CTLA4-Ig protects tacrolimus-induced oxidative stress via inhibiting the AKT/FOXO3 signaling pathway in rats.

BACKGROUND/AIMS: Although the conversion from tacrolimus (TAC) to cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig) is effective in reducing TAC-induced nephrotoxicity, it remains unclear whether CTLA4-Ig has a direct effect on TAC-induced renal injury. In this study, we evaluated the effects of CTLA4-Ig on TAC-induced renal injury in terms of oxidative stress. METHODS: In vitro study was performed to assess the effect of CTLA4-Ig on TAC-induced cell death, reactive oxygen species (ROS), apoptosis, and the protein kinase B (AKT)/forkhead transcription factor (FOXO) 3 pathway in human kidney 2 cells. In the in vivo study, the effect of CTLA4-Ig on TAC-induced renal injury was evaluated using renal function, histopathology, markers of oxidative stress (8-hydroxy-2'-deoxyguanosine) and metabolites (4-hydroxy-2-hexenal, catalase, glutathione S-transferase, and glutathione reductase), and activation of the AKT/FOXO3 pathway with insulin-like growth factor 1 (IGF-1). RESULTS: CTLA4-Ig significantly decreased cell death, ROS, and apoptosis caused by TAC. TAC treatment increased apoptotic cell death and apoptosis-related proteins (increased Bcl-2-associated X protein and caspase-3 and decreased Bcl-2), but it was reversed by CTLA4-Ig treatment. The activation of p-AKT and p-FOXO3 by TAC decreased with CTLA4-Ig treatment. TAC-induced renal dysfunction and oxidative marker levels were significantly improved by CTLA4-Ig in vivo. Concomitant IGF-1 treatment abolished the effects of CTLA4-Ig. CONCLUSION: CTLA4-Ig has a direct protective effect on TAC-induced renal injury via the inhibition of AKT/FOXO3 pathway.

Comparison of thoracoabdominal versus abdominal-transhiatal surgical approaches in Siewert type II adenocarcinoma at the esophagogastric junction: Protocol for a prospective multicenter randomized controlled trial.

Background: Siewert type II adenocarcinoma of the esophagogastric junction (Siewert II AEG) can be resected by the right thoracoabdominal surgical approach (RTA) or abdominal-transhiatal surgical approach (TH) under minimally invasive conditions. Although both surgical methods achieve complete tumor resection, there is a debate as to whether the former method is superior to or at least noninferior to the latter in terms of surgical safety. Currently, a small number of retrospective studies have compared the two surgical approaches, with inconclusive results. As such, a prospective multicenter randomized controlled trial is necessary to validate the value of RTA (Ivor-Lewis) compared to TH. Methods: The planned study is a prospective, multicenter, randomized clinical trial. Patients (n=212) with Siewert II AEG that could be resected by either of the above two surgical approaches will be included in this trial and randomized to the RTA group (n=106) or the TH group (n=106). The primary outcome will be 3-year disease-free survival (DFS). The secondary outcomes will include 5-year overall survival (OS), incidence of postoperative complications, postoperative mortality, local recurrence rate, number and location of removed lymph nodes, quality of life (QOL), surgical Apgar score, and duration of the operation. Follow-ups are scheduled every three months for the first 3 years after the surgery and every six months for the next 2 years. Discussion: Among Siewert II AEG patients with resectable tumors, this is the first prospective, randomized clinical trial comparing the surgical safety of minimally invasive RTA and TH. RTA is hypothesized to provide better digestive tract reconstruction and dissection of mediastinal lymph nodes while maintaining a high quality of life and good postoperative outcome. Moreover, this trial will provide a high level of evidence for the choice of surgical procedures for Siewert II AEG. Clinical trial registration: Chinese Ethics Committee of Registering Clinical Trials, identifier (ChiECRCT20210635); Clinical Trial.gov, identifier (NCT05356520).

Enhanced external counterpulsation modulates the heartbeat evoked potential.

