Pacidusin B isolated from Phyllanthus acidus triggers ferroptotic cell death in HT1080 cells.

Cancer cells generally exhibit 'iron addiction' phenotypes, which contribute to their vulnerability to ferroptosis inducers. Ferroptosis is a newly discovered form of programmed cell death caused by iron-dependent lipid peroxidation. In the present study, pacidusin B, a dichapetalin-type triterpenoid from Phyllanthus acidus (L.) Skeels (Euphorbiaceae), induces ferroptosis in the HT1080 human fibrosarcoma cell line. Cells treated with pacidusin B exhibited the morphological characteristic 'ballooning' phenotype of ferroptosis. The biochemical hallmarks of ferroptosis were also observed in pacidusin B-treated cells. Both oxidative stress and ER stress play significant roles in pacidusin B-induced ferroptosis. The activation of the PERK-Nrf2-HO-1 signaling pathway led to iron overload, while inhibition of GPX4 further sensitized cancer cells to ferroptosis. Furthermore, the molecular docking study showed that pacidusin B docked in the same pocket in xCT as the ferroptosis inducer erastin. These results revealed that pacidusin B exerts anticancer effects via inducing ER-mediated ferroptotic cell death.

Impacts of reclamation marsh restoration on greenhouse gas emission in the Sanjiang Plain, China.

To understand the variations in greenhouse gas fluxes during the process of returning cropland to wetland in the Sanjiang Plain, we selected naturally restored wetlands of 4, 7, 11, 16 and 20 years as research objects to compare with a cultivated site (soybean plantation for 13 years) and an uncultivated marsh dominated by Deyeuxia purpurea and Carex schmidtii. We measured carbon dioxide (CO2) and methane (CH4) fluxes using a static chamber-gas chromatography and explored the main influencing factors. The results showed that there were seasonal variations in growing-season CO2 and CH4 fluxes of the restored wetlands, with the seasonal trends in greenhouse gases becoming gradually similar to that of natural marsh with increasing restoration time. The mean growing-season CO2 fluxes increased during the early stage of restoration, but then decreased during the late stage, which decreased from 893.4 mg·m-2·h-1 to 494.0 mg·m-2·h-1 in the 4-year and 20-year sites, respectively. Mean CH4 fluxes increased with restoration time, ranging from a weak CH4 sink (soybean fields, -0.6 mg·m-2·h-1) to a CH4 source of 87.8 mg·m-2·h-1(20-year restored site). The CH4 fluxes of experimental plots were consistently lower than that of natural marsh (96.4 mg·m-2·h-1). Increases in water level and soil conductivity resulting from restoration were the main driving factors for the decrease in CO2 fluxes. The increases in water level and soil dissolved organic carbon resulting from restoration were the primary drivers for the increase of CH4 fluxes in the restored wetlands. The global warming potentials increased with restoration time, ranging from 27.8 t·CO2-eq·hm-2(soybean fields) to 130.8 t·CO2-eq·hm-2(plot of 20-year restoration), which gradually approached that of natural marsh (156.3 t·CO2-eq·hm-2). The emission of GHGs from restored wetlands in the Sanjiang Plain gradually approached those of natural marsh. Further monitoring is required to identify the maturity of restored wetlands for achieving greenhouse gas emissions equivalent to that of natural marshland.

Risk of Severe COVID-19 in Prevalent Users of Alpha-1 Adrenergic Receptor Antagonists: A National Case-Control Study of Medicare Beneficiaries.

