polymeric core coated by a red blood cell (RBC) membrane is developed. With A-type or B-type RBC membrane camouflaging, the nanoplatform is capable of specifically capturing anti-A or anti-B IgM antibodies within B-type or A-type whole blood, thereby decreasing the corresponding IgM antibody levels and then allowing the incompatible blood transfusions. In addition to IgM, the anti-RBC IgG antibody in a passive immunization murine model can likewise be neutralized by this nanoplatform, leading to prolonged circulation time of incompatible donor RBCs. Noteworthily, nanoplatform made by expired RBCs (>42 days stored hypothermically) and then subjected to lyophilization does not impair their effect on antibody neutralization. Most importantly, antibody-captured RBC-NP do not exacerbate the risk of inflammation, complement activation, and coagulopathy in an acute hemorrhagic shock murine model. Overall, this biomimetic nanoplatform can safely neutralize the antibody to enable incompatible blood transfusion.

Picropodophyllin inhibits epithelial ovarian cancer cells in vitro and in vivo.

Epithelial ovarian cancer (EOC) is one of the leading causes of gynecological cancer death. Approximately 70% of the patients experience recurrence accompanied by the development of drug resistance 2-3 years after chemotherapy. Picropodophyllin (PPP) is a newly identified insulin-like growth factor-1 receptor (IGF-1R) inhibitor that has been shown to have anticancer properties. In this study, we investigated the effect of PPP on EOC growth in vitro and in vivo. The EOC cell line SKOV-3 was treated with increasing concentrations of PPP or cisplatin, and cell viability and apoptosis were evaluated. To study the effects of PPP on EOC growth, apoptosis, and toxicity in vivo, a BALB/c nude mouse xenograft model was established. Mice were treated with normal saline (controls), PPP, cisplatin, or PPP in combination with cisplatin. In addition, the expression of phosphorylated IGF-1R (pIGF-1R) was examined in vitro and in vivo. PPP induced a dose-dependent decrease in SKOV-3 cell viability in vitro and reduced tumor volume and weight in the in vivo xenograft model. Furthermore, PPP in combination with cisplatin was more effective in inhibiting the growth of SKOV-3 cells and xenografts than either drug alone. PPP-mediated growth inhibition was associated with apoptosis induction in vitro and in vivo. PPP was well tolerated in vivo and exerted its effects with minimal hepatotoxicity and renal toxicity. PPP downregulated the expression of pIGF-1R in vitro and in vivo, an effect that appeared to be associated with its growth inhibitory properties. Our results indicate that PPP may have therapeutic application in the treatment of EOC.

Doxorubicin Detoxification in Healthy Organs Improves Tolerability to High Drug Doses for Enhanced Antitumor Therapy.

With its well-documented toxicity, the use of doxorubicin (Dox) for cancer treatment requires trade-offs between safety and effectiveness. This limited use of Dox also hinders its functionality as an immunogenic cell death inducer, thus impeding its usefulness for immunotherapeutic applications. Here, we develop a biomimetic pseudonucleus nanoparticle (BPN-KP) by enclosing GC-rich DNA within erythrocyte membrane modified with a peptide to selectively target healthy tissue. By localizing treatment to organs susceptible to Dox-mediated toxicity, BPN-KP acts as a decoy that prevents the drug from intercalating into the nuclei of healthy cells. This results in significantly increased tolerance to Dox, thereby enabling the delivery of high drug doses into tumor tissue without detectable toxicity. By lessening the leukodepletive effects normally associated with chemotherapy, dramatic immune activation within the tumor microenvironment was also observed after treatment. In three different murine tumor models, high-dose Dox with BPN-KP pretreatment resulted in significantly prolonged survival, particularly when combined with immune checkpoint blockade therapy. Overall, this study demonstrates how targeted detoxification using biomimetic nanotechnology can help to unlock the full potential of traditional chemotherapeutics.

Vaginal Epithelial Cell Membrane-Based Phototherapeutic Decoy Confers a "Three-in-One" Strategy to Treat against Intravaginal Infection of Candida albicans.