Introduction: Accumulating evidence suggests that enhanced external counterpulsation (EECP) influences cardiac functions, hemodynamic characteristics and cerebral blood flow. However, little is known about whether or how the EECP affects the brain-heart coupling to produce these physiological and functional changes. We aimed to determine if the brain-heart coupling is altered during or after EECP intervention by assessing the heartbeat evoked potential (HEP) in healthy adults. Methods: Based on a random sham-controlled design, simultaneous electroencephalography and electrocardiography signals as well as blood pressure and flow status data were recorded before, during and after two consecutive 30-min EECP in 40 healthy adults (female/male: 17/23; age: 23.1 ± 2.3 years). HEP amplitude, frequency domain heart rate variability, electroencephalographic power and hemodynamic measurements of 21 subjects (female/male: 10/11; age: 22.7 ± 2.1 years) receiving active EECP were calculated and compared with those of 19 sham control subjects (female/male: 7/12; age: 23.6 ± 2.5 years). Results: EECP intervention caused immediate obvious fluctuations of HEP from 100 to 400 ms after T-peak and increased HEP amplitudes in the (155-169) ms, (354-389) ms and (367-387) ms time windows after T-peak in the region of the frontal pole lobe. The modifications in HEP amplitude were not associated with changes in the analyzed significant physiological measurements and hemodynamic variables. Discussion: Our study provides evidence that the HEP is modulated by immediate EECP stimuli. We speculate that the increased HEP induced by EECP may be a marker of enhanced brain-heart coupling. HEP may serve as a candidate biomarker for the effects and responsiveness to EECP.

Irradiation stent with 125I plus tace versus sorafenib plus tace for hepatocellular carcinoma with major portal vein tumor thrombosis: a multicenter randomized trial.

BACKGROUND AND AIM: Treatment strategy of hepatocellular carcinoma (HCC) and Vp4 [main trunk] portal vein tumor thrombosis (PVTT) remains limited due to post treatment liver failure. We aimed to assess the efficacy of irradiation stent placement with 125I plus transcatheter arterial chemoembolization (TACE) (ISP-TACE) compared to sorafenib plus TACE (Sora-TACE) in these patients. METHODS: In this multicenter randomized controlled trial, participants with HCC and Vp4 PVTT without extrahepatic metastases were enrolled from November 2018 to July 2021 at 16 medical centers. The primary endpoint was overall survival (OS). The secondary endpoints were hepatic function, time to symptomatic progression, patency of portal vein, disease control rate, and treatment safety. RESULTS: Of 105 randomized participants, 51 were assigned to the ISP-TACE group, 54 were assigned to the Sora-TACE group. The median OS was 9.9 months versus 6.3 months (95% CI: 0.27, 0.82; P=0.01). Incidence of acute hepatic decompensation was 16% (8 of 51) versus 33% (18 of 54) (P=0.036). The time to symptomatic progression was 6.6 months versus 4.2 months (95% CI: 0.38,0.93; P=0.037). The median stent patency was 7.2 months (interquartile range, 4.7-9.3) in the ISP-TACE group. The disease control rate was 86% (44 of 51) versus 67% (36 of 54) (P=0.018). Incidences of adverse events ≥ grade 3 were comparable between the safety populations of the two groups: 16 of 49 (33%) versus 18 of 50 (36%) (P=0.73). CONCLUSION: Irradiation stent placement plus TACE showed superior results compared with sorafenib plus TACE in prolonging OS in patients with HCC and Vp4 PVTT.

Maternal exposure to fine particulate matter and brain-derived neurotrophic factor (BDNF) in the fetus: A prospective cohort study.

Maternal exposure to ambient fine particulate matter (PM2.5) during pregnancy has been associated with impaired neurobehavioral development in children. However, the specific mechanism remains unclear. Brain derived neurotrophic factor (BDNF) is an important growth factor in the nervous system. We evaluated the associations of maternal PM2.5 exposures with fetal BDNF in the umbilical cord blood in a prospective cohort study. A total of 711 eligible mother-infant pairs from the Shanghai Birth Cohort were included in the current study. Daily maternal exposures to ambient PM2.5 were assessed with a gap-filling approach at 1 * 1 km2 resolution based on self-reported home addresses. The concentrations of BDNF in the cord blood were measured by ELISA. A linear regression model was applied to evaluate the association of maternal ambient PM2.5 exposure with fetal BDNF level at birth. The median concentration of BDNF was 13,403 pg/ml. Vaginal deliveries and female infants had higher BDNF levels than cesarean deliveries and male infants. One natural log (ln) unit increase in maternal PM2.5 exposure during the second trimester was significantly associated with - 0.20 (95% CI: -0.36, -0.05) ln-unit decrease in BDNF level in all births. These effects were stronger and more significant in vaginal deliveries and in male infants. Our study suggests that BDNF in the cord blood may serve as a potential biomarker in assessing the neurodevelopmental effects of maternal PM2.5 exposure.