BACKGROUND: Alpha-1 adrenergic receptor antagonists prevent cytokine storm in mouse sepsis models. This led to the hypothesis that alpha-1 blockers may prevent severe coronavirus disease 2019 (COVID-19), which is characterized by hypercytokinemia and progressive respiratory failure. METHODS: We performed an observational case-control study in male Medicare beneficiaries aged 65 years or older, with or without benign prostatic hyperplasia (BPH), and treated with alpha-1 receptor blockers or 5-alpha reductase inhibitors. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were estimated for outcomes of uncomplicated and severe COVID-19 hospitalization (intensive care unit admission, invasive mechanical ventilation, or death). RESULTS: There were 20,963 cases of hospitalized COVID-19 matched to 101,161 controls on calendar date and neighborhood of residence. In the primary analysis (males with BPH), there was no difference in risk of uncomplicated COVID-19 hospitalization (aOR 1.08, 95% CI 0.996-1.17) or hospitalization with severe complications (aOR 0.97, 95% CI 0.88-1.08). In the secondary analysis (males with or without BPH), the corresponding aORs were 1.02 (95% CI, 0.96-1.09) (uncomplicated) and 0.99 (95% CI, 0.91-1.07) (complicated), respectively. Subgroup and sensitivity analyses yielded similar results. Of note, there was no difference in risk of severe COVID-19 hospitalization when comparing non-selective vs selective alpha-1 blocker use (aOR 0.98, 95% CI 0.86-1.10), higher- vs lower-dose alpha-1 blocker use (aOR 0.96, 95% CI 0.86-1.08), or current vs remote alpha-1 blocker use (aOR 1.04, 95% CI 0.91-1.18). CONCLUSIONS: Prevalent use of alpha-1 receptor blockers was not associated with a protective or harmful effect on risk of uncomplicated or severe hospitalized COVID-19.

Acute pain pathways: protocol for a prospective cohort study.

INTRODUCTION: Opioid analgesics are often used to treat moderate-to-severe acute non-cancer pain; however, there is little high-quality evidence to guide clinician prescribing. An essential element to developing evidence-based guidelines is a better understanding of pain management and pain control among individuals experiencing acute pain for various common diagnoses. METHODS AND ANALYSIS: This multicentre prospective observational study will recruit 1550 opioid-naïve participants with acute pain seen in diverse clinical settings including primary/urgent care, emergency departments and dental clinics. Participants will be followed for 6 months with the aid of a patient-centred health data aggregating platform that consolidates data from study questionnaires, electronic health record data on healthcare services received, prescription fill data from pharmacies, and activity and sleep data from a Fitbit activity tracker. Participants will be enrolled to represent diverse races and ethnicities and pain conditions, as well as geographical diversity. Data analysis will focus on assessing patients' patterns of pain and opioid analgesic use, along with other pain treatments; associations between patient and condition characteristics and patient-centred outcomes including resolution of pain, satisfaction with care and long-term use of opioid analgesics; and descriptive analyses of patient management of leftover opioids. ETHICS AND DISSEMINATION: This study has received approval from IRBs at each site. Results will be made available to participants, funders, the research community and the public. TRIAL REGISTRATION NUMBER: NCT04509115.

Identification of limonoids from Walsura yunnanensis and evaluation of their cytotoxicity against cancer cell lines.

Three new limonoids, walsurauias A-C (1-3), along with four known ones, were isolated from the leaves and twigs of Walsura yunnanensis C. Y. Wu. Their structures were determined on the basis of comprehensive spectroscopic data analysis. The new limonoids were screened for their cytotoxic activity (IC50 0.81-5.73 µM) against four human cancer cell lines, including A549, HepG2, HCT116 p21KO and CNE-2. And α,ß-unsaturated ketone moieties in rings A and B are essential for their cytotoxic activity. Selected compounds were further investigated. Compounds 1-3 effectively induced G2/M cell cycle arrest and apoptosis in a dose-dependent manner in cancer cells. In addition, compounds 1-3 inhibited the colony formation and compounds 2 and 3 suppressed the migration of cancer cells.

Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells.

Rationale: Colorectal cancer (CRC) is a common malignant tumor of the digestive system. However, the efficacy of surgery and chemotherapy is limited. Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death (RCD) and plays a vital role in tumor suppression. Ferroptosis inducing agents have been studied extensively as a novel promising way to fight against therapy resistant cancers. The aim of this study is to investigate the mechanism of action of tagitinin C (TC), a natural product, as a novel ferroptosis inducer in tumor suppression. Methods: The response of CRC cells to tagitinin C was assessed by cell viability assay, clonogenic assay, transwell migration assay, cell cycle assay and apoptosis assay. Molecular approaches including Western blot, RNA sequencing, quantitative real-time PCR and immunofluorescence were employed as well. Results: Tagitinin C, a sesquiterpene lactone isolated from Tithonia diversifolia, inhibits the growth of colorectal cancer cells including HCT116 cells, and induced an oxidative cellular microenvironment resulting in ferroptosis of HCT116 cells. Tagitinin C-induced ferroptosis was accompanied with the attenuation of glutathione (GSH) levels and increased in lipid peroxidation. Mechanistically, tagitinin C induced endoplasmic reticulum (ER) stress and oxidative stress, thus activating nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). As a downstream gene (effector) of Nrf2, heme oxygenase-1 (HO-1) expression increased significantly with the treatment of tagitinin C. Upregulated HO-1 led to the increase in the labile iron pool, which promoted lipid peroxidation, meanwhile tagitinin C showed synergistic anti-tumor effect together with erastin. Conclusion: In summary, we provided the evidence that tagitinin C induces ferroptosis in colorectal cancer cells and has synergistic effect together with erastin. Mechanistically, tagitinin C induces ferroptosis through ER stress-mediated activation of PERK-Nrf2-HO-1 signaling pathway. Tagitinin C, identified as a novel ferroptosis inducer, may be effective chemosensitizer that can expand the efficacy and range of chemotherapeutic agents.