Phototherapy is an effective strategy to control Candida albicans (C. albicans) infection without raising the concern of drug resistance. Despite its effectiveness, a higher dose of phototherapeutic power is required for C. albicans elimination compared to bacteria that have to be used, which is readily accompanied by off-target heat and toxic singlet oxygen to damage normal cells, thus limiting its usefulness for antifungal applications. Here to overcome this, we develop a "three-in-one" biomimetic nanoplatform consisting of an oxygen-dissolved perfluorocarbon camouflaged by a photosensitizer-loaded vaginal epithelial cell membrane. With a cell membrane coating, the nanoplatform is capable of specifically binding with C. albicans at the superficial or deep vaginal epithelium, thereby centering the phototherapeutic agents on C. albicans. Meanwhile, the cell membrane coating endows the nanoplatform to competitively protect healthy cells from candidalysin-medicated cytotoxicity. Upon candidalysin sequestration, pore-forming on the surface of the nanoplatform accelerates release of the preloaded photosensitizer and oxygen, resulting in enhanced phototherapeutic power for improved anti-C. albicans efficacy under near-infrared irradiation. In an intravaginal C. albicans-infected murine model, treatment with the nanoplatform leads to a significantly decreased C. albicans burden, particularly when leveraging candidalysin for further elevated phototherapy and C. albicans inhibition. Also, the same trends hold true when using the nanoplatform to treat the clinical C. albicans isolates. Overall, this biomimetic nanoplatform can target and bind with C. albicans and simultaneously neutralize the candidalysin and then transform such toxins that are always considered a positive part in driving C. albicans infection with the power of enhancing phototherapy for improved anti-C. albicans efficacy.

Autophagy Protects Ocular Surface Against Overactivated Inflammation by Degrading Retinoic Acid-Induced Gene-I in Human Conjunctival Epithelial Cells.

Purpose: To evaluate the pathological role of autophagy in dry eye diseases by detecting the autophagic degradation of RIG-I, a master RNA-sensing receptor in cells. Methods: RNA-sequencing analysis and qPCR analysis of the expression level of genes related to IFN-I signaling pathway was used to evaluate the inflammatory level of cells overexpressed with RIG-I or empty vector, which was further confirmed by WB analysis. Chemical treatment (3-methyladenine, chloroquine, NH4Cl, rapamycin, torin 1 or trehalose) or gene knockdown was used to modulate autophagy. When the autophagy level was regulated, the autophagic degradation of RIG-I and its pathological role in dry eye diseases were determined by detecting the protein level of RIG-I and the level of cell inflammation. Results: Cells that overexpressed RIG-I showed increased expression of genes involved in the IFN-I signaling pathway compared with cells transfected with an empty vector. Inhibition of autophagy leaded to the accumulation of RIG-I in HCECs, combined with the aggravation of the RIG-I-mediated IFN-I signaling pathway. Contrarily, promoting the autophagic degradation of RIG-I by trehalose treatment could alleviate IFN-I signaling pathway. Conclusions: Autophagy could protect the ocular surface against IFN-I signaling pathway by degrading RIG-I in HCECs. This process may restrict the overactivation of inflammation in the pathological development of dry eye disease.

[Levonorgestrel-releasing intrauterine system and combined oral contraceptives as conservative treatments for recurrent ovarian endometriosis: a comparative clinical study].