Progresses in lignin, cellulose, starch, chitosan, chitin, alginate, and gum/carbon nanotube (nano)composites for environmental applications: A review.

Water sources are becoming increasingly scarce, and they are contaminated by industrial, residential, and agricultural waste-derived organic and inorganic contaminants. These contaminants may pollute the air, water, and soil and invade the ecosystem. Because carbon nanotubes (CNTs) can undergo surface modification, they can combine with other substances to create nanocomposites (NCs), including biopolymers, metal nanoparticles, proteins, and metal oxides. Furthermore, biopolymers are significant classes of organic materials that are widely used for various applications. They have drawn attention due to their benefits, such as environmental friendliness, availability, biocompatibility, safety, etc. As a result, the synthesis of a composite made of CNT and biopolymers can be very effective for various applications, especially those involving the environment. In this review, we reported environmental applications (including removal of dyes, nitro compounds, hazardous materials, toxic ions, etc.) of composites made of CNT and biopolymers such as lignin, cellulose, starch, chitosan, chitin, alginate, and gum. Also, the effect of different factors such as the medium pH, the pollutant concentration, temperature, and contact time on the adsorption capacity (AC) and the catalytic activity of the composite in the reduction or degradation of various pollutants has been systematically explained.

Autophagy and regulation of aquaporins in the kidneys.

Aquaporins (AQPs) are water channel proteins that facilitate the transport of water molecules across cell membranes. To date, seven AQPs have been found to be expressed in mammal kidneys. The cellular localization and regulation of the transport properties of AQPs in the kidney have been widely investigated. Autophagy is known as a highly conserved lysosomal pathway, which degrades cytoplasmic components. Through basal autophagy, kidney cells maintain their functions and structure. As a part of the adaptive responses of the kidney, autophagy may be altered in response to stress conditions. Recent studies revealed that autophagic degradation of AQP2 in the kidney collecting ducts leads to impaired urine concentration in animal models with polyuria. Therefore, the modulation of autophagy could be a therapeutic approach to treat water balance disorders. However, as autophagy is either protective or deleterious, it is crucial to establish an optimal condition and therapeutic window where autophagy induction or inhibition could yield beneficial effects. Further studies are needed to understand both the regulation of autophagy and the interaction between AQPs and autophagy in the kidneys in renal diseases, including nephrogenic diabetes insipidus.

Demethylation of lignin with mild conditions and preparation of green adhesives to reduce formaldehyde emissions and health risks.

Demethylated lignin (DL) was prepared in a NaOH/urea solution at room temperature, and the DL solution was directly substituted for phenol to prepare demethylated lignin phenol formaldehyde (DLPF). The 1H NMR results showed that the benzene ring's -OCH3 content dropped from 0.32 mmol/g to 0.18 mmol/g, whereas the functional group content of the phenolic hydroxyl group increased by 176.67 %, increasing the reactivity of DL. The bonding strength of 1.24 MPa and formaldehyde emission of 0.059 mg/m3 met the Chinese national standard with a 60 % replacement of DL with phenol. The volatile organic compound (VOC) emissions of DLPF and PF were simulated, with 25 types of VOCs were found in PF plywood and 14 types found in DLPF plywood. Terpene and aldehyde emissions from DLPF plywood rose, but total VOC emissions were 28.48 % less than those from PF. For carcinogenic risks (CR), both PF and DLPF showed ethylbenzene and naphthalene as carcinogenic VOCs, whereas DLPF had a lower total CR of 6.50 × 10-5. Both plywood had a noncarcinogenic risks of <1, which was within the permissible range to harm humans. In this study, the mild modification conditions of DL benefit its large-scale production, and DLPF effectively reduces the VOCs released from plywood in indoor environments, diminishing the health risks to humans.