Occurrence of adverse events among patients with inflammatory bowel disease in the HealthCore Integrated Research Database.

OBJECTIVES: Inflammatory bowel disease (IBD) is a chronic condition commonly requiring lifelong care. Both IBD and IBD-related treatments can cause significant morbidity, and it is often difficult to differentiate their relative etiologic contribution to adverse events (AEs). The objectives of this study were to assess the rates of select AEs among patients with IBD as a function of disease severity and of the use of anti-tumor necrosis factor alpha (anti-TNFα) medications. METHODS: We conducted a retrospective cohort study of IBD patients in the HealthCore Integrated Research Database (HIRD(TM)) between January 2004 and January 2011 to determine rates of AEs in patients with mild and moderate to severe IBD. Key study endpoints were select prespecified malignant neoplasms, infections, and other AEs of interest. RESULTS: A total of 33,386 IBD patients (52.7% ulcerative colitis; 47.3% Crohn's disease) met the inclusion criteria, and 60% had been followed for ≥1 year. Patients with moderate to severe IBD had increased rates of infections, lymphatic and digestive tract cancers, gastrointestinal (GI) perforations, and myocardial infarctions versus patients with mild IBD. Patients with IBD who used anti-TNFα therapies during the study had increased incidence of many types of infections, certain GI cancers (including rectal and anal cancer), intestinal perforations, and kidney stones compared with patients who had never used anti-TNFα therapies. CONCLUSIONS: Results from this large US cohort provide descriptive information on AE rates in a population of IBD patients undergoing routine care, estimating background incidence rates of AEs that are not readily available in the published literature. Our study findings may be limited owing to a lack of generalizability and potential for misclassification due to reliance on medical diagnosis and treatment and procedure codes to identify disease, comorbidities, and treatments. Further research and validation of our findings in other populations and databases are needed.

Orodental manifestations of facial port-wine stains.

BACKGROUND: Patients with facial port-wine stains (PWS) often demonstrate oral manifestations of their disorder; however, the spectrum and prevalence of such findings among a cohort of patients with PWS has not been established. As a result, dermatologists and oral health specialists may be uncertain how to counsel their patients with PWS regarding oral hypervascularity, bony oral changes, and oral hygiene. OBJECTIVES: We sought to identify physical findings and complications involving the teeth, oral cavity, and perioral structures in individuals with facial PWS. METHODS: This was a cross-sectional study of 30 patients with facial PWS. Descriptive data were collected through anonymous paired surveys completed by patients and their dentists, and analyzed (Fisher exact test) for trends based on physical findings and stage of the PWS. RESULTS: The most common orodental manifestations according to patients were enlargement of the lip (53.3%), stained gums (46.7%), abnormal bite (30%), and spontaneous bleeding of the gums (26.7%). Staining of the gingiva correlated significantly with gingival hyperplasia (P = .006), maxillary hyperplasia (P = .014), and widened interdental spaces (P = .002), and in all cases gingival staining predated these findings. Lip hyperplasia was reported more frequently by patients than by their dentists (50% vs 18.2%, P = .008). Orodental manifestations were more common among patients with darker and thicker PWS. Hemorrhage after dental procedures was rare (4.5%). LIMITATIONS: Modest sample size and difficulty recruiting control subjects are limitations. CONCLUSIONS: Facial PWS commonly affect the orodental structures, and intraoral staining may predict future complications.

Three-dimensional white light camera to aid lipoabdominoplasty: a pilot project.