OBJECTIVE: To evaluate and compare the efficiency and safety of levonorgestrel-releasing intrauterine system (LNG-IUS) and combined oral contraceptives (COC) in the treatment of recurrent ovarian endometriosis after conservative surgery or conservative surgery plus medical therapy. METHODS: A total of 48 patients with recurrent ovarian endometriosis underwent randomization. The regimens of LNG-IUS (n = 24) and COC (n = 24) were offered. The volume of ovarian endometriotic cysts was recorded before treatment and at 6, 12, 18 and 24 months. The volume of ovarian endometriotic cysts, pain score of visual analogue scale (VAS), menstrual pattern, body weight, serum CA125 and serum lipids were compared to the pretreatment level within each treatment group, as well as between two treatment groups during the same period. RESULTS: (1) At 18 months after LNG-IUS, the cysts in 2 subjects entirely disappeared. At 24 months, 18 patients had a disappearance of cysts. The overall size reduction was statistically significant (9.2 ± 3.0) vs (0.9 ± 1.5) cm(3) (P < 0.01). In the COC group, 12 subjects had a complete resolution of cysts at 24 months. The overall size reduction was statistically significant (9.4 ± 2.2) vs (2.9 ± 3.1) cm(3) (P < 0.01). At 18 & 24 months, the cyst size reduction was significantly larger in the LNG-INS group than the COC group (2.4 ± 1.5) vs (4.7 ± 2.6) cm(3) (P < 0.01) and (0.9 ± 1.5) vs (2.9 ± 3.1) cm(3) (P < 0.05); (2) There was a significant improvement of dysmenorrhea, chronic pelvic pain and dyspareunia at 6- & 12-month follow-up in both groups; (3) serum CA125 decreased at 6 & 12 months in both groups with statistical significance. It decreased more sharply in the LNG-IUS group and remained at low levels beyond 12 months; (4) within 6 months of LNS-IUS, irregular bleeding and spotting were the major side effects. Beyond that period the symptoms were significantly relieved. Weight gain and dyslipidemia were the major side effects of COC. CONCLUSION: For patients with recurrent ovarian endometriosis after conservative surgery or conservative surgery plus medical therapy, LNG-IUS and COC may be used to control and reduce endometriotic cysts, relieve pain and reduce the level of CA125. LNG-IUS has the advantages of a greater convenience and minor systemic side effects.

[Evaluation of levonorgestrel-releasing intrauterine system in treatment of recurrent endometriosis after conservative surgery].

OBJECTIVE: To evaluate the efficiency of levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of recurrent endometriosis after conservative surgery or conservative surgery combined with medical treatment. METHODS: Twenty-three patients with recurrent endometriosis after conservative surgery or conservative surgery combined with medical treatment were treated by LNG-IUS. All patients rejected further operation and had no desire of fertility. The visual analogue scale (VAS) scores of pain, menstrual model, weight and serum CA125 level and the volume of ovarian endometriotic cysts before and after 3, 6, 12, 24 and 36 months of treatment were recorded and compared. RESULTS: (1) VAS score:after 12 months of using LNG-IUS, dysmenorrheal, chronic pelvic pain or dyspareunia were relieved significantly. VAS score were dropped from 5.9±2.3, 4.3±2.0 to 1.0±0.7, 1.4±1.1 (P<0.01). (2) Volum of cysts:after 6 months of using LNG-IUS, the volume of recurrent ovarian endometriotic cysts in 11 patients were reduced from (11.4±6.1) cm3 to (5.5±3.4) cm3 significantly (P<0.01). At 12 months of follow-up, it suggested that 2 patients' ovarian endometriotic cysts disappeared. At 24 months follow-up, 9 patients ovarian endometriotic cysts disappeared (3) CA125: serum CA125 decreased from (65.5±19.6) kU/L to (42.1±13.6) kU/L at 6 months after treatment remarkably (P<0.01). Continued to decrease after 12 months and then become steady. Irregular bleeding and spotting was the main side effects, weight gain was also observed in few patients. CONCLUSIONS: LNG-IUS could be used in treatment of recurrent endometriosis after conservative surgery or conservative surgery combined with medical treatment effectively. It could relieve pain, reduce the level of CA125 and decrease the size of ovarian endometriotic cysts. LNG-IUS seems to be an effective, safe, and long term treatment for endometriosis with fewer side effects and better compliance.

Research progress of single nucleotide polymorphism in stress urinary incontinence.

Stress urinary incontinence (SUI), as one of the manifestations of pelvic floor dysfunction diseases with high incidence, seriously affects women's physical and mental health and quality of life. The etiology and pathogenesis of SUI are complex and not yet completely clear, now believed to be involved with environmental factors, genetic factors and cross-cutting factors between the two. SUI genetic susceptibility may be related to single nucleotide polymorphism. This article reviews the current studies on SUI-related single nucleotide polymorphisms.

Short-term effects of delivery methods on postpartum pelvic floor function in primiparas: a retrospective study.