The role of multi-low molecular weight organic acids on phenanthrene biodegradation: Insight from cellular characteristics and proteomics.

Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic and ubiquitous pollutants that need to be solved. The low-molecular-weight organic acid (LMWOA) holds the promise to accelerate the capacity of microbes to degrade PAHs. However, the degradation mechanism(s) with multi-LMWOAs has not been understood yet, which is closer to the complex environmental biodegradation in nature. Here, we demonstrated a comprehensive cellular and proteomic response pattern by investigating the relationship between a model PAH degrading strain, B. subtilis ZL09-26, and the mixture LMWOAs (citric acid, glutaric acid, and oxalic acid). As a result, multi-LMWOAs introduced a highly enhanced phenanthrene (PHE) degradation efficiency with up to 3.1-fold improvement at 72 h, which is accompanied by the enhancement of strain growth and activity, but the releasement of membrane damages and oxidative stresses. Moreover, a detailed proteomic analysis revealed that the synergistic perturbation of various metabolic pathways jointly governed the change of cellular behaviors and improved PHE degradation in a network manner. The obtained knowledge provides a foundation for designing the artificial LMWOAs mixtures and guides the rational remediation of contaminated soils using bio-stimulation techniques.

Application of smart devices in investigating the effects of air pollution on atrial fibrillation onset.

Few studies have examined the link between short-term exposure to air pollutants and atrial fibrillation (AF) episodes. This study aims to examine the association of hourly criteria air pollutants with AF episodes. We employ a smart device-based photoplethysmography technology to screen AF from 2018 to 2021. Hourly concentrations of six criteria air pollutants are matched to the onset hour of AF for each participant. We adopt a time-stratified case-crossover design to capture the acute effects of air pollutants on AF episodes, using conditional logistic regression models. Subgroup analyses are conducted by age, gender, and season. A total of 11,906 episodes of AF are identified in 2976 participants from 288 Chinese cities. Generally, the strongest associations of air pollutants are present at lag 18-24 h, with positive and linear exposure-response relationships. For an interquartile range increase in inhalable particles, fine particles, nitrogen dioxide, and carbon monoxide, the odds ratio (OR) of AF is 1.19 [95% confidential interval (CI): 1.03, 1.37], 1.38 (95%CI: 1.14, 1.67), 1.60 (95%CI: 1.16, 2.20) and 1.48 (95%CI: 1.19, 1.84), respectively. The estimates are robust to the adjustment of co-pollutants, and they are larger in females, older people, and in cold seasons. There are insignificant associations for sulfur dioxide and ozone. This nationwide case-crossover study demonstrates robust evidence of significant associations between hourly exposure to air pollutants and the onset of AF episodes, which underscores the importance of ongoing efforts to further improve air quality as an effective target for AF prevention.

Tdrd3-null mice show post-transcriptional and behavioral impairments associated with neurogenesis and synaptic plasticity.

The Topoisomerase 3B (Top3b) - Tudor domain containing 3 (Tdrd3) protein complex is the only dual-activity topoisomerase complex in animals that can alter the topology of both DNA and RNA. TOP3B mutations in humans are associated with schizophrenia, autism and cognitive disorders; and Top3b -null mice exhibit several phenotypes observed in animal models of psychiatric and cognitive disorders, including impairments in cognitive and emotional behaviors, aberrant neurogenesis and synaptic plasticity, and transcriptional defects. Similarly, human TDRD3 genomic variants have been associated with schizophrenia, verbal shorten-memory and learning, and educational attainment. However, the importance of Tdrd3 in normal brain function has not been examined in animal models. Here we built a Tdrd3 -null mouse strain and demonstrate that these mice display both shared and unique defects when compared to Top3b- null mice. Shared defects were observed in cognitive behaviors, synaptic plasticity, adult neurogenesis, newborn neuron morphology, and neuronal activity-dependent transcription; whereas defects unique to Tdrd3 -deficient mice include hyperactivity, changes in anxiety-like behaviors, increased new neuron complexity, and reduced myelination. Interestingly, multiple genes critical for neurodevelopment and cognitive function exhibit reduced levels in mature but not nascent transcripts. We infer that the entire Top3b-Tdrd3 complex is essential for normal brain function, and that defective post-transcriptional regulation could contribute to cognitive impairment and psychiatric disorders.