BACKGROUND: Historically, torso obesity has been difficult to quantify. Digital technology has recently encroached into body contouring surgery but has not been developed by surgeons to aid with their anatomical mandates. METHODS: For 3 years, the authors tested a three-dimensional digital body camera that used nonintrusive white light phase profilometry to produce a "point cloud" image of the subject. The result of the 2-minute scan process was an accurate three-dimensional body model of the subject, consisting of over 1.2 million surface points. The point cloud was compressed to provide programmable measurement extraction profiles that automatically extracted linear and circumferential measurements. Subjects were scanned and anthropometrically measured preoperatively and at 3, 6, and 9 months postoperatively. Seven circumferential measures (waist, hips, abdomen, bilateral thighs, and bilateral knees) were collected. RESULTS: Fifty-two lipoabdominoplasty subjects participated in this pilot project. Lin's correlation coefficient was used to compare concordance between camera scan and anthropometric measurements and to compare the camera's reliability. When Lin's correlation coefficient was applied to our data, the composite Lin's correlation coefficient comparisons between the camera and anthropometric measurements were 0.9663 ± 0.0035 preoperatively and 0.9634 ± 0.0027 postoperatively. Anthropometric hip, waist, abdominal, and thigh circumferences all correlated closely with digital white light technology preoperatively (waist, 0.8602; hip, 0.6705; and abdomen, 0.8033) and improved at 6 months postoperatively (waist, 0.9197; and abdomen, 0.8031). CONCLUSION: In this project, Lin's correlation coefficient indicated that the digital camera was as accurate as and more efficient than anthropometric measuring for circumferential measurements.

Effect of axonal load on the functional and aesthetic outcomes of the cross-facial nerve graft procedure for facial reanimation.

BACKGROUND: To improve the ability to prognosticate the final surgery outcomes, this study was carried out to explore the correlation between the number of motor axons given to cross-facial nerve grafts for smile restoration and the aesthetic and functional outcomes. METHODS: Sixty-nine cases had adequate nerve biopsy specimens and were selected for the authors' study. Patient information was collected from chart review. Using Terzis' evaluation scale, smile functional and aesthetic outcomes as depicted in standardized videos were graded by a panel of four independent reviewers. Digital images of nerve specimens in stages I and II were obtained by using a microscope with a digital camera attachment. Using MetaMorph software, the number of motor axons was calculated, with the exception of the nerve specimens at the distal nerve grafts in stage II, which were quantitated manually. Mann-Whitney and Fisher's exact tests were used to test the effects of axon numbers and other factors on the outcomes. RESULTS: The donor axonal input correlated with the axon number at the distal end of the nerve graft and also correlated with the improvement of evaluation; however, no significance was found between the counts at the distal end of the nerve graft and the clinical outcomes. An important observation was that patients with a donor nerve count of 900 or higher showed a greater likelihood of achieving satisfactory results. CONCLUSION: The axon count at the donor nerve has a stronger influence on the final results.

Polycystic ovary syndrome, body mass index and outcomes of assisted reproductive technologies.

The purpose of this study was to examine the effects of polycystic ovary syndrome (PCOS) and body mass index (BMI) on selected indicators of IVF or intracytoplasmic sperm injection (ICSI) treatment success. A retrospective cohort study was conducted using existing data on 69 IVF/ICSI treatment cycles undergone by PCOS women and an individually matched sample of 69 IVF/ICSI treatment cycles undergone by non-PCOS women at a major fertility treatment centre. BMI (kg/m(2)) was analysed as a continuous and categorical (<25, 25-29.9, > or =30)variable. Results indicated that PCOS was directly associated with the number of oocytes retrieved. Irrespective of PCOS status, continuous BMI was inversely associated with total and mature oocytes retrieved. Multiple linear regression analyses indicated no significant effects of PCOS or continuous BMI on the number of mature oocytes fertilized per mature oocyte retrieved or inseminated. Similarly, multiple logistic regression analyses suggested no significant effect of PCOS and continuous BMI on the odds of pregnancy, miscarriage or live birth. Furthermore, categorical BMI did not influence process and outcome measures of IVF/ICSI treatment success. PCOS and continuous BMI appear to have significant and distinct effects on early stages, but not on later stages, of IVF/ICSI treatment.