BACKGROUND: The present study sought to investigate the short-term effects of different delivery methods on postpartum pelvic floor function in Chinese primiparas. METHODS: Primiparous women who delivered a full-term, cephalic, singleton infant at our hospital between January 1, 2018 and August 15, 2019 were recruited into this study. All women underwent pelvic floor function screening at 6-8 weeks postpartum. Tests included postpartum Pelvic Organ Prolapse Quantification (POP-Q) score, incidence of urinary incontinence, pelvic floor muscle (PFM) strength, and Pelvic Floor Distress Inventory Questionnaire-Short Form 20 (PFDI-20) score. RESULTS: A total of 284 postpartum women were recruited into the study. Of the participants, 147 had undergone vaginal delivery, 37 had undergone intrapartum cesarean delivery (ICD), and 100 had undergone elective cesarean delivery (ECD). Points Aa, Ba, Ap, and Bp showed a greater degree of prolapse in the vaginal delivery group than in the ECD group (P≤0.05). UI was less prevalent in ECD group relative to the vaginal delivery group (P≤0.05). Tonic PFM contraction was weaker in the vaginal delivery group than in the ECD and ICD groups (P≤0.05). Significant differences were also observed between the vaginal delivery group and the ECD group with respect to PFDI-20 scores (P≤0.05). CONCLUSIONS: Compared with vaginal delivery, ECD was strongly linked to a lower risk of pelvic organ prolapse (POP) and UI, stronger tonic PFM strength, and lower PFDI-20 scores. ECD confers relatively better protection against pelvic floor dysfunction (PFD) than does ICD.

Determination of parecoxib and valdecoxib in rat plasma by UPLC-MS/MS and its application to pharmacokinetics studies.

BACKGROUND: The present study aimed to develop and validate a rapid, selective, and reproducible ultra-performance liquid chromatography-tandem mass spectrometry separation method for the simultaneous determination of the levels of parecoxib and its main metabolite valdecoxib in rat plasma. Moreover, this method was applied to investigate the pharmacokinetics of parecoxib and valdecoxib in rats. METHODS: Following the addition of celecoxib as an internal standard, one-step protein precipitation by acetonitrile was used for sample preparation. The effective chromatographic separation was carried out using an ACQUITY UPLC®BEH C18 reversed phase column (2.1 mm × 50 mm, 1.7 µm particle size) with acetonitrile and water (containing 0.1% formic acid) as the mobile phase. The procedure was performed in less than 3 min with a gradient elution pumped at a flow rate of 0.4 ml/min. The electrospray ionization source was applied and operated in the positive ion mode and multiple reaction monitoring mode was used for quantification using the following: target fragment ions: m/z 371 → 234 for parecoxib, m/z 315 → 132 for valdecoxib and m/z 382 → 362 for celecoxib. RESULTS: The method validation demonstrated optimal linearity over the range of 50-10,000 ng/ml (r2 ≥ 0.9996) and 2.5-500 ng/ml (r2 ≥ 0.9991) for parecoxib and valdecoxib in rat plasma, respectively. CONCLUSIONS: The present study demonstrated a simple, sensitive and applicable method for the quantification of parecoxib and its main pharmacologically active metabolite valdecoxib following sublingual vein administration of 5 mg/kg parecoxib in rats.

Design and Synthesis of Novel Nordihydroguaiaretic Acid (NDGA) Analogues as Potential FGFR1 Kinase Inhibitors With Anti-Gastric Activity and Chemosensitizing Effect.

Aberrant fibroblast growth factor receptor-1 (FGFR1), a key driver promoting gastric cancer (GC) progression and chemo-resistance, has been increasingly recognized as a potential therapeutic target in GC. Hereon, we designed and synthesized a series of asymmetric analogues using Af23 and NDGA as lead compounds by retaining the basic structural framework (bisaryl-1,4-dien-3-one) and the unilateral active functional groups (3,4-dihydroxyl). Thereinto, Y14 showed considerable inhibitory activity against FGFR1. Next, pharmacological experiments showed that Y14 could significantly inhibit the phosphorylation of FGFR1 and its downstream kinase AKT and ERK, thus inhibiting the growth, survival, and migration of gastric cancer cells. Furthermore, compared with 5-FU treatment alone, the combination of Y14 and 5-FU significantly reduced the phosphorylation level of FGFR1, and enhanced the anti-cancer effect by inhibiting the viability and colony formation in two gastric cancer cell lines. These results confirmed that Y14 exerted anti-gastric activity and chemosensitizing effect by inhibiting FGFR1 phosphorylation and its downstream signaling pathway in vitro. This work also provides evidence that Y14, an effective FGFR1 inhibitor, could be used alone or in combination with chemotherapy to treat gastric cancer in the future.