Mortality and associated risk factors between young and elderly maintenance haemodialysis patients: a multicentre retrospective cohort study in China.

OBJECTIVES: Mortality and associated risk factors in young and elderly haemodialysis patients with end-stage kidney disease (ESKD) have not been well examined in China. Therefore, we aimed to assess the all-cause mortality and risk factors associated with all-cause mortality between young and elderly haemodialysis patients in China. DESIGN: A population-based multicentre retrospective cohort study. SETTING: Using the Dialysis Initiation based on Fuzzy mathematics Equation study data, patients with ESKD undergoing maintenance haemodialysis from 24 centres in China from 1 January 2008 to 30 September 2015. PARTICIPANTS: 1601 enrolled patients with ESKD were categorised into young group (18-44 years old) and elderly (≥60 years old) group. OUTCOME MEASURES: The primary outcome was all-cause mortality. We estimated overall survival using a log-rank test. Cox proportional hazard regression analysis was implemented to identify risk factors and HR associated all-cause mortality. RESULTS: During a mean follow-up of 48.17±25.59 months, of the 1601 subjects, 319 (19.92%) patients death, including 64 (9.97%) in young group and 255 (26.59%) in elderly group, respectively. The cumulative survival in elderly group was lower than young group (Log Rank tests=63.31, p<0.001). Multivariate Cox proportional hazards analysis showed the cardiovascular disease (HR, 2.393; 95% CI 1.532 to 3.735; p<0.001), cerebrovascular disease (HR, 2.542; 95% CI 1.364 to 4.739; p=0.003) and serum albumin<3.5 g/dL (HR, 1.725; 95% CI 1.091 to 2.726; p=0.020) at the haemodialysis initiation were associated with increased risk of all-cause mortality in elderly groups; however, the cardiovascular disease only was associated with increased risk of all-cause mortality in young groups. CONCLUSIONS: The all-cause mortality of elderly haemodialysis patients were higher than young haemodialysis patients in China. Identified risk factors associated all-cause mortality may inform development of age-appropriate treatment, intervention strategies and improve survival prognosis of this unique population.

Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001).

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4-11.0) versus 8.0 months (95% CI, 6.6-9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1-27.3] vs. 15.7 months [13.0-20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

Tantalum-Zirconium Co-Doped Metal-Organic Frameworks Sequentially Sensitize Radio-Radiodynamic-Immunotherapy for Metastatic Osteosarcoma.

Due to radiation resistance and the immunosuppressive microenvironment of metastatic osteosarcoma, novel radiosensitizers that can sensitize radiotherapy (RT) and antitumor immunity synchronously urgently needed. Here, the authors developed a nanoscale metal-organic framework (MOF, named TZM) by co-doping high-atomic elements Ta and Zr as metal nodes and porphyrinic molecules (tetrakis(4-carboxyphenyl)porphyrin (TCPP)) as a photosensitizing ligand. Given the 3D arrays of ultra-small heavy metals, porous TZM serves as an efficient attenuator absorbing X-ray energy and sensitizing hydroxyl radical generation for RT. Ta-Zr co-doping narrowed the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy gap and exhibited close energy levels between the singlet and triplet photoexcited states, facilitating TZM transfer energy to the photosensitizer TCPP to sensitize singlet oxygen (1 O2 ) generation for radiodynamic therapy (RDT). The sensitized RT-RDT effects of TZM elicit a robust antitumor immune response by inducing immunogenic cell death, promoting dendritic cell maturation, and upregulating programmed cell death protein 1 (PD-L1) expression via the cGAS-STING pathway. Furthermore, a combination of TZM, X-ray, and anti-PD-L1 treatments amplify antitumor immunotherapy and efficiently arrest osteosarcoma growth and metastasis. These results indicate that TZM is a promising radiosensitizer for the synergistic RT and immunotherapy of metastatic osteosarcoma.

Protein phosphatase PPM1A inhibition attenuates osteoarthritis via regulating TGF-ß/Smad2 signaling in chondrocytes.