Effects of doxycycline on serum and endometrial levels of MMP-2, MMP-9 and TIMP-1 in women using a levonorgestrel-releasing subcutaneous implant.

BACKGROUND: Endometrial spotting and/or bleeding (ESB) occurs in levonorgestrel subcutaneous implant (LNG SI) users. Matrix metalloproteinases (MMPs) may play a role in ESB. STUDY DESIGN: Women between 18 and 40 years with regular menstrual cycles had a baseline evaluation followed by LNG SI insertion and randomization to doxycycline (DOX; 20 mg) or placebo (PL) twice a day. MMP-2, MMP-9 and tissue inhibitor of MMP-1 (TIMP-1) in serum and the endometrium were estimated at baseline and at 1, 3 and 6 months after insertion. RESULTS: LNG increased serum MMP-9, while DOX decreased MMP-9 levels compared to PL after 1 month (p<.05). DOX decreased endometrial MMP-9 at 1 and 6 months compared to baseline and PL (p<.05). DOX increased endometrial TIMP-1 at 6 months compared with baseline and PL (p<.05). MMP-2 levels were unchanged. CONCLUSION: LNG SI increased serum MMP-9 and TIMP-1 levels, while DOX decreased both serum and endometrial MMP-9 levels.

Impact of polycystic ovary syndrome on selected indicators of in vitro fertilization and intracytoplasmic sperm injection treatment success.

OBJECTIVES: To examine the effect of polycystic ovary syndrome (PCOS), a marker of the metabolic syndrome, on selected indicators of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment success. METHODS: A retrospective cohort study was conducted using existing data on 69 IVF/ICSI treatment cycles undergone by PCOS women and a caliper-matched sample of 69 IVF/ICSI treatment cycles undergone by non-PCOS women over a 7-year period at a major fertility treatment center. Matching criteria were age and date at IVF/ICSI treatment initiation. Process and outcome measures were used to define successful IVF/ICSI treatment. Statistical significance was determined at an alpha level of 0.05. RESULTS: The total number of oocytes and the number of immature oocytes retrieved in the process of an IVF/ICSI cycle were significantly higher in the context of PCOS. No significant differences were observed among PCOS and non-PCOS groups on various IVF/ICSI cycle outcomes, including high-grade embryo, pregnancy achievement, miscarriage, and live birth status. CONCLUSIONS: Although IVF/ICSI yields more oocytes in the context of PCOS, IVF/ICSI outcomes do not differ significantly by PCOS status. Prospective cohort studies are needed to examine short-term and long-term health effects of PCOS in the context of IVF/ICSI.

Short term changes in melatonin and cortisol serum levels after a single administration of estrogen to menopausal women.

OBJECTIVES: It has been well-documented that serum melatonin levels are insensitive to estrous or menstrual ovarian steroid variations in the female rat or the human. However, a negative coupling has been already demonstrated between the nocturnal serum melatonin peak and serum E2 concentration during the late premenopausal period in the woman. The objection of the present study was designed to determine if diurnal serum melatonin values can be also lowered by a single administration of estrogen. METHODS: We performed a detailed analysis of variations of serum estradiol, LH, FSH, melatonin and cortisol after one single I.M. injection of 2 mg of a conjugated estrogen, delestrogen (estradiol valerate) in 0.1 ml of oil. A 15 ml blood collection was done at 8:00 a.m. before the injection, and at 8:30 a.m., 9:00 a.m., 10:00 a.m., 12:00 noon, and 4:00 p.m. 17beta-estradiol, LH and FSH were determined by microparticle enzyme immunoassays kits. Melatonin determination was made using a RIA kit and cortisol was assayed by a RIA method. RESULTS: A significant rise in serum 17beta-estradiol was already seen by one hour after the injection of estradiol valerate. Then, an almost linear increase was observed up to at last eight hours after the injection of estradiol valerate. A significant decrease in serum LH was not seen before four hours after the injection of estradiol valerate. Overall, there was a trend toward a decline in serum melatonin and cortisol concentration. The decreasing trend of cortisol serum level was tested as significant over time (p< 0.001). However, the decrease in serum concentration did not reach a significant level for melatonin. CONCLUSION: Overall, these results show that after menopause an acute administration of estrogen during the early diurnal period of the day leads to a significant rapid decrease in cortisol serum values, but to only a partial non significant decrease in melatonin serum values.