[Six cases with Behcet's disease presenting cervical ulcer].

OBJECTIVE: To investigate the clinical feature and strategy on diagnosis and treatment of cervical ulcer in Behcet's disease. METHODS: From Jan 2000 to Apr 2008, the medical documents of 6 cases with cervical ulcer in Behcet's disease were reviewed retrospectively, who were treated in No.2 hospital affiliated to Wenzhou Medical School RESULTS: (1) General information: all 6 patients with cervical ulcer were diagnosed as Behcet's disease clinically, the mean age of all patients is 33.5 years. (2) CLINICAL FEATURE: the initial symptoms was oral ulcer in 5 cases and erythematic nodosum in 1 case. The typical characteristics of cervical ulcer in Behcet's disease was vaginal purulent discharge. Five among 6 cases presented it. The cervical ulcer in Behcet's disease exhibited the following features: the isolated well-defined ulcers with different size and different deep distributed on the uterine cervix, and the top of ulcer was covered by yellow discharge which was not easy to erase. The duration between the onset symptom and cervical ulcer was calculated to be 2.1 to 7 years. (3) Risk factors for cervical ulcer: operation of drawing intrauterine devices (IUD) in 2 cases, artifical abortion in 2 cases, cervical biopsy in 1 cases, and no factors in the other one case was identified. (4) TREATMENT: The cervical ulcer in Behcet's disease can be treated by the topical application of recombinant bovine basic fibroblast growth factor (rb-bFGF). If ulcer disease existing in other site, systemic corticosteroids management was warranted. (5) Recurrence: 1 case with recurrent disease was observed after 8 months when completing treatment, the other 5 cases did not show recurrence during 3 months-8 years follow-up. CONCLUSIONS: The cervical ulcer in Behcet's disease most commonly occurred after cervical operation. The diagnosis should be derived from comprehensive symptoms analysis. The topical application of rb-bFGF on ulcer site of cervix could get satisfied outcome. When necessary, systemic corticosteroids administration could be considered.

Quick synthesis of a novel combinatorial delivery system of siRNA and doxorubicin for a synergistic anticancer effect.

Purpose: Combining siRNA and other chemotherapeutic agents into one nanocarrier can overcome the multidrug resistance (MDR) phenomenon by synergistically MDR relative genes silencing and elevated chemotherapeutic activity. Most of these systems are typically fabricated through complicated procedures, which involves materials preparation, drug loading and modifications. Herein, the purpose of this study is to develop a new and fast co-delivery system of siRNA and doxorubicin for potentially synergistic cancer treatment. Methods: The co-delivery system is constructed conveniently by a stable complex consisting of doxorubicin bound to siRNA via intercalation firstly, followed by interacting with (3-Aminopropyl)triethoxysilane (APTES) electrostatically and Tetraethyl orthosilicate (TEOS) co-condensed, and the characterizations of the resultant nanocarrier are also investigated. Furthermore, this study evaluates the synergistic anti-cancer efficacy in MCF-7/MDR cells after treatment of siRNA and doxorubicin 'two in one' nanocarriers. Results: We establish a new and fast method to craft a co-delivery system of siRNA and doxorubicin with controllable and nearly uniform size, and the entire fabrication process only costs in about 10 minutes. The resultant co-delivery system presents high loading capacities of siRNA and doxorubicin, and the encapsulated doxorubicin plays a pH-responsive control release. Further, biological functionality tests of the synthesized co-delivery nanocarriers show high inhibition of P-gp protein encoded by MDR-1 gene in MCF-7/MDR cells (a variant of human breast cancer cell line with drug resistance) after transfection of these nanocarriers carrying MDR-1 siRNA and doxorubicin simultaneously, which sensitize the MCF-7/MDR cells to doxorubicin, overall leading to improved cell suppression. Conclusion: Collectively, this co-delivery system not only serves as potent therapeutics for synergistic cancer therapy, it also may facilitate the bench-to-bedside translation of combinatorial delivery system as a robust drug nanocarrier by allowing for fabricating a simply and fast nanocarrier for co-delivery of siRNA and doxorubicin with predictable high production rate.