TGF-ß signaling is crucial for modulating osteoarthritis (OA), and protein phosphatase magnesium-dependent 1A (PPM1A) has been reported as a phosphatase of SMAD2 and regulates TGF-ß signaling, while the role of PPM1A in cartilage homeostasis and OA development remains largely unexplored. In this study, we found increased PPM1A expression in OA chondrocytes and confirmed the interaction between PPM1A and phospho-SMAD2 (p-SMAD2). Importantly, our data show that PPM1A KO substantially protected mice treated with destabilization of medial meniscus (DMM) surgery against cartilage degeneration and subchondral sclerosis. Additionally, PPM1A ablation reduced the cartilage catabolism and cell apoptosis after the DMM operation. Moreover, p-SMAD2 expression in chondrocytes from KO mice was higher than that in WT controls with DMM induction. However, intraarticular injection with SD-208, repressing TGF-ß/SMAD2 signaling, dramatically abolished protective phenotypes in PPM1A-KO mice. Finally, a specific pharmacologic PPM1A inhibitor, Sanguinarine chloride (SC) or BC-21, was able to ameliorate OA severity in C57BL/6J mice. In summary, our study identified PPM1A as a pivotal regulator of cartilage homeostasis and demonstrated that PPM1A inhibition attenuates OA progression via regulating TGF-ß/SMAD2 signaling in chondrocytes and provided PPM1A as a potential target for OA treatment.

A dual-activity topoisomerase complex promotes both transcriptional activation and repression in response to starvation.

Topoisomerases are required to release topological stress generated by RNA polymerase II (RNAPII) during transcription. Here, we show that in response to starvation, the complex of topoisomerase 3b (TOP3B) and TDRD3 can enhance not only transcriptional activation, but also repression, which mimics other topoisomerases that can also alter transcription in both directions. The genes enhanced by TOP3B-TDRD3 are enriched with long and highly-expressed ones, which are also preferentially stimulated by other topoisomerases, suggesting that different topoisomerases may recognize their targets through a similar mechanism. Specifically, human HCT116 cells individually inactivated for TOP3B, TDRD3 or TOP3B topoisomerase activity, exhibit similarly disrupted transcription for both starvation-activated genes (SAGs) and starvation-repressed genes (SRGs). Responding to starvation, both TOP3B-TDRD3 and the elongating form of RNAPII exhibit concomitantly increased binding to TOP3B-dependent SAGs, at binding sites that overlap. Notably, TOP3B inactivation decreases the binding of elongating RNAPII to TOP3B-dependent SAGs while increased it to SRGs. Furthermore, TOP3B-ablated cells display reduced transcription of several autophagy-associated genes and autophagy per se. Our data suggest that TOP3B-TDRD3 can promote both transcriptional activation and repression by regulating RNAPII distribution. In addition, the findings that it can facilitate autophagy may account for the shortened lifespan of Top3b-KO mice.

Targeted isolation of cyclooxygenase-2 inhibitors from Saussurea obvallata using affinity ultrafiltration combined with preparative liquid chromatography.

Saussurea obvallata (S. obvallata) is widely used in Qinghai-Tibet Plateau with high medicinal and edible values of reducing inflammation. But, the individual components and mechanisms of action still ill-defined. In this work, an integrated method using affinity ultrafiltration combined with preparative liquid chromatography was developed to identify and separate cyclooxygenase-2 (COX-2) inhibitors from S. obvallata. The sample was pretreated using on-line medium pressure liquid chromatography to yield the active fraction. Then, the potential COX-2 ligands were screened out using affinity ultrafiltration from the targeted fraction and the identified compounds were isolated via preparative liquid chromatography. As a result, four main compounds, coniferin (1), syringin (2), roseoside (3) and grasshopper ketone (4) were targeted isolated with IC50 values of 12.34 ± 1.81, 4.04 ± 0.43, 13.91 ± 2.46 and 7.97 ± 1.21 µM, respectively. Results of this work demonstrated that the developed strategy was effective for the targeted separation of COX-2 inhibitors from natural product extracts.

Association between in vitro fertilization-embryo transfer and hearing loss: risk factors for hearing loss among twin infants in a cohort study.

Assisted reproductive technologies (ART), including in vitro fertilization-embryo transfer (IVF-ET) and intracytoplasmic sperm injection (ICSI), are known to contribute a higher risk of birth defects; however, studies have rarely evaluated the association between IVF-ET and diagnostic hearing loss (HL). This study aimed to evaluate the prevalence of and risk factors for HL and to clarify the association between IVF-ET and HL among twinborn infants. We enrolled 1860 live-born twin neonates born at a hospital in China from January 2017 to December 2020. After multi-step hearing screening, participants were diagnosed with HL by pediatric audiologists at 6 months of age. The prevalence of hearing loss and the adjusted odds ratios (AORs) for specific risk factors were estimated using generalized estimation equation (GEE) models in twin-born infants. Characteristics and prevalence of failure for hearing screening and HL were measured in IVF-ET twin infants. IVF-ET conception and preterm birth conferred a higher risk of hearing loss, with increased adjusted odds ratios (AOR [95% confidence intervals (CI)] IVF-ET: 2.82 [1.17-6.80], P = 0.021; preterm birth: 6.14 [2.30-16.40], P < 0.001) than the control group, respectively. Among the 1860 twin infants, more IVF-ET twins failed in dual-step hearing screening (3.26%) and were diagnosed with hearing loss (2.21%) than those conceived by spontaneous pregnancy. CONCLUSION: IVF-ET conception and premature birth were associated with a higher risk of hearing impairment. Twin infants conceived by IVF-ET tended to fail in hearing screening and be diagnosed with hearing loss. These observations provide a more comprehensive approach for the prevention and management of deafness in twin-born children. WHAT IS KNOWN: • IVF-ET technologies conferred a higher risk of birth defects. WHAT IS NEW: • Premature birth and IVF-ET conception were associated with a higher risk of hearing loss among twin infants. • Twin infants conceived by IVF-ET tended to fail in hearing screening and diagnosed with hearing loss.

Drosophila transmembrane protein 214 (dTMEM214) regulates midgut glucose uptake and systemic glucose homeostasis.

The availability of glucose transporter in the small intestine critically determines the capacity for glucose uptake and consequently systemic glucose homeostasis. Hence a better understanding of the physiological regulation of intestinal glucose transporter is pertinent. However, the molecular mechanisms that regulate sodium-glucose linked transporter 1 (SGLT1), the primary glucose transporter in the small intestine, remain incompletely understood. Recently, the Drosophila SLC5A5 (dSLC5A5) has been found to exhibit properties consistent with a dietary glucose transporter in the Drosophila midgut, the equivalence of the mammalian small intestine. Hence, the fly midgut could serve as a suitable model system for the study of the in vivo molecular underpinnings of SGLT1 function. Here, we report the identification, through a genetic screen, of Drosophila transmembrane protein 214 (dTMEM214) that acts in the midgut enterocytes to regulate systemic glucose homeostasis and glucose uptake. We show that dTMEM214 resides in the apical membrane and cytoplasm of the midgut enterocytes, and that the proper subcellular distribution of dTMEM214 in the enterocytes is regulated by the Rab4 GTPase. As a corollary, Rab4 loss-of-function phenocopies dTMEM214 loss-of-function in the midgut as shown by a decrease in enterocyte glucose uptake and an alteration in systemic glucose homeostasis. We further show that dTMEM214 regulates the apical membrane localization of dSLC5A5 in the enterocytes, thereby revealing dTMEM214 as a molecular regulator of glucose transporter in the midgut.

Classification and Gene Structure of Aquaporins.

Aquaporins (AQPs) are a family of membrane water channels that basically function as regulators of intracellular and intercellular water flow. To date, 13 AQPs, distributed widely in specific cell types in various organs and tissues, have been characterized in humans. A pair of NPA boxes forming a pore is highly conserved among all aquaporins and is also key residues for the classification of AQP superfamily into four groups according to primary sequences. AQPs may also be classified based on their transport properties. So far, chromosome localization and gene structure of 13 human AQPs have been identified, which is definitely helpful for studying phenotypes and potential targets in naturally occurring and synthetic mutations in human or cells.