Phthalates are plasticizers in various products and regarded as endocrine disruptors due to their anti-androgen effects. Environmental occurrence and toxicities of parent phthalates have been widely ...reported, while the current state of knowledge on their metabolites is rarely summarized. Based on the available literature, the present review mainly aims to 1) characterize the potential metabolites of phthalates (mPAEs) using the pharmacokinetics evidences acquired via animal or human models; 2) examine the molecular and cellular mechanism involved in toxicity for mPAEs; 3) investigate the exposure levels of mPAEs in different human specimens (e.g., urine, blood, seminal fluid, breast milk, amniotic fluid and others) across the globe; 4) discuss the models and related parameters for phthalate exposure assessment. We suggest there is subtle difference in toxic mechanisms for mPAEs compared to their parent phthalates due to their alternative chemical structures. Human monitoring studies performed in Asia, America and Europe have provided the population exposure baseline levels for typical phthalates in different regions. Urine is the preferred matrix than other specimens for phthalate exposure study. Among ten urinary mPAEs, the largest proportions of di-(2-ethylhexyl) phthalate (DEHP) metabolites (40%), monoethyl phthalate (mEP) (43%) and DEHP metabolites/mEP (both 29%) were observed in Asia, America and Europe respectively, and mono-5-carboxy-2-ethypentyl phthalate was the most abundant compounds among DEHP metabolites. Daily intakes of phthalates can be accurately calculated via urinary mPAEs if the proper exposure parameters were determined. Further work should focus on combining epidemiological and biological evidences to establish links between phthalates exposure and biological phenotypes. More accurate molar fractions (FUE) of the urinary excreted monoester related to the ingested diesters should be collected in epidemiological or pharmacokinetic studies for different population.
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•Metabolites display different toxic mechanism compared to parent phthalates.•Differences exist in distribution of phthalate metabolites in multiple human specimens.•Urinary profiles of phthalates vary markedly for people on different continents.•Reasonable FUE data are suggested for phthalate exposure assessment by human experiments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Two new water-stable cadmium(ii)-metal organic frameworks (MOFs), namely Cd2(L1)(1,4-NDC)2n (1) and Cd(L2)(1,4-NDC)n (2) (L1 = 1,4-bis(benzimidazol-1-yl)-2-butylene, L2 = ...1,4-bis(2-methylbenzimidazol-1-yl)-2-butylene and 1,4-H2NDC = 1,4-naphthalenedicarboxylic acid), were synthesized and characterized. 1 exhibits an unusual 3D framework with the Schläfli symbol of {42·5·62·7}{42·52·72}{42·53·62·73}2, and 2 is a classical sqc6 network. 1 and 2 display excellent pH and water stability, and the integrity of the frameworks was well maintained at different pH values (pH = 3–13) and after long-term water treatment. 1 is the first dual-function luminescent sensor for sensing acetylacetone and Cr2O72− in aqueous solutions with high sensitivity, selectivity and excellent recyclability. This material is an excellent dual-responsive recyclable luminescent sensor.
Melatonin, a major hormone of the pineal gland, exerts many beneficial effects on mitochondria. Several studies have shown that melatonin can protect against toxin‐induced oocyte quality impairment ...during maturation. However, there is little information regarding the beneficial effects of melatonin on toxin‐exposed early embryos, and the mechanisms underlying such effects have not been determined. Rotenone, a chemical widely used in agriculture, induces mitochondrial toxicity, therefore, damaging the reproductive system, impairing oocyte maturation, ovulation, and fertilization. We investigated whether melatonin attenuated rotenone exposure‐induced impairment of embryo development by its mitochondrial protection effect. Activated oocytes were randomly assigned to four groups: the control, melatonin treatment, rotenone‐exposed, and “rotenone + melatonin” groups. Treatment with melatonin abrogated rotenone‐induced impairment of embryo development, mitochondrial dysfunction, and ATP deficiency, and significantly decreased oxidative stress and apoptosis. Melatonin also increased SIRT1 and PGC‐1α expression, which promoted mitochondrial biogenesis. SIRT1 knockdown or pharmacological inhibition abolished melatonin's ability to revert rotenone‐induced impairment. Thus, melatonin rescued rotenone‐induced impairment of embryo development by reducing ROS production and promoting mitochondrial biogenesis. This study shows that melatonin rescues toxin‐induced impairment of early porcine embryo development by promoting mitochondrial biogenesis.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Objective
To investigate aquaporin‐4 antibody (AQP4‐IgG) dynamics and relapse risk in patients with seropositive neuromyelitis optica spectrum disorder treated with immunosuppressants.
Methods
This ...observational cohort study with prospectively collected data included 400 neuromyelitis optica spectrum disorder patients seropositive for AQP4‐IgG and treated with immunosuppressants. Serum AQP4‐IgG was detected by fixed cell‐based assay every 6 months.
Results
After treatment with immunosuppressants, 128 patients became AQP4‐IgG seronegative. The median time to become seronegative for 400 patients was 76.4 months (61.4 months, NA). Among those patients with negative change of AQP4‐IgG, the mean annualized relapse rate significantly decreased after patients became seronegative (0.20 vs 0.77, p < 0.001), and a positive correlation was observed between time to become seronegative and relapse (OR 1.018, 95% CI 1.001–1.035, p < 0.05). Independent risk factors for AQP4‐IgG becoming seronegative were older age at onset, initiation of immunosuppressants at onset, and shorter disease duration before maintenance therapy. Independent risk factors for relapse included younger age (≤46.4 years) at onset, poly‐system involvement in the first attack, and unchanged or increased AQP4‐IgG titer. The relapse risk was not associated with sex, combination with connective tissue disease, seropositivity for systemic autoimmune antibodies, or incomplete recovery from the first attack.
Interpretation
Patients with younger age at onset, poly‐system involvement in the first attack, and unchanged or increased titer of AQP4‐IgG are most likely to experience relapse under treatment with immunosuppressants. Time to AQP4‐IgG becoming seronegative and change of AQP4‐IgG titer may become the surrogate efficacy biomarkers in clinical trials. ANN NEUROL 2023;93:1069–1081
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objectives
S‐nitrosoglutathione reductase (GSNOR), a protein denitrosylase, protects the mitochondria from mitochondrial nitrosative stress. Mammalian preimplantation embryos are mitochondria‐rich, ...but the effects of GSNOR on mitochondrial function in preimplantation embryos are not well‐studied. In the present study, we investigate whether GSNOR plays a role in mitochondrial regulation during porcine preimplantation embryo development.
Materials and Methods
GSNOR dsRNA was employed to knock down the expression of GSNOR, and Nω‐Nitro‐L‐arginine methyl ester hydrochloride (L‐NAME), a pan‐NOS inhibitor, was used to prevent protein S‐nitrosylation. Mitochondrial amount and function in embryo development were assessed by performing immunofluorescence staining, Western blot, fluorescent probe and real‐time reverse transcription PCR.
Results
GSNOR knock‐down significantly impaired blastocyst formation and quality and markedly induced the increase in protein S‐nitrosylation. Notably, GSNOR knock‐down‐induced overproduction of S‐nitrosylation caused mitochondrial dysfunction, including mitochondrial membrane potential depolarization, mitochondria‐derived reactive oxygen species (ROS) increase and ATP deficiency. Interestingly, GSNOR knock‐down‐induced total mitochondrial amount increase, but the ratio of active mitochondria reduction, suggesting that the damaged mitochondria were accumulated and mitochondrial clearance was inhibited. In addition, damaged mitochondria produced more ROS, and caused DNA damage and apoptosis. Importantly, supplementation with L‐NAME reverses the increase in S‐nitrosylation, accumulation of damaged mitochondria, and oxidative stress‐induced cell death. Interestingly, autophagy was downregulated after GSNOR knock‐down, but reversed by L‐NAME treatment. Thus, GSNOR maintains mitochondrial homeostasis by promoting autophagy and the clearing of damaged mitochondria in porcine preimplantation embryos.
Mitophagy and mitochondrial biogenesis maintain mitochondrial function and contents via promoting damaged mitochondrial clearance, and production of new and healthy mitochondria. Furthermore, autophagy degrades unnecessary proteins and dysfunctional organelles. However, decrease in GSNOR protein levels by knock‐down of GSNOR mRNA induces an increase in protein SNOs and prevents mitophagy and autophagy. Thus, GSNOR knock‐down further induces accumulation of damaged mitochondria, oxidative stress and cell death. These harmful effects could be reversed via treatment with L‐NAME.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
In the past 37 years, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has undergone various major transmission routes in China, with the world most complex co-circulating ...HIV-1 subtypes, even the prevalence is still low. In response to the first epidemic outbreak of HIV in injecting drug users and the second one by illegal commercial blood collection, China issued the Anti-Drug Law and launched the Blood Donation Act and nationwide nucleic acid testing, which has avoided 98,232 to 211,200 estimated infections and almost ended the blood product-related infection. China has been providing free antiretroviral therapy (ART) since 2003, which covered >80% of the identified patients and achieved a viral suppression rate of 91%. To bend the curve of increasing the disease burden of HIV and finally end the epidemic, China should consider constraining HIV spread through sexual transmission, narrowing the gaps in identifying HIV cases, and the long-term effectiveness and safety of ART in the future.
Severe fever with thrombocytopenia syndrome (SFTS), an emerging tick-borne infectious disease caused by a novel phlebovirus (SFTS virus, SFTSV), was listed among the top 10 priority infectious ...diseases by the World Health Organization due to its high fatality of 12%-50% and possibility of pandemic transmission. Currently, effective anti-SFTSV intervention remains unavailable. Here, by screening a library of FDA-approved drugs, we found that benidipine hydrochloride, a calcium channel blocker (CCB), inhibited SFTSV replication in vitro. Benidipine hydrochloride was revealed to inhibit virus infection through impairing virus internalization and genome replication. Further experiments showed that a broad panel of CCBs, including nifedipine, inhibited SFTSV infection. The anti-SFTSV effect of these two CCBs was further analyzed in a humanized mouse model in which CCB treatment resulted in reduced viral load and decreased fatality rate. Importantly, by performing a retrospective clinical investigation on a large cohort of 2087 SFTS patients, we revealed that nifedipine administration enhanced virus clearance, improved clinical recovery, and remarkably reduced the case fatality rate by >5-fold. These findings are highly valuable for developing potential host-oriented therapeutics for SFTS and other lethal acute viral infections known to be inhibited by CCBs in vitro.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Spindlin 1 (SPIN1), which contains Tudor‐like domains, regulates maternal transcripts via interaction with a messenger RNA (mRNA)‐binding protein. SPIN1 is involved in tumorigenesis in somatic cells ...and is highly expressed in cancer cells. Nevertheless, the role of SPIN1 in porcine oocyte maturation remains totally unknown. To explore the function of SPIN1 in porcine oocyte maturation, knockdown, and overexpression techniques were used. SPIN1 mRNA was identified in maternal stages ranging from GV to MII. SPIN1 was localized in the cytoplasm and to chromosomes during meiosis. SPIN1 knockdown accelerated first polar body extrusion. Oocytes with overexpressed SPIN1 were arrested at the MI stage. SPIN1 depletion caused meiotic spindle defects and chromosome instability. The BUB3 signal was investigated, confirming that SPIN1 affects the stability of Bub3 mRNA as well as BUB3 expression. Further, overexpression of SPIN1 inhibited the degradation and regulation of G2/mitotic‐specific cyclin‐B1. In summation, SPIN1 regulates the meiotic cell cycle by modulating the activation of the spindle assembly checkpoint.
Spindlin 1 (SPIN1) is an important gene for the first meiotic division of porcine oocytes. Oocytes were arrested at the MI stage following SPIN1 overexpression, inducing a longer BUB3 poly (A) tail length and the subsequent high translation of BUB3, further preventing the decrease of activity of CDK1. However, SPIN1 knockdown accelerated the first polar body extrusion with abnormal spindle formation and chromosome segregation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Application of silicon‐based anodes is significantly challenged by low initial Coulombic efficiency (ICE) and poor cyclability. Traditional pre‐lithiation reagents often pose safety concerns due to ...their unstable chemical nature. Achieving a balance between water‐stability and high ICE in prelithiated silicon is a critical issue. Here, we present a lithium‐enriched silicon/graphite material with an ultra‐high ICE of ≥110 % through a high‐stable lithium pre‐storage methodology. Lithium pre‐storage prepared a nano‐drilled graphite material with surficial lithium functional groups, which can form chemical bonds with adjacent silicon during high‐temperature sintering. This results in an unexpected O−Li−Si interaction, leading to in situ pre‐lithiation of silicon nanoparticles and providing high stability in air and water. Additionally, the lithium‐enriched silicon/graphite materials impart a combination of high ICE, high specific capacity (620 mAh g−1), and long cycling stability (>400 cycles). This study opens up a promising avenue for highly air‐ and water‐stable silicon anode prelithiation methods.
Different from water‐sensitive pre‐lithiated silicon‐based anodes, a lithium‐enriched silicon/graphite material is designed by lithium pre‐storage. This is a new prelithiation strategy employing nano‐drilled graphite with surficial lithium functional groups, which allow for the extraction of lithium to form a special unit, exhibiting both high initial Coulombic efficiency and excellent stability in air and water.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Aim
To investigate whether diabetes and fasting blood glucose (FBG) levels affect the efficacy of remote ischaemic conditioning (RIC) using the database included in the Remote Ischaemic Conditioning ...for Acute Moderate Ischaemic Stroke (RICAMIS) trial.
Methods
A total of 1707 patients were enrolled in this post hoc study, including 535 patients with diabetes and 1172 without diabetes. Each group was further divided into RIC and control subgroups. The primary outcome was excellent functional outcome, defined as a modified Rankin Scale (mRS) score of 0 to 1 at 90 days. The difference in the proportion of patients with excellent functional outcome between the RIC subgroup and control subgroup was compared in diabetic and non‐diabetic patients, respectively, and the interactions of treatment assignment with diabetes status and FBG were evaluated.
Results
Compared with the control group, RIC produced a significantly higher proportion of patients with excellent functional outcome in the non‐diabetic group (70.5% vs. 63.2%; odds ratio OR 1.487, 95% confidence interval CI 1.134‐1.949; P = 0.004), while a similar, but not significant difference was observed in the diabetic group (65.3% vs. 59.8%; OR 1.424, 95% CI 0.978‐2.073; P = 0.065). Similar results were observed in patients with normal FBG levels (69.3% vs. 63.7%; OR 1.363, 95% CI 1.011‐1.836; P = 0.042) and those with high FBG levels (64.2% vs. 58%; OR 1.550, 95% CI 1.070‐2.246; P = 0.02). Furthermore, we did not find an interaction effect of intervention (RIC or control) by different diabetes status or FBG levels on clinical outcomes (P > 0.05 for all). However, diabetes (OR 0.741, 95% CI 0.585‐0.938; P = 0.013) and high FBG (OR 0.715, 95% CI 0.553‐0.925; P = 0.011) were independently associated with functional outcomes in patients overall.
Conclusion
Diabetes and FBG levels did not influence the neuroprotective effect of RIC in acute moderate ischaemic stroke, although diabetes and high FBG levels were independently associated with functional outcomes